Mesenchymal Stem Cells (MSC), also termed Mesenchymal Stromal Cells, are multipotent cells that can differentiate into a variety of cell types and have the capacity for self renewal. MSC have been shown to differentiate in vitro or in vivo into adipocytes, chondrocytes, osteoblasts, myocytes, neurons, hepatocytes, and pancreatic islet cells. Optimized PromoCell media are available to support both the growth of MSC and their differentiation into several different lineages. Recent experiments suggest that differentiation capabilities into diverse cell types vary between MSC of different origin.

PromoCell hMSC are harvested from normal human adipose tissue,bone marrow, andumbilical cord matrix (Whartons jelly) of individual donors.

The cells are tested for their ability to differentiate in vitro into adipocytes, chondrocytes, and osteoblasts. OurhMSC show a verified marker expression profile that complies with ISCT* recommendations, providing well characterized cells.

*ISCT (International Society for Cellular Therapy) Cytotherapy (2006) Vol. 8, No. 4, 315-317

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Cardiac Stem Cells Comments Off on Human Mesenchymal Stem Cells (hMSC) – PromoCell | October 16th, 2021

KENILWORTH, N.J. & TOKYO--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted positive opinions recommending approval of the combination of KEYTRUDA, Mercks anti-PD-1 therapy, plus LENVIMA (marketed as KISPLYX in the European Union [EU] for the treatment of advanced renal cell carcinoma [RCC]), the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, for two different indications. One positive opinion is for the first-line treatment of adult patients with advanced RCC, and the other is for the treatment of adult patients with advanced or recurrent endometrial carcinoma (EC) who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery or radiation. Decisions on the CHMPs recommendations will be given by the European Commission for marketing authorization in the EU, and are expected in the fourth quarter of 2021. If approved, this would be the first combination of an anti-PD-1 therapy with a tyrosine kinase inhibitor approved for the treatment of two different types of cancer in the EU.

The positive CHMP opinions are based on data from two pivotal Phase 3 trials: CLEAR (Study 307)/KEYNOTE-581 evaluating the combination in adult patients with advanced RCC and KEYNOTE-775/Study 309 evaluating the combination in certain patients with advanced EC.

In CLEAR/KEYNOTE-581, KEYTRUDA plus LENVIMA demonstrated statistically significant improvements versus sunitinib in the efficacy outcome measures of overall survival (OS), reducing the risk of death by 34% (HR=0.66 [95% CI, 0.49-0.88]; p=0.0049) versus sunitinib, and progression-free survival (PFS), reducing the risk of disease progression or death by 61% (HR=0.39 [95% CI, 0.32-0.49]; p<0.0001) with a median PFS of 23.9 months versus 9.2 months for sunitinib. Additionally, the confirmed objective response rate was 71% (95% CI: 66-76) (n=252) for patients who received KEYTRUDA plus LENVIMA versus 36% with sunitinib (95% CI: 31-41) (n=129).

In KEYNOTE-775/Study 309, KEYTRUDA plus LENVIMA demonstrated statistically significant improvements in the studys dual efficacy outcome measures of OS, reducing the risk of death by 38% (HR=0.62 [95% CI, 0.51-0.75]; p<0.0001) with a median OS of 18.3 months versus 11.4 months for chemotherapy (investigators choice of doxorubicin or paclitaxel), and PFS, reducing the risk of disease progression or death by 44% (HR=0.56 [95% CI, 0.47-0.66]; p<0.0001), with a median PFS of 7.2 months versus 3.8 months for chemotherapy (investigators choice of doxorubicin or paclitaxel).

KEYTRUDA plus LENVIMA demonstrated a survival benefit for advanced renal cell carcinoma in the first-line setting and represents an important potential new treatment option for these patients. Additionally, KEYTRUDA plus LENVIMA is the first anti-PD-1 and tyrosine kinase inhibitor combination to demonstrate a survival benefit in advanced endometrial carcinoma patients, and the benefit was shown regardless of mismatch repair status, said Dr. Gregory Lubiniecki, Vice President, Clinical Research, Merck Research Laboratories. We are pleased that the CHMP has recognized the important role of the combination therapy in these difficult-to-treat cancers.

We appreciate the positive opinions rendered by the EU CHMP recommending approval of KEYTRUDA plus LENVIMA in advanced renal cell carcinoma and advanced endometrial carcinoma, underscoring the potential significance of the outcomes observed in the CLEAR/KEYNOTE-581 and KEYNOTE-775/Study 309 trials, said Dr. Takashi Owa, President, Oncology Business Group at Eisai. We are grateful to the patients who participated in these studies, their families and clinicians. Their commitment made these meaningful milestones possible.

The safety of KEYTRUDA in combination with axitinib or LENVIMA in advanced RCC, and in combination with LENVIMA in advanced EC has been evaluated in a total of 1,456 patients with advanced RCC or advanced EC. In these patient populations, the most frequent adverse reactions were diarrhea (58%), hypertension (54%), hypothyroidism (46%), fatigue (41%), decreased appetite and nausea (40% each), arthralgia (30%), vomiting, weight decreased, dysphonia and abdominal pain (28% each), proteinuria (27%), palmar plantar erythrodysesthesia syndrome and rash (26% each), stomatitis and constipation (25% each), musculoskeletal pain and headache (23% each) and cough (21%).

About Renal Cell Carcinoma (RCC)

Worldwide, it is estimated there were more than 431,000 new cases of kidney cancer diagnosed and more than 179,000 deaths from the disease in 2020. In Europe, it is estimated there were more than 138,000 new cases of kidney cancer diagnosed and more than 54,000 deaths from the disease in 2020. Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses are RCC. Renal cell carcinoma is about twice as common in men as in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Approximately 30% of patients with RCC will have metastatic disease at diagnosis. Survival is highly dependent on the stage at diagnosis, and the five-year survival rate is 13% for patients diagnosed with metastatic disease.

About Endometrial Cancer

Endometrial cancer begins in the inner lining of the uterus, which is known as the endometrium and is the most common type of cancer in the uterus. Worldwide, it was estimated there were more than 417,000 new cases and more than 97,000 deaths from uterine body cancers in 2020 (these estimates include both endometrial cancers and uterine sarcomas; more than 90% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial cancer cases and deaths are slightly lower than these estimates). In Europe, it is estimated there were more than 130,000 new cases and more than 29,000 deaths in 2020. The five-year relative survival rate for metastatic endometrial cancer (stage IV) is estimated to be approximately 17%.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS 1)] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA, in combination with LENVIMA, is indicated for the first-line treatment of adult patients with advanced RCC.

Endometrial Carcinoma

KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any settings and are not candidates for curative surgery or radiation.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (20%) and increased aspartate aminotransferase (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

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Merck and Eisai Receive Positive EU CHMP Opinions for KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) in Two Different Types of Cancer - Business...

Cardiac Stem Cells Comments Off on Merck and Eisai Receive Positive EU CHMP Opinions for KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) in Two Different Types of Cancer – Business… | October 16th, 2021

The Autologous Stem Cell Based Therapies market report delivers a complete analysis of critical aspects such as the predominant trends and growth opportunities that will assure considerable returns in the ensuing years. Also, it offers various solutions to tackle the present and upcoming challenges in the industry vertical. Besides, the document expounds the size and share of market segments including the product landscape, application spectrum, and geographical ambit. Furthermore, it discusses the after-effects of COVID-19 pandemic on this domain, uncovering the top revenue generating strategies for the approaching years.

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Autologous Stem Cell Based Therapies Market Consumption Status and Prospects Professional Market Research Report 2025 - Northwest Diamond Notes

Cardiac Stem Cells Comments Off on Autologous Stem Cell Based Therapies Market Consumption Status and Prospects Professional Market Research Report 2025 – Northwest Diamond Notes | October 16th, 2021

Introduction

The growing burden of ischemic heart disease (IHD) is a major public health issue. The most harmful type of IHD is acute myocardial infarction (MI), which leads to loss of tissue and impaired cardiac performance, accounting for two in five deaths in China.1 Timely revascularization after MI, including percutaneous coronary intervention, thrombolytic treatment and bypass surgery, is key to improving cardiac function and preventing post-infarction pathophysiological remodeling.2 However, these effective but invasive approaches cannot be used in all patients owing to their applicability, which is limited based on specific clinical characteristics, and the possibility of severe complications such as bleeding and reperfusion injury.2,3 Attempts to limit infarct size and improve prognosis using pharmacotherapy (including antiplatelet and antiarrhythmic drugs and angiotensin-converting enzyme inhibitors) without reperfusion has been proven generally inefficient, due to non-targeted drug distribution and side effects, and short half-life of some drugs.1,3,4 Consequently, many patients in which this approach is used still progress to cardiac hypertrophy and heart failure.1 Growth and rupture of atherosclerotic plaques and the ensuing thrombosis are the major causes of acute MI.4 Currently available interventions for atherosclerosis (AS) including statins can reduce acute MI, but the effects vary between individuals, and leave significant residual risks.58 Some chemotherapies, such as docetaxel9 and methotrexate,10,11 also seem to have beneficial effects in AS; however, systemic administration of these drugs is limited because of their adverse effects.12 The demand for safer and more efficient therapies and prevention strategies for MI is therefore increasing.

Several optimized strategies have so far been explored, one of which is the application of nanoparticles (NPs). These nanoscale particles have been widely used in the treatment of tumors and neural diseases.13,14 NPs enable delivery of therapeutic compounds to target sites with high spatial and temporal resolution, enhancement of tissue engineering processes and regulation of the behaviour of transplants such as stem cells. The application of NPs improves the therapeutic effects and minimizes the adverse effects of traditional or novel therapies, increasing the likelihood that they can be successfully translated to clinical settings.1518 However, research on NPs in this field is still in its infancy.5,1921 This review summarizes the latest NP-based strategies for managing acute MI, mostly published within the past 7 years, with a particular focus on effects and mechanisms rather than particle types, which have been extensively covered in other reviews (Figure 1). In addition, we offer an initial viewpoint on the value of function-based systems over those based on materials, and discuss future prospects in this field.

Figure 1 Overview of nanoparticle-based strategies for the treatment and prevention of myocardial infarction. Nanoparticles are capable of delivering therapeutic agents and nucleic acids in a stable and targeted manner, improving the properties of tissue engineering scaffolds, labeling transplanted cells and regulating cell behaviors, thus promoting the cardioprotective effects of traditional or novel therapies.

A multitude of NP types are currently under investigation, including lipid-based NPs, polymeric NPs, micelles, inorganic NPs, and exosomes. Virus can also be considered as NPs; however they will not be discussed in this review.22 NPs made from different materials show similar in vivo metabolic kinetic characteristics and protective effects on infarcted heart.19,20 Function-based NP types, oriented towards a specific purpose, may be preferable compared with traditional types, on account of their practicality in basic research and clinical translation. In this review, we discuss NPs used in the treatment and prevention of MI that fall into the following four categories: 1) circulation-stable nanocarriers (polymeric, lipid or inorganic particles); 2) targeted delivery vectors (magnetic or particles modified to improve target specificity); 3) enhancers of tissue engineering; and 4) regulators of cell behavior (Figure 1). We propose that the choice of each NP for any given application should be primarily based on the roles or mechanisms they perform.

Many NPs, whether composed of either naturally occurring or synthetic materials, act as nanocarriers to improve the circulating stability of therapeutic agents.15,16 Polymeric NPs comprise one of the most widely employed types, with excellent biocompatibility, tunable mechanical properties, and the ability be easily modified with therapeutic agents using a broad range of chemical techniques.23,24 The most commonly used polymer for these NPs is polylactide-co-glycolide (PLGA), which has Food and Drug Administration approval.25,26 Recently, there has been a therapeutic emphasis on polydopamine (PDA), from which several related nanomaterials have been created, including PDA NPs and PDA NP-knotted hydrogels.27,28 NPs made from polylactic acid (PLA),29,30 poly--caprolactone (PCL),31 polyoxalates,32 polyacrylonitrile,33 chitosan29,34 and hollow mesoporous organosilica35 have also been constructed and administered in vitro in cells and in vivo in animal models.

Lipid NPs or liposomes are also considered promising candidates for the delivery of therapeutic agents, due to their morphology, which is similar to that of cellular membranes and ability to carry both lipophilic and hydrophilic drugs. These non-toxic, non-immunogenic and biodegradable amphipathic nanocarriers can be designed to reduce capture by reticuloendothelial cells, increase circulation time, and achieve satisfactory targeting.36,37 Solid lipid NPs (SLNs) combine the advantages of polymeric NPs, fat emulsions, and liposomes, remaining in a solid state at room temperature. Active key components of SLNs are mainly physiological lipids, dispersed in aqueous solution containing a stabilizer (surfactant).38 Micelles are made by colloidal aggregation in a solution through self-assembly of amphiphilic polymers, or a simple lipidic layer of transfer vehicles;39 these have been used in cellular and molecular imaging40 and treatment41 for a long time.

Inorganic NPs used in basic IHD research are classified as metal, metal compounds, carbon,42 or silicon NPs;43 these are relatively inert, stable, and biocompatible. Gold (Au),44 silver (Ag)45 and copper (Cu)46 are commonly used materials in their production. These NPs can be delivered orally,47 or injected intravenously48 or intraperitoneally.56 However, they are more widely used to construct electrically conductive myocardial scaffolds in tissue engineering.49,50 Myocardial patches and scaffolds are promising therapeutic approaches to repairing heart tissue after IHD; incorporating conductive NPs can further improve functionality, introducing beneficial physical properties and electroconductivity. Some organic particles, such as liposomes anchored with poly(N-isopropylacrylamide)-based copolymer groups, are also suitable for the production of effective nanogels or patches for this purpose.37

Several metal compounds have been used for treatment of IHD.5154 The application of magnetic particles made from iron oxide has been of particular interest in recent research. These NPs are more prone to manipulation with an external magnetic field, and thus serve as powerful tools for targeted delivery of therapeutics. In addition, modification with targeted peptides or antibodies is another approach to the construction of targeted delivery systems.

Another strategy to protect cardiac performance after MI is the transplantation of cells; however, the beneficial effects of this are currently limited.58 Many NPs can improve the behavior of cells; in this context, they may stimulate cardioprotective potential. In particular, exosomes a major subgroup of extracellular vesicles (EVs) with a diameter of 30150nm, which are secreted via exocytosis55 represent novel, heterogeneous, biological NPs with an endogenous origin. They are able to carry a variety of proteins, lipids, nucleic acids, and other bioactive substances.5557 Mechanistic studies have confirmed that exosomes offer a cell-free strategy to rescue ischemic cardiomyocytes (CMs).59,60

The physical properties of NPs, including size, shape, and surface charge, impact on how biological processes behave, and consequently, responses in the body.61 The recommended definition of NPs in pharmaceutical technology and biomedicine includes a limitation that more than 50% of particles should be in a size distribution range of 10100 nm.39 However, this is not strictly distinguished in studies, so for the purposes of this review, we have relaxed this definition. Small NPs have a faster uptake and processing speed and longer blood circulation half-lives than larger ones; a decreased surface area results in increased reactivity to the microenvironment and greater speed of release of the compounds they carry.6163 However, an exception to this principle is that, among particles of less than 50 nm diameter, larger NPs have longer circulatory half-lives.64,65 NPs can be spherical, discoidal, tubular or dendritic.61,63 The impact of NP shape on uptake and clearance has also been revealed;66,67 for instance, spheres endocytose more easily,20 while micelles and filomicelles target aortic macrophages, B cells, and natural killer (NK) cells in the immune system more effectively than polymersomes.68 In terms of charge, cationic NPs are more likely to interact with cells than negatively charged or neutral particles because the mammalian cell membrane is negatively charged.62 As a result, positively charged particles are reported to be more likely to destabilize blood cell membranes and cause cell lysis.61 Additionally, the rate of drug release is largely determined by the diameter of the pore. Motivated by the idea, Palma-Chavez et al developed a multistage delivery system by encapsulating PLGA NPs in micron-sized PLGA outer shells.69

Some types of NPs, such as micelles, possess coreshell morphological structures: a core composed of hydrophobic block segments is surrounded by hydrophilic polymer blocks in a shell that stabilizes the entire micelle. The core provides enough space to accommodate compounds, while the shell protects drug molecules from hydrolysis and enzymatic degradation.36 Surface chemical composition largely governs the chemical interactions between NPs and molecules in the body. Appropriate surface coatings can create a defensive layer, protect encapsulated cargo, and affect biological behaviors. Coating with inert polymers like polyethylene glycol (PEG) is the most commonly used method, which hinders interactions with proteins, alters the composition of the protein corona, attenuate NP recognition by opsonins which tag particles for phagocytosis, and extend the half-life of particles.36,70 Additionally, PEG coating helps the therapeutic agents reach ischemic sites, because PEGylated macromolecules tend to diffuse in the interstitial space of the heart.71 Functionalization of gangliosides can further attenuate the immunogenicity of PEGylated liposomes without damaging therapeutic efficacy.72 Removal of detachable PEG conjugates in the microenvironment of the target sites improves capture by cells. Wang and colleagues synthesized PDA-coated tanshinone IIA NPs by spontaneous hydrophobic self-assembly.73 Polyethyleneimine (PEI) is capable of condensing nucleic acid and overcoming hamper of cell membrane. Therefore, modification with PEI is mainly used for the transport of DNA and RNA.74 Of note, despite their inertness, novel NPs composed of metals can also be modified with compounds such as PEG, thiols, and disulfides.48,75 Hydrogels mixed with peptide-coated Au NPs attain greater viscosity than hydrogels mixed with Au NPs.24

Targeted delivery is a primary goal in the development of nanocarriers. Passive targeting is based on enhanced permeability in ischemic heart tissue, which does not meet the needs of clinical application.76 This fact has prompted work on targeting agent modification and magnetic guidance. Conjugation with specific monoclonal antibodies is a feasible method for delivering drug payloads targeted to ischemic lesions. Copper sulfide (CuS) NPs coupled to antibodies targeting transient receptor potential vanilloid subfamily 1 (TRPV1), permit specific binding to vascular smooth muscle cells (SMCs), and can also act as a switch for photothermal activation of TRPV1 signaling.52 In another study conducted by Liu and colleagues, two types of antibodies, binding CD63 (expressed on the surface of exosomes) or myosin light chain (MLC, expressed on injured CMs) are utilized to allow NPs to capture exosomes and accumulate in ischemic heart tissue. These NPs have a unique structure comprising an ferroferric oxide core and PEG-decorated silica shell, which simultaneously enables magnetic manipulation and molecule conjugation via hydrazone bonds.21 Targeted peptides such as atrial natriuretic peptide (ANP),43 S2P peptide (plague-targeting peptide),77 and stearyl mannose (type 2 macrophage-targeting ligand)16 allow NPs to precisely target atherosclerotic tissue and ischemic heart lesions. Modification with EMMPRIN-binding peptide (AP9) has been shown to enable more rapid uptake of micelles by H9C2 myoblasts and primary CMs and to deliver drug payloads targeted to lesions in vivo.78,79 Another strategy for targeted nanocarriers is to produce cell mimetic carriers. Using the inflammatory response as a marker after MI,76 Boada and colleagues synthesized biomimetic NPs (leukosomes) by integrating membrane proteins purified from activated J774 macrophages into the phospholipid bilayer of NPs. Local chronic inflammatory lesions demonstrated overexpression of adhesion molecules, which bound leukosomes efficiently.80

The biocompatibility of NPs is difficult to predict because any interaction with molecules or cells can cause toxic effects. Generally, NPs remain in blood, but can also extravasate from vasculature with enhanced permeability, or accumulate in the mononuclear phagocyte system.81 Important causes of NP-associated toxicity include: oxidative stress injury and cell apoptosis secondary to the production of free radicals, lack of anti-oxidants, phagocytic cell responses, and the composition of some types of particles.61 Hepatotoxicity, nephrotoxicity and any other potential off-target organ damage caused by accumulation of particles, especially those with poor degradability and slow clearance, are also essential to explore in toxicity tests.82 Additionally, the evaluation of evoked immune responses according to the expression of inflammatory factors and stimulation of leukocytes in cell lines and animal models is also important.83

A few studies have reported NP-associated acute and chronic hazards in pharmacological applications, although some of these observations may be contentious. Specifically, aggregation of non-functionalized carbon nanotubes (CNTs) has been observed owing to inherent hydrophobicity of these particles.61 Aside from inflammation and T lymphocyte apoptosis, multi-walled CNTs can rupture cell membranes, resulting in macrophage cytotoxic effects.84,85 Silica NPs induce vascular endothelial dysfunction and promoted the release of proinflammatory and procoagulant factors, mediated by miR-451a negative regulation of the interleukin 6 receptor/signal transducer and activator of transcription/transcription factor (IL6R/STAT/TF) signaling pathway.8688 Metal NPs, such as Au and Ag, can also penetrate the cell membrane, increase oxidative stress and decrease cell viability.89,90 Consequently, exposure to Au may cause nephrotoxicity91 and reversible cardiac hypertrophy.92 El-Hussainy and colleagues observed myocardial dysfunction in rats given alumina NPs.93,94 Nemmar and colleagues investigated the toxicity of ultrasmall superparamagnetic iron oxide nanoparticles (SPIONs) administered intravenously, which resulted in cardiac oxidative stress and DNA damage as well as thrombosis.95 Cell-derived exosomes and a majority of natural polymers are considered relatively safe;83 however, Babiker and colleagues demonstrated that dendritic polyamidoamine NPs compromise recovery from ischemia/reperfusion (I/R) injury in isolated rat hearts.96 The effects of degradation byproducts are also of concern.83 An advantage of the nanoscale size of NPs is that their injection is unlikely to block the microvascular system; however, it remains controversial whether NPs give rise to arrhythmias.97 These factors highlight that examining the biocompatibility of NPs both in vitro and in vivo is a vital component of preclinical or clinical research.

NP toxicity depends on many parameters, including material composition, coating, size, shape, surface charges and concentration.39 For instance, larger particles seem to be more favorable from a toxicology standpoint.83 However, single-walled CNTs are considered more harmful than multi-walled CNTs, due to their smaller size resulting in less aggregation and increased uptake by macrophages.61 Cationic AuNPs are more toxic compared with anionic AuNPs, which appear to be nontoxic.98 Generally speaking, NP-associated toxicity can be lowered by functionalization with nontoxic surface molecules, stabilization and localization in the region of interest by using scaffolds.24,99 The toxicity of CNTs mediated by oxidative stress and inflammation was reduced using these strategies in several studies.24,100 Local application and targeted delivery also enabled dose reduction and concurrently decreased the incidence of adverse effects. Administration of therapeutic agents directly into the infarcted or peri-infarcted myocardium is a conventional approach with a low risk of inducing embolization.

NP is a suitable method for the administration of therapeutic agents in terms of the minimization of side effects, enhanced stability of cargo, and possibility of controlled delivery and release.76 Detailed information on the experimental design and results of the latest studies on the use of NPs as therapeutic vectors are provided in Table 1. Recently, several drugs approved for clinical use as immunosuppressants have been suggested as potentially effective cardioprotective agents. For example, NPs containing cyclosporine A inhibited apoptosis and inflammation in ischemic myocardium by improving mitochondrial function.25,101 Commercial methotrexate also showed minor cardioprotective effects; additionally, when loaded into lipid core NPs, adenosine bioavailability and echocardiographic and morphometric results were all improved a rats model of MI.102 Margulis and colleagues developed a method to fabricate NPs via a supercritical fluids setup, which loaded and transferred celecoxib, a lipophilic nonsteroidal anti-inflammatory drug, into the NPs. These celecoxib-containing NPs alleviated ejection function damage and ventricular dilation by inducing significant levels of neovascularization.103 Furthermore, a series of investigations indicated that drugs used for hypoglycemia (eg pioglitazone, exenatide and liraglutide)104106 and lipid lowering (statins)107 attenuate the progression of post-MI heart failure, and are therefore also potential therapeutic cargoes for NPs in the treatment of MI.

NP systems also offer an alternative method for delivering plant-derived therapeutic agents, most of which belong to traditional Chinese medicine. Its of vital importance because of the criticization on adverse reactions caused by direct injection of such complexes. Cheng and colleagues designed a dual-shell polymeric NP as a multistage, continuous, targeted vehicle of resveratrol, a reactive oxygen species (ROS) scavenger. Due to the severe oxide stress in areas of infarction, the proposed antioxidant-delivery NPs represent a new method to effectively treat MI. These NPs are modified with two peptides, targeting ischemic myocardium and mitochondria, respectively; cardioprotective effects have been confirmed in both hypoxia/reoxygenated (H/R) H9C2 cells and I/R rats.108 In addition, Dong and colleagues also demonstrated that puerarin-SLNs produced smaller areas of infarction in a MI rat model, evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining. These particles were modified with cyclic arginyl-glycyl-aspartic acid peptide, a specific targeting moiety to v3 integrin receptors, which are highly expressed on endothelial cells (ECs) during angiogenesis.109 In a recent study, quercetin was loaded into mesoporous silica NPs, which enhanced the inhibition of cell apoptosis and oxidative stress, improving ventricular remodeling and promoting the recovery of cardiac function by activating the janus kinase 2 (JAK2)/STAT3 pathway.110 Similarly, curcuminpolymer NPs, administered by gavage, improved serum inflammatory cytokine levels compared with direct administration of curcumin.111

Translation of novel bioactive agents into clinical practice has been limited, owing to lack of sufficient bioavailability and systemic toxicity.76 Encapsulating small molecules such as 3i-1000 (an inhibitor of the GATA4NKX2-5 interaction),43 TAK-242 (inhibitor of toll-like receptor 4, TLR4)112 and C143 (inhibitor of ERK1/2)113 in NPs promotes myocardial repair after MI without the risk of uncontrolled and off-target adverse effects. Administration of vascular endothelial growth factor (VEGF) causes elevated vascular permeability and tissue edema. The cardioprotective effects of VEGF-loaded polymeric NPs injected either intravenously114 or intramyocardially115 eliminated vascular leakage due to promotion of lymphangiogenesis. Further studies have confirmed these results and add to the evidence that combined delivery of VEGF with other growth factors is recommended, since VEGF primarily drives the formation of new capillaries.116 Furthermore, in line with previous research, similar therapeutic effects have been demonstrated in studies using polymeric NPs loaded with stromal cell derived factor 1 (SDF-1) and insulin-like growth factor 1 (IGF-1).117,118

We also notice that some novel payloads in NPs-based therapy for MI have been studied. For example, deoxyribozyme-AuNP can silence tumor necrosis factor- (TNF-).119 A target that is implicated in irreversible heart damage after MI; its effects are mediated by free radical production, downregulation of contractile proteins, and initiation of pro-inflammatory cytokine cascades. Mesoporous iron oxide NPs containing the hydrogen sulfide donor compound diallyl trisulfide act as a platform for the controlled and sustained release of this therapeutic gas molecule. The application of these NPs at appropriate concentrations, resulted in the preservation of cardiac systolic performance without any observable detrimental effects on homeostasis in vivo.15

With increasing insight into the molecular mechanisms of MI, a particular emphasis on gene therapy has emerged. Gene expression can be modulated by DNA fragments, messenger RNA (mRNA), microRNA (miRNA) and small interfering RNA (siRNA), which thus represent new approaches for treating ischemia. Currently available nucleic acid delivery systems are mainly divided into viral and non-viral systems. However, virus-based approaches are limited by their potential for uncontrollable mutagenesis.36 From a clinical point of view, NP represents a suitable choice as novel non-viral nucleic acid vector, which could feasibly transfect in a stable, targeted, and sustained manner (as shown in Table 2).

Table 2 NPs-Based Nucleic Acid Delivery Systems for Treatment for MI Reported in the Last 7 Years

As a common gene vehicle, plasmids face the risk of being destroyed by DNase and immunoreactivity in the serum, and transduction in non-target organs.120 A recent study by Kim and colleagues aligns with current research trends focused on virus-free therapies, in which carboxymethylcellulose NPs were designed to transfer 5-azacytidine to halt proliferation, and deliver plasmid DNA containing GATA4, myocyte enhancer factor 2C (MEF2C), and TBX5 to induce reprogramming and cardiogenesis of mature normal human dermal fibroblasts.121 In a methodological study, lipidoid NPs were used to successfully deliver pseudouridine-modified mRNA, encoding enhanced green fluorescent protein.122

MiRNAs act as essential regulators of cellular processes through post-transcriptional suppression; increasing evidence reveals miRNAs play critical roles in cardiovascular diseases. An miRNA-transferring platform with self-accelerating nucleic acid release, containing a heparin core and an ethanolamine-modified poly(glycidyl methacrylate) shell, has been constructed and used as an efficient vector of miR-499, which inhibits cardiomyocyte apoptosis.123 Intravenous administration of anionic hyaluronan-sulfate NPs (mean diameter 130 nm) enable the stable delivery of miR-21 mimics, thus modulating the expression of TNF, transforming growth factor (TGF), and suppressor of cytokine signaling 1 (SOCS1). Consequently, these NPs switch the phenotype of macrophages from pro-inflammatory to reparative, promote neovascularization and reduced collagen deposition.124 Interestingly, silencing miR-21 using antagomiR-21a-5p in a nanoparticle formulation has also been shown to reduce expression of pro-inflammatory cytokines in vitro, and attenuate inflammation and fibrosis in mice with autoimmune myocarditis.125 A number of other potentially therapeutic miRNAs have also been successfully transferred to CMs in recent works, including miR-146a, miR-146b-5p, miR-181b, miR-199-3p, miR-214-3p, miR-194-5p and miR-122-5p.126128 Evaluation of angiogenesis, cardiac function, and scar size in these studies indicated that injectable miRNANPs can deliver miRNA to restore injured myocardium efficiently and safely. Yang and colleagues developed an in vivo miRNA delivery system incorporating a shear-thinning hydrogel and NPs characterized by surface presence of miRNA and cell-penetrating peptide (CPP).126 Additionally, angiotensin II type 1 receptor-targeting peptide-modified NPs serve as targeted carriers for anti-miR-1 antisense oligonucleotide, significantly reducing apoptosis and infarct size.129

SiRNAs inhibit gene expression by mediating mRNA cleavage in a sequence-specific manner, highlighting NP-based RNA interference as another viable approach to modulate cellular phenotype and attenuate cardiac failure. Dosta and colleagues demonstrated that poly(-amino ester) particles modified by adding lysine-/histidine-oligopeptides could represent a system for the transfer of siRNA.130 Studies have now revealed that chemokine CC motif ligand 2 (CCL2) and its cognate receptor CC chemokine receptor 2 (CCR2) promoted excessive Ly6Chigh inflammatory monocyte infiltration in infarcted area and aggravate myocardial injury.131 Photoluminescent mesoporous silicon nanoparticles (MSNPs) carrying siCCR2 have been reported to improve the effectiveness of transplanted mesenchymal stem cells (MSCs) in reducing myocardial remodeling after acute MI.131 Targeted transportation and enhanced uptake with minimum leakage improved the efficiency of delivery via NPs, significantly outperforming the control group. Taken together, these studies demonstrate that NPs act as promising drug delivery systems in the treatment of MI.

Myocardial patches and scaffolds, consisting of either bioactive hydrogels or nanofibers, are minimally invasive, relatively localized, and targeted approaches to repair the heart after IHD. Those biomaterials must have an anisotropic structure, mechanical elasticity, electrical conductivity, and the ability to promote ischemic heart repair.132 A variety of NPs have been applied in this field, among which inorganic NPs have been the focus of most research efforts.42 These investigations of inorganic NPs can be divided into four categories based on their effects and the mechanisms involved, which are described in this section.

NPs enhance physical properties and electroconductivity, which is essential for the biomaterials to properly accommodate cardiac cells and subsequently resulted in cell retention, cell-cell coupling and robust synchronized beating behavior. CNTs are able to increase the required physical properties of scaffolds, such as maximum load, elastic modulus, and toughness.133,134 Gelatin methacrylate (GelMA) also has decreased impedance, hydrogel swelling ratio, and pore diameter, as well as increased Youngs modulus when combined with gold nanorods (AuNRs).135 Given this insight, highly electroconductive NPs have been increasingly investigated.34,99 Specifically, Ahadian and colleagues revealed that a higher integrated CNT concentration in gels resulted in greater conductivity.136 Zhou and colleagues verified the therapeutic effects of patches incorporating single-walled CNT for myocardial ischemia, which halted progressive cardiac dysfunction and regenerated the infarcted myocardium.137 Spherical AuNPs have also been shown to increase the conductivity of chitosan hydrogels in a concentration-dependent manner.138 Interestingly, silicon NPs mimic the effects of AuNRs without affecting conductivity or stiffness, as reported by Navaei and colleagues.139

Several studies demonstrate the effects of CNT on CM functions. When CMs are cultured on multi-walled CNT substrates or treated with CNT-integrated patches, these cells show spontaneous electrical activity.34,99,140 Brisa and colleagues functionalized reverse thermal gels with AuNPs, investigating the phenotype of CMs in vitro; the growth of cells with a CM phenotype was observed, along with gap junction formation.141 CMs exposed to AuNR-containing GelMa show higher affinity, leading to packed and uniform tissue structure.135 These conductive scaffolds also facilitate the robustness and synchrony of spontaneous beating in CMs without damaging their viability and metabolic activity.

Combined incorporation of inorganic NPs and cells represents a feasible strategy to promote therapeutic effects. Despite some reports on the cytotoxicity of Au,89,90 no significant loss of viability, metabolism, migration, or proliferation of MSCs in scaffolds containing AuNP is reported. A CNT-embedded, electrospun chitosan/polyvinyl alcohol mesh is reported to promote the differentiation of MSCs to CMs.142 In another approach, Baei and colleagues added AuNPs to chitosan thermosensitive hydrogels seeded with MSCs.138 There was a significant increase in expression of early and mature cardiac markers, indicating enhanced cardiomyogenic differentiation of MSCs compared to the matrix alone, while no difference in growth was observed. Gao et al created a fibrin scaffold, in which cells and AuNPs were suspended simultaneously; these bioactive patches were shown to promote left ventricular function and decrease infarct size and apoptosis in the periscar boarder zone myocardium in swine models of acute MI.97 These studies of AuNP-containing scaffolds demonstrated reduced infarct and fibrotic size, as well as facilitated angiogenesis and cardiac function, which can be attributed at least in part to the enhanced expression of connexin 43 and atrial natriuretic peptide, and activation of the integrin-linked kinase(ILK)/serine-threonine kinase (p-AKT)/GATA4 pathway.49,143,144 Scaffolds containing Ag NPs evoke M2 polarization of macrophages in vitro;145 which may also play a role in cardioprotective action because M2 macrophages are capable of promoting cardiac recovery via the secretion of anti-inflammatory cytokines, collagen deposition, and neovascularization.146

Similarly, CNT also act synergically with poly(N-isopropylacrylamide) scaffolds containing adipose-derived stem cells;147 significant improvement of cardiac function and increased implantation and proliferation of stem cells has been observed with these scaffolds, compared with scaffolds without CNT.147 Selenium NPs148 and titania NPs53 have been shown to improve the mechanical and conductive properties of chitosan patches, promoting their ability to support proliferation and the synchronous activity of cells growing on these patches.

Mounting evidence demonstrates the unique benefits of using cardiac scaffolds with magnetic NPs such as SPIONs; these benefits include, but are not limited to, significant improvements in cell proliferation149 and assembly of electrochemical junctions.150 Given that magnetic manipulation enhances the therapeutic efficacy of iron oxide NPs in cardiac scaffolds, Chouhan and colleagues designed a magnetic actuator device by incorporating magnetic iron oxide NPs (MIONs) in silk nanofibers; this resulted in more controlled drug release properties, as well as the promotion of proliferation and maturation in CMs.151 Magnetic NPs can be used to label induced pluripotent stem cell (iPSC)-derived CMs via conjugation with antibodies against signal-regulatory protein . Zwi-Dantsis and colleagues reported the construction of tailored cardiac tissue microstructures, achieved by orienting MION-labelled cells along the applied field to impart different shapes without any mechanical support.152 However, the interactions between and effects of NPs and cells in scaffolds, and the cardioprotective efficacy of patches in which NP-labelled cells are suspended, require further elucidation.

Polymeric nanomaterials have also been investigated in the context of cardiac bioengineering materials; for instance, water-swollen polymer NPs have been used to prepare nanogels. With a 3D structure containing cross-linked biopolymer networks, nanogels can encapsulate, protect, and deliver various agents.83,153 PDA-coated tanshinone IIA NPs suspended in a ROS-sensitive, injectable hydrogel via PDA-thiol bonds significantly improved cardiac performance, accompanied by inhibition of the expression of inflammation factors in rat model.73 After implanting cryogel patches consisting of GelMa and linked conductive polypyrrole NPs154 or scaffolds of electrospun GelMA/polycaprolactone with GelMA-polypyrrole NPs,155 left ventricular (LV) ejection fraction (EF) has been shown to increase, with a concurrent decrease in infarct size, in MI animal models.

Progenitor or stem cell-based therapy in the form of injections and engineered cardiac patches, discussed in the previous section, has been recognized as a promising strategy to improve the cardiac niche and ameliorate adverse remodeling processes and fibrosis after acute MI.56,156,157 However, poor survival and low engraftment rates for transplanted cells are still major challenges in this field.157 Among possible optimization strategies, combining NPs with stem cell therapy is of great interest (Table 3).

Table 3 Studies Combining NPs and Cell Therapy Reported in the Last 7 Years

Accumulating evidence has shown two main mechanisms for NP-loaded cell therapy in the context of MI treatment. Firstly, various NP types could efficiently improve survival and cell proliferation, modulating differentiation of implanted cells in the ischemic microenvironment.62,158 Specifically, electrically driven nanomanipulators could guide cardiomyogenic differentiation of MSCs: in a previous study, electroactuated gold NPs were administrated with pulsed electric field stimulation, and tube-like morphological alterations were observed, along with upregulation of cardiac specific markers.143 Adipose-derived stem cells that load PLGA-simvastatin NPs promoted differentiation of these cells into SMCs and ECs, and had cardioprotective effects in a mouse model of MI induced by left anterior descending ligation.17 Secondly, engraftment rate is another important factor affecting treatment efficacy in this context.159 Zhang and colleagues designed silica-coated, MION-labelled endothelial progenitor cells; intravenous administration of these cells in a rat model of MI significantly improved cardiac performance, as indicated by echocardiogram, morphological, and histological evidence, and neovascularization. This indicates magnetic guidance may potentially address the problem of low levels of stem cell retention, which has typically been observed.51 In particular, NPs can link the therapeutic cells to injured CMs, thereby promoting cell anchorage and engraftment. To this end, Cheng and colleagues established a magnetic, bifunctional cell connector by conjugating NPs with two antibodies: one against cell determinant (CD)45, which is expressed on bone marrow-derived stem cells, and one against MLC. The magnetic core of this NP also enabled physical enrichment in ischemic heart tissue using external magnets.160 More than one mechanism may be involved in a study. Chen and colleagues fabricated a sustained release carrier of insulin-like growth factor (IGF), a pro-survival agent, via in situ growth of Fe3O4 NPs on MSNPs. In this study, the NPs promoted both the survival and retention of MSCs, and intramyocardial injection of the NP-labeled MSCs was able to ameliorate functional and histological damage without any obvious toxicity in vivo.161 However, SPION labeling does not seem to improve therapeutic efficiency, as demonstrated by Wang and colleagues in a study using hypoxia-preconditioned SPION-labeled adipose-derived stem cells (ASCs).162

Primary criticisms of cell-based therapies include their potential immunogenicity, arrhythmogenicity and tumorigenicity. It is widely accepted that the beneficial effects of cell-based therapy are mainly attributable to paracrine effects rather than directly replenishing lost CMs;56 researchers are therefore investigating of cell-free approaches. Exosomes have attractive properties including stable transport, homing to target tissues or cells, and penetration of biological barriers, as well as being more biocompatible with lower immunogenicity than cell-based approaches. Interestingly, post-MI circulating exosomes serve as important cardioprotective messengers.163,164 Manipulating their biodistribution has proven to be a viable strategy to reduce infarct size, promoting angiogenesis and ejection functions.21 However, from a therapeutic standpoint, the lack of control over endogenous exosome production and cargo encapsulation limits the use of this naturally-present mechanism for therapeutic enhancement. The low purity and weak targeting of natural exosomes are two further obstacles to overcome before clinical application. Strategies to address these include finding robust sources; optimized isolation methods for higher yields, efficiency and purity; and improving therapeutic payloads. These have been systematically summarized in other reviews.165167

AS is considered a low-grade, chronic inflammatory disease, characterized by accumulation and deposition of cholesterol in arteries, as well as remodeling of the extracellular matrix in the intima and inner media.12,168 Inflammation of ECs, proliferation of SMCs, and recruitment of monocytes and macrophages play a critical role in the development of AS. NPs allow for the packaging of large amounts of therapeutic compounds in a compact nanostructure, specifically targeting pathological mechanisms and attenuating atherogenesis. Optimization of the loaded drug and NP target together lead to enhanced efficacy while minimizing side effects.169 In this section, we summarize recent breakthroughs in the order of pathological progression, as shown in Table 4.

Primary prevention refers to control of the risk factors of AS, one of which is hypertension.170 PLA NPs have been shown to improve the efficacy of aliskiren, the first oral direct renin inhibitor and the first in a new class of antihypertensive agents.29 Encapsulation in nanocarriers also renders the application of anandamide viable, which was once limited; recent research revealed that this new therapy could lower blood pressure and LV mass index in rats.171 Similar results were observed in a study in which angiotensinogen was silenced using small hairpin RNA.172 NPs may also help to make more anti-hypertensive drugs available, reduce side effects such as asthma, and lessen the effective dosage by providing sustained drug release over time. The link between AS and diabetes mellitus, which describes a group of metabolic disorders, has also been investigated in numerous studies.173 Possible mechanisms include oxidative stress, altered protein kinase signaling, and epigenetic modifications. Cetin and colleagues successfully constructed NP-based drug delivery systems for the administration of metformin, an oral antihyperglycemic agent with low oral bioavailability and short biological half-life.174 NPs are also promising tools for improving the oral bioavailability of insulin, which is of great interest because oral insulin will significantly increase patients compliance.175,176

The inflammatory hypothesis of AS is now widely established, making selective targeting and accumulation of NPs in inflammatory lesions attractive therapeutic strategies. Targeting macrophages in apoE-/- mice has been shown to result in decreased phagocytosis and suppression of inflammatory genes in lesional macrophages, thus lessening burden of atherosclerotic plaques.177 Tom and colleagues used NPs consisting of high-density lipoprotein (HDL), a known atheroprotective bionanomaterial, as carriers for TNF receptor-associated factor in mice, and observed reductions in both leukocyte recruitment and macrophage activation.178 Both single-walled CNT and HDL-NPs have a favorable safety profile. In a pathological context, activated endothelial tissue expresses more adhesion molecules, such as selectins, than usual. These molecules are thus potential targets for cardiovascular nanomedicine. Glycoprotein Ib (GPIb)179 and biotinylated Sialyl Lewis A (sLeA)69 specifically bind to selectins, leading to the accumulation of conjugated NPs in injured vessels; an in vitro study demonstrated that GPIb-conjugated NPs could bind to target surfaces, where they were taken up by activated ECs under shear stress conditions. In another study, Sager and colleagues simultaneously inhibited five adhesion molecules associated with leukocyte recruitment in post-MI apoE-/- mice. Inflammation in plaque and ischemic heart, rendering acute coronary events and post-MI complications less likely to occur.180 However, targeting inflammatory process may have heterogeneous effects in humans because the targeting moieties and target receptors may be overexpressed in several different pathologic conditions in addition to AS. Oxidation is another factor involved in the development of AS. Upregulation of endothelial nitric oxide synthase (eNOS) leads to vascular construction and other AS-promoting effects. Pechanova and colleagues observed that the application of PLA NPs resulted in larger decreases in NOS than direct administration.29

Aside from these processes, avoiding plaque rupture and thrombosis could be another therapeutic aim. Nakashiro and colleagues showed that delivering pioglitazone via NPs inhibited plaque rupture in apoE-/- mice.181 The integrin 3 is upregulated in angiogenic vasculature, which is ubiquitous in plaque ruptures, which may lead to MI.182 3 integrin-targeted NPs provide a site-specific drug delivery platform that has been shown to successfully stabilize plaques in rabbits.182 Ji and colleagues used NPs composed of albumin with an average diameter of 225.6 nm to deliver a plasmid containing the tissue-type plasminogen activator gene (t-PA); this system plays a role in preventing thrombosis in addition to attenuating intimal thickness and proliferation of vascular SMCs.183 NPs consisting of engineered amphipathic cationic peptide and serine/threonine protein kinase JNK2 siRNA also reduces thrombotic risk, plaque necrotic area, and vascular barrier disorder in mice given the equivalent of a 14-week western diet.184

Innovation and development of therapies based on NPs in recent years has led to significant advances towards complete repair of the injured myocardium following acute MI. Nevertheless, developing clinically relevant solutions remains difficult for several reasons. Firstly, as shown in tables, there is little consistency among studies regarding the characteristics of NPs, their payloads, and their methods of administration, as well as methods used for evaluating cardiac repair. It can be difficult to control characteristics such as the size of the synthesized particles in a narrow range, even within single studies. Such significant heterogeneity can lead to differences in observed results in repeated experiments, or under different conditions. Secondly, although many studies have focused on the health effects of unintentional exposure to NPs by inhalation or ingestion,185,186 most of the studies on medical applications of NPs have not reported on toxicity of NP systems until recently.73 Remarkably, there has not been a consensus on NP-associated adverse effects in existing reports, making assessments of biocompatibility a priority for NP characterization.

NPs have emerged as a powerful tool for controlling cell signaling pathways in regenerative strategies using novel therapeutics and drugs that are unsuitable for direct administration. One advantage of the application of NP systems is the ability to release the drug payload or regulate gene expression in a stable and controlled manner. Therefore, many otherwise serious side effects, such as sudden arrhythmic deaths resulting from persistent and uncontrolled expression of miRNA by viral vectors, may be completely avoided.187 More research is required to develop stable and efficient methods of NP production, improve encapsulation efficiency of drugs, and achieve satisfactory targeting. In particular, a greater focus on investigating NP-based switches, including optical, electrical and magnetic methods, has enabled the regulation of cell signaling, exemplified by the development of a CuS NP-based photothermal switch.52 Optimizing tissue engineering scaffolds containing conductive NPs is a promising strategy for the protection of the myocardium after ischemia by mimicking the myocardial extracellular matrix. Improvements in understanding of cardiac repair mechanisms, and how these biomaterials may interfere with them, is therefore urgently needed. Furthermore, heart repair is complex and involves many processes, including apoptosis, angiogenesis, inflammatory infiltration, and fibrosis. Therefore, novel treatments should be designed using NP-based integrative strategies based on these multiple different mechanisms. However, its important to highlight that synergistic effects of different drug payloads, NPs, and NPcell combined strategies should be addressed, as not all may be compatible with one another. Future research should focus on these aspects to translate NP-based therapeutic strategies for MI into practical and effective clinical use.

The authors report no conflicts of interest in this work.

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Therapy and Prevention Strategies for Myocardial Infarction | IJN - Dove Medical Press

Cardiac Stem Cells Comments Off on Therapy and Prevention Strategies for Myocardial Infarction | IJN – Dove Medical Press | October 5th, 2021

Learn how these advanced 3D tissue models generated on the Mantarray platform can improve the physiological relevance of preclinical cardiac and skeletal muscle models, accelerating the discovery of new medicines.

TORONTO (PRWEB) October 05, 2021

3D cellular models and organs-on-chips are poised to add tremendous value by providing human data earlier in the drug discovery pipeline. There is intense interest in adopting these 3D models in preclinical and translational research, but their complex implementation has remained a roadblock for many labs.

In this webinar, Curi Bio will present its Mantarray platform, which represents an easy-to-use, flexible, and scalable system for generating 3D EMTs at high-throughput with the ability to measure contractility in parallel. The platform features a novel method of casting 3D tissues that can be easily performed by nearly any cell biology researcher and can be readily adapted to a variety of cell lines and extracellular matrices. In addition, Mantarrays novel magnetic sensing modality permits contractility measurement of 24 tissues in parallel and in real time, while the cloud data analysis portal takes the guesswork out of analyzing and comparing results across experiments.

Register for this webinar to hear an overview of the technology, along with application examples across various use cases, including:

Learn how these advanced 3D tissue models generated on the Mantarray platform can improve the physiological relevance of preclinical cardiac and skeletal muscle models, accelerating the discovery of new medicines.

Join Dr. Nicholas Geisse, Chief Science Officer at Curi Bio, for the live webinar on Friday, October 22, 2021 at 1pm EDT.

For more information, or to register for this event, visit Mantarray: Scalable Human-Relevant 3D-Engineered Cardiac and Skeletal Muscle Tissues for Safety and Efficacy Studies.

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Mantarray: Scalable Human-relevant 3D Engineered Cardiac and Skeletal Muscle Tissues for Therapeutics Discovery Upcoming Webinar Hosted by Xtalks -...

Cardiac Stem Cells Comments Off on Mantarray: Scalable Human-relevant 3D Engineered Cardiac and Skeletal Muscle Tissues for Therapeutics Discovery Upcoming Webinar Hosted by Xtalks -… | October 5th, 2021

It is too late for conservation efforts to save the northern white rhinoceros, but with recent scientific advancements there may still be hope to bring back this beloved species. In a recently published paper, scientist Marisa Korody and her colleagues at San Diego Zoo Global (USA) and at the Department of Molecular Medicine at Scripps Research (USA) describe their exciting progress on using stem cells to revive the northern white rhino.

The northern white rhino is functionally extinct, meaning there are not enough of these rhinos left to save the species. In fact there are only two northern white rhinos left: a mother and a daughter. But for decades, scientists have preserved cell samples from 15 northern white rhinos containing enough genetic material to potentially bring this species back from the brink. These preserved samples hold fibroblast cells the type of skin cells that secrete collagen from white rhinos. With these scientists newly developed methods, fibroblast cells can be converted into something much more valuable: induced pluripotent stem cells. These stem cells can differentiate into any cell type in the body including heart cells, muscle cells, and reproductive cells.

In theory, by converting fibroblast cells into reproductive cells, scientists could create genetically unique rhino embryos. Alongside other assisted reproduction technologies, scientists could implant a new embryo into a closely-related southern white rhino, where the baby northern white rhino could develop as an otherwise normal pregnancy. By completing this process multiple times, scientists may be able to establish a stable population of northern white rhinos.

In 2011, this research team generated induced pluripotent stem cells from the samples of another endangered species, but unfortunately since this process was found to harm the recipient genomes, this method was largely unsuccessful. Despite this setback, in 2015 the authors met with colleagues worldwide to consider ways to save the northern white rhino, and they concluded that methods involving induced pluripotent stem cells may still be the most promising solution. Over the following years, the scientists worked to improve their methods, and these improvements are documented in their recent paper. These experiments represent the first step in a long-term plan to bring the northern white rhino back through assisted reproduction techniques.

Right from the start, the scientists faced a whole host of challenges. Through trial and error they modified the growth medium for the cells, optimizing it for rhinoceros cells. With their improved growth medium, scientists successfully generated induced pluripotent stem cell lines from 11 rhinoceros individuals. This has never been done before and represents a huge stride forward in the path to recovering this species.

Before trying to make their first rhino, the scientists needed to stress these induced pluripotent stem cells and sequence their genomes to determine if the cell quality is good enough to potentially produce new, viable rhinos. They maintained colonies of these cells in long-term cultures and exposed these colonies to different conditions to give insight into how resilient these cells could be. These tests demonstrated that long-term culture did not affect the potential for these cells to differentiate into cardiac lineage cells, confirming that these cells are stable long-term. The researchers also confirmed that these pluripotent cells could potentially produce gametes, the egg and sperm cells that are used for sexual reproduction. These advancements indicate that with these newly developed protocols, induced pluripotent stem cells are a promising tool that could someday help recover the northern white rhino.

Although this study includes some exciting results, there is still much work to do. For example, scientists must now sequence the genomes of the northern and southern white rhino so other researchers can analyze the stem cells ability to stay the same over time. Despite the work that still needs to be done, these promising advancements could someday help the northern white rhino population recover. This method may also work for saving other endangered or extinct species, as long as the genetic material needed is available. Long-term, these scientists plan to continue a series of experiments that could ultimately bring this beloved rhino, and potentially other endangered species, back from the brink of extinction.

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Stem cells may be the key to saving white rhinos from extinction - Sciworthy

Cardiac Stem Cells Comments Off on Stem cells may be the key to saving white rhinos from extinction – Sciworthy | October 5th, 2021

Today is International Heart Day, and Cosmos is looking back on the stories that make our hearts flutter.

Scientists have taken another step in the quest to create a Google map of the human body by putting together a detailed cellular and molecular map of the healthy heart.

An international team analysed almost half a million individual cells and cell nuclei from six different regions of the heart, obtained from 14 organ donors whose hearts were healthy but unsuitable for transplantation.

The result is theHeart Cell Atlas, which, shows the huge diversity of cells and reveals heart muscle cell types, cardiac protective immune cells and an intricate network of blood vessels. It also predicts how the cells communicate to keep the heart working.

Sometimes, the heart just stops for no perceivable reason. Sudden cardiac arrest (SCA) is a prevalent hidden killer, even for younger people: 40% of those who die from SCA are under 50 years old.

SCA is not as rare as we would like it to be, says cardiologist Elizabeth Paratz, whos undertaking her PhD at the Baker Heart and Diabetes Institute, Melbourne. In the last year in Victoria, 750 young people under 50 have suffered an SCA. This is almost exactly five times the road toll over the same time in this age group, yet we hear a lot more publicity about road fatalities in young people.

Paratz is researching the prevalence and causes of SCA, as well as looking at ways to diagnose it better. There are multiple causes of SCA, and theyre hard to pinpoint in young people.

The controversial use of stem cells to help patients recover from a heart attack may work, but not because it grows new heart muscle.

Research in mice has found that injecting stem cells into the heart triggers an immune response that makes the scar stronger and the heart beat more forcefully.

Thestudy, published in the journalNature, suggests the current practice of injecting stem cells into a patients blood may not be optimal: direct injection into the heart could be more effective.

In a preclinical trial on a beating human heart, researchers have found that a drug candidate developed from the venom of the worlds deadliest spider, the funnel web, may hold promise for heart attack treatment and transplants.

The researchers, led by Meredith Redd of the University of Queensland (UQ), and Sarah Scheuer of Victor Chang Cardiac Research Institute, tested a protein called Hi1a, found in the Fraser Island (Kgari) funnel web venom, on a beating heart that had been exposed to heart attack stresses.

After a heart attack, blood flow to the heart is reduced, resulting in a lack of oxygen to heart muscle, says Nathan Palpant of UQ, corresponding author of the paper.

The lack of oxygen causes the cell environment to become acidic, which combine to send a message for heart cells to die.

The Hi1a protein from spider venom blocks acid-sensing ion channels in the heart, so the death message is blocked, cell death is reduced, and we see improved heart cell survival.

The Chinese Finger Trap a tubular braided novelty beloved by kids and pranksters around the world provided the inspiration for a nifty bit of biotech that looks set to save sick kids a whole lot of heartache. Literally.

Pedro del Nido from Boston Childrens Hospital in the US heads a team that has designed a proof-of-concept device that promises to dramatically cut down on surgery for children with certain types of heart defects.

At present, kids with defective mitral and tricuspid heart valves must undergo surgery in which a corrective implant is installed. The problem, however, is that children grow: the heart increases in size, and requires at least one, and often several, further surgical interventions so that a correspondingly larger implant can be installed.

Needless to say, these repeated bouts of open-heart surgery are extremely traumatic and disruptive.

Now, however, Nido and Karp may have come up with an elegant and clever solution: an implant that grows with the organ.

Link:
Five Heart Stories For International Heart Day - Cosmos

Cardiac Stem Cells Comments Off on Five Heart Stories For International Heart Day – Cosmos | October 5th, 2021

Shahid Akhter, editor, ETHealthworld spoke to Dr. Dinesh Bhurani, Director, Department of Hemato-Oncology & Bone Marrow Transplant, Rajiv Gandhi Cancer Institute and Research Centre, to know about the progress of NPRD and the challenges associated with blood stem cell transplants.

How do you think the National Policy for Rare Diseases will impact the treatment of patients suffering from rare blood disorders? Will it help reduce the lag that we often see in policy and practice when it comes to healthcare systems?National Policy on Rare Diseases is a step-in right direction and must be welcomed by the Indian medical fraternity. It not only recognizes rare diseases for the first time in India but also has brought forward the possibility of affordable treatment for life-threatening rare diseases which were not previously covered under the national health program. The policy advocates access for treatment through center of excellences, crowd funding and financial assistance.

The NPRD in a bid to enable patients suffering from rare blood disorders has laid emphasis on the option of one-time curative treatment through hematopoietic stem cell transplant for diseases such as Severe Combined Immunodeficiency (SCID), Chronic Granulomatous disease, Wiskott Aldrich Syndrome, Osteopetrosis, and Fanconi Anaemia. By committing to provide a Rs. 20 lakhs cover for the one-time treatment cost of diseases falling under Group 1 through the umbrella scheme of Rashtriya Arogya Nidhi, the NPRD has attempted to provide coverage to almost 40 per cent of the population who are eligible under the Pradhan Mantri Jan Arogya Yojana. The NPRD as a policy that advocates affordable and accessible healthcare and has the potential to lead to the creation of a conducive healthcare ecosystem whereby multisectoral partnerships can collaboratively work towards reduction in the lag between policy and practice often seen otherwise, thereby leading people to live healthier and fuller lives.

Another reason for low number of donors in India is the misconception that stem cell donation comes with a cost to donor. This idea is completely misplaced and untrue as the cost of procedure starting from sample collection, donation and travel is free of cost, and covered under the cost of treatment of a patient for whom the donation is needed. Added to this is the fact that the number of organizations working in the country in the space of blood stem cell transplant is limited at best, thus awareness generation as compared to other health issues is nominal. However, the situation is gradually evolving and ICMR in its 2021 guidelines has gone on to recognize seven registries across the country as active stakeholders in this ecosystem. This recognition by ICMR will hopefully lead to greater awareness generation.

For blood stem cell transplant knowledge is key in establishing patient donor linkage, and by storing the requisite information with them, these registries do just that. Technology is a tool that has been successfully leveraged by stakeholders in the ecosystem to establish linkages. The Hap- E Search is one such tool that has been used by hospitals in the country to find donor matches for their patients. This software is perhaps one of the most enabling tools available to us in the ecosystem, as it helps find HLA matches not just in the country but across the world. This software is now being used by many government hospitals like AIIMS, Delhi and PGIMER Chandigarh. Once the matching donor is found via the HAP-E Search, the donor is encouraged to make the donation, provided counselling and support to donate blood stem cells, and post donation the stem cells are transported to the patients location.

The NPRD proposed crowdfunding and PPP models to ensure more patients availing treatment for rare diseases. How beneficial do you think such partnerships can be to enable blood stem cell transplant ecosystem?Treatment for rare diseases has been found to be expensive across the world. It is thus that despite stem cell transplants being a proven effective solution in the case of some blood disorders, affordability continues to be a challenge for patients and their families. With treatment costs ranging anywhere between Rs. 15-45 lakh, it remains out of reach for most patients in the country. Also, blood disorders, classified as rare, have limited infrastructure in health systems, networks, and subsidies for patients to access treatments are few. In such a scenario, crowdfunding is definitely a feasible option for patients that would ensure that they do not have to forego treatment due to a paucity of resources.

As per the NPRD, the money raised through crowdfunding would directly get credited to the treatment centre thus ensuring that there is adequate linkage. Further, the public private partnership model suggested by the government has enabled it to avail the support of non- governmental and not-for- profit agencies present in the country. This is truly commendable as not only will this ensure more patient donor linkage in the blood stem transplant ecosystem but will also lead to greater awareness generation and registrations of donors as well. One significant organization that has already partnered with the government in this arena is the DKMS BMST Foundation India. With over 50,000 blood stem cell donors registered with them, this organization has been steadily working towards enabling the ecosystem. In the case of rare diseases, it is imperative that stakeholders do not work in isolation and the government working alongside the private can lead to greater hope for many patients with greater amenities and facilities for treatment being made accessible to them.

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DBMR has added another report named Exosome therapeutic Market with information Tables for recorded and figure years addressed with Chats and Graphs spread through Pages with straightforward definite examination. The a-list report concentrates on broad assessment of the market development expectations and limitations. The systems range from new item dispatches, extensions, arrangements, joint endeavors, organizations, to acquisitions. This report includes profound information and data on what the markets definition, characterizations, applications, and commitment and furthermore clarifies the drivers and restrictions of the market which is gotten from SWOT investigation. Worldwide market examination report serves a great deal for the business and presents with answer for the hardest business questions. While making Exosome therapeutic Market report, examination and investigation has been completed with one stage or the mix of a few stages relying on the business and customer necessities.

Market definition canvassed in the predominant Exosome therapeutic Market advertising report investigates the market drivers that show factors causing ascend in the market development and market limitations which demonstrate the components causing fall in the market development. It helps clients or other market members to know about the issues they might confront while working in this market throughout a more extended timeframe. This statistical surveying report additionally concentrates on utilization of market, central participants included, deals, value, income and portion of the overall industry with volume and an incentive for every area. The greatness and straightforwardness proceeded in Exosome therapeutic Market business research report makes acquire the trust and dependence of part organizations and clients.

Global Exosome Therapeutic Market By Type (Natural Exosomes, Hybrid Exosomes), Source (Dendritic Cells, Mesenchymal Stem Cells, Blood, Milk, Body Fluids, Saliva, Urine Others), Therapy (Immunotherapy, Gene Therapy, Chemotherapy), Transporting Capacity (Bio Macromolecules, Small Molecules), Application (Oncology, Neurology, Metabolic Disorders, Cardiac Disorders, Blood Disorders, Inflammatory Disorders, Gynecology Disorders, Organ Transplantation, Others), Route of administration (Oral, Parenteral), End User (Hospitals, Diagnostic Centers, Research & Academic Institutes), Geography (North America, Europe, Asia-Pacific and Latin America)

Market Analysis and Insights:Global Exosome Therapeutic Market

Exosome therapeutic market is expected to gain market growth in the forecast period of 2019 to 2026. Data Bridge Market Research analyses that the market is growing with a CAGR of 21.9% in the forecast period of 2019 to 2026 and expected to reach USD 31,691.52 million by 2026 from USD 6,500.00 million in 2018. Increasing prevalence of lyme disease, chronic inflammation, autoimmune disease and other chronic degenerative diseases are the factors for the market growth.

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Exosomes are used to transfer RNA, DNA, and proteins to other cells in the body by making alteration in the function of the target cells. Increasing research activities in exosome therapeutic is augmenting the market growth as demand for exosome therapeutic has increased among healthcare professionals.

Increased number of exosome therapeutics as compared to the past few years will accelerate the market growth. Companies are receiving funding for exosome therapeutic research and clinical trials. For instance, In September 2018, EXOCOBIO has raised USD 27 million in its series B funding. The company has raised USD 46 million as series a funding in April 2017. The series B funding will help the company to set up GMP-compliant exosome industrial facilities to enhance production of exosomes to commercialize in cosmetics and pharmaceutical industry.

Increasing demand for anti-aging therapies will also drive the market. Unmet medical needs such as very few therapeutic are approved by the regulatory authority for the treatment in comparison to the demand in global exosome therapeutics market will hamper the market growth market. Availability of various exosome isolation and purification techniques is further creates new opportunities for exosome therapeutics as they will help company in isolation and purification of exosomes from dendritic cells, mesenchymal stem cells, blood, milk, body fluids, saliva, and urine and from others sources. Such policies support exosome therapeutic market growth in the forecast period to 2019-2026.

This exosome therapeutic market report provides details of market share, new developments, and product pipeline analysis, impact of domestic and localised market players, analyses opportunities in terms of emerging revenue pockets, changes in market regulations, product approvals, strategic decisions, product launches, geographic expansions, and technological innovations in the market. To understand the analysis and the market scenario contact us for anAnalyst Brief, our team will help you create a revenue impact solution to achieve your desired goal.

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Competitive Landscape and Exosome Therapeutic Market Share Analysis

Global exosome therapeutic market competitive landscape provides details by competitor. Details included are company overview, company financials, revenue generated, market potential, investment in research and development, new market initiatives, global presence, production sites and facilities, company strengths and weaknesses, product launch, product trials pipelines, concept cars, product approvals, patents, product width and breadth, application dominance, technology lifeline curve. The above data points provided are only related to the companys focus related to global exosome therapeutic market.

The major players covered in the report are evox THERAPEUTICS, EXOCOBIO, Exopharm, AEGLE Therapeutics, United Therapeutics Corporation, Codiak BioSciences, Jazz Pharmaceuticals, Inc., Boehringer Ingelheim International GmbH, ReNeuron Group plc, Capricor Therapeutics, Avalon Globocare Corp., CREATIVE MEDICAL TECHNOLOGY HOLDINGS INC., Stem Cells Group among other players domestic and global. Exosome therapeutic market share data is available for Global, North America, Europe, Asia-Pacific, and Latin America separately. DBMR analysts understand competitive strengths and provide competitive analysis for each competitor separately.

Many joint ventures and developments are also initiated by the companies worldwide which are also accelerating the global exosome therapeutic market.

For instance,

Partnership, joint ventures and other strategies enhances the company market share with increased coverage and presence. It also provides the benefit for organisation to improve their offering for exosome therapeutics through expanded model range.

Global Exosome Therapeutic Market Scope and Market Size

Global exosome therapeutic market is segmented of the basis of type, source, therapy, transporting capacity, application, route of administration and end user. The growth among segments helps you analyse niche pockets of growth and strategies to approach the market and determine your core application areas and the difference in your target markets.

Based on type, the market is segmented into natural exosomes and hybrid exosomes. Natural exosomes are dominating in the market because natural exosomes are used in various biological and pathological processes as well as natural exosomes has many advantages such as good biocompatibility and reduced clearance rate compare than hybrid exosomes.

Exosome is an extracellular vesicle which is released from cells, particularly from stem cells. Exosome functions as vehicle for particular proteins and genetic information and other cells. Exosome plays a vital role in the rejuvenation and communication of all the cells in our body while not themselves being cells at all. Research has projected that communication between cells is significant in maintenance of healthy cellular terrain. Chronic disease, age, genetic disorders and environmental factors can affect stem cells communication with other cells and can lead to distribution in the healing process. The growth of the global exosome therapeutic market reflects global and country-wide increase in prevalence of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases, along with increasing demand for anti-aging therapies. Additionally major factors expected to contribute in growth of the global exosome therapeutic market in future are emerging therapeutic value of exosome, availability of various exosome isolation and purification techniques, technological advancements in exosome and rising healthcare infrastructure.

Rising demand of exosome therapeutic across the globe as exosome therapeutic is expected to be one of the most prominent therapies for autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases treatment, according to clinical researches exosomes help to processes regulation within the body during treatment of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases. This factor has increased the research activities in exosome therapeutic development around the world for exosome therapeutic. Hence, this factor is leading the clinician and researches to shift towards exosome therapeutic. In the current scenario the exosome therapeutic are highly used in treatment of autoimmune disease, chronic inflammation, Lyme disease and chronic degenerative diseases and as anti-aging therapy as it Exosomes has proliferation of fibroblast cells which is significant in maintenance of skin elasticity and strength.

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Exosome therapeutic Market Country Level Analysis

The global exosome therapeutic market is analysed and market size information is provided by country by type, source, therapy, transporting capacity, application, route of administration and end user as referenced above.

The countries covered in the exosome therapeutic market report are U.S. and Mexico in North America, Turkey in Europe, South Korea, Australia, Hong Kong in the Asia-Pacific, Argentina, Colombia, Peru, Chile, Ecuador, Venezuela, Panama, Dominican Republic, El Salvador, Paraguay, Costa Rica, Puerto Rico, Nicaragua, Uruguay as part of Latin America.

Country Level Analysis, By Type

North America dominates the exosome therapeutic market as the U.S. is leader in exosome therapeutic manufacturing as well as research activities required for exosome therapeutics. At present time Stem Cells Group holding shares around 60.00%. In addition global exosomes therapeutics manufacturers like EXOCOBIO, evox THERAPEUTICS and others are intensifying their efforts in China. The Europe region is expected to grow with the highest growth rate in the forecast period of 2019 to 2026 because of increasing research activities in exosome therapeutic by population.

The country section of the report also provides individual market impacting factors and changes in regulation in the market domestically that impacts the current and future trends of the market. Data points such as new sales, replacement sales, country demographics, regulatory acts and import-export tariffs are some of the major pointers used to forecast the market scenario for individual countries. Also, presence and availability of global brands and their challenges faced due to large or scarce competition from local and domestic brands, impact of sales channels are considered while providing forecast analysis of the country data.

Huge Investment by Automakers for Exosome Therapeutics and New Technology Penetration

Global exosome therapeutic market also provides you with detailed market analysis for every country growth in pharma industry with exosome therapeutic sales, impact of technological development in exosome therapeutic and changes in regulatory scenarios with their support for the exosome therapeutic market. The data is available for historic period 2010 to 2017.

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An absolute way to forecast what future holds is to comprehend the trend today!Data Bridge set forth itself as an unconventional and neoteric Market research and consulting firm with unparalleled level of resilience and integrated approaches. We are determined to unearth the best market opportunities and foster efficient information for your business to thrive in the market. Data Bridge endeavors to provide appropriate solutions to the complex business challenges and initiates an effortless decision-making process.

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Exosome therapeutic Market Report- Trends Key Programs Analysis and Competitive Landscape and Forecast 2028 Amite Tangy Digest - Amite Tangy Digest

Cardiac Stem Cells Comments Off on Exosome therapeutic Market Report- Trends Key Programs Analysis and Competitive Landscape and Forecast 2028 Amite Tangy Digest – Amite Tangy Digest | October 5th, 2021

SYDNEY, Oct. 5, 2021 /PRNewswire/ -- Clinical stage drug development company Pharmaxis Ltd (ASX: PXS) today announced further positive results of data analysis from a phase 1c clinical trial (MF-101) studying its drug PXS-5505 in patients with the bone marrow cancer myelofibrosis for 28 days at three dosage levels.

Assessment with Pharmaxis' proprietary assays of the highest dose has shown inhibition of the target enzymes, LOX and LOXL2, at greater than 90% over a 24-hour period at day 7 and day 28. The trial safety committee has reviewed the results and having identified no safety signals, has cleared the study to progress to the phase 2 dose expansion phase where 24 patients will be treated at the highest dose twice a day for 6 months.

Pharmaxis CEO Gary Phillips said, "We are very pleased to have completed the dose escalation phase of this study with such clear and positive findings.We will now immediately progress to the phase 2 dose expansion study where we aim to show PXS-5505 is safe to be taken longer term with the disease modifying effects that we have seen in the pre-clinical models. The trial infrastructure and funding is in place and we are on track to complete the study by the end of 2022."

Independent, peer-reviewed research has demonstrated the upregulation of several lysyl oxidase family members in myelofibrosis.The level of inhibition of LOX achieved in the current study at all three doses significantly exceeds levels that caused disease modifying effects with PXS-5505 in pre-clinical models of myelofibrosis with improvements in blood cell count, diminished spleen size and reduced bone marrow fibrosis. LOXL2 was inhibited to a similar degree and based on pre-clinical work such high inhibition is likely replicated for other LOX family members (LOXL1, 3 and 4).[1] Study data can be viewed in the full announcement.

Commenting on the results of the trial, Dr Gabriela Hobbs, Assistant Professor, Medicine, Harvard Medical School & Clinical Director, Leukaemia, Massachusetts General Hospital said, "Despite improvements in the treatment of myelofibrosis, the only curative therapy remains an allogeneic stem cell transplantation, a therapy that many patients are not eligible for due to its morbidity and mortality. None of the drugs approved to date consistently or meaningfully alter the fibrosis that defines this disease. PXS-5505 has a novel mechanism of action by fully inhibiting all LOX enzymes. An attractive aspect of this drug is that so far in healthy controls and in this phase 1c study in myelofibrosis patients, the drug appears to be very well tolerated. This is meaningful as approved drugs and those that are undergoing study, are associated with abnormal low blood cell counts. Preliminary data thus far, demonstrate that PXS-5505 leads to a dramatic, >90% inhibition of LOX and LOXL2 at one week and 28 days. This confirms what's been shown in healthy controls as well as mouse models, that this drug can inhibit the LOX enzymes in patients. Inhibiting these enzymes is a novel approach to the treatment of myelofibrosis by preventing the deposition of fibrosis and ultimately reversing the fibrosis that characterizes this disease."

The phase 1c/2a trial MF-101 cleared by the FDA under the Investigational New Drug (IND) scheme aims to demonstrate that PXS-5505, the lead asset in Pharmaxis' drug discovery pipeline, is safe and effective as a monotherapy in myelofibrosis patients who are intolerant, unresponsive or ineligible for treatment with approved JAK inhibitor drugs. Trial sites will now open to recruit myelofibrosis patients into the 6-month phase 2 study in Australia, South Korea, Taiwan and the USA.

An effective pan-LOX inhibitor for myelofibrosis would open a market that is conservatively estimated at US$1 billion per annum.

While Pharmaxis' primary focus is the development of PXS-5505 for myelofibrosis, the drug also has potential in several other cancers including liver and pancreatic cancer where it aims to breakdown the fibrotic tissue in the tumour and enhance the effect of chemotherapy treatment.

Trial Design

Name of trial

PXS5505-MF-101: A phase 1/2a study to evaluate safety, pharmacokinetic and pharmacodynamic dose escalation and expansion study of PXS-5505 in patients with primary, post-polycythaemia vera or post-essential thrombocythemia myelofibrosis

Trial number

NCT04676529

Primary endpoint

To determine the safety of PXS-5505 in patients with myelofibrosis

Secondary endpoints

Blinding status

Open label

Placebo controlled

No

Trial design

Randomised, multicentre, 4 week duration phase 1 (dose escalation) followed by 6 month phase 2 (dose expansion)

Treatment route

Oral

Treatment frequency

Twice daily

Dose level

Dose escalation: three escalating doses

Dose expansion: one dose

Number of subjects

Dose escalation: minimum of three patients to maximum of 18 patients

Dose expansion: 24 patients

Subject selection criteria

Patients with primary or secondary myelofibrosis who are intolerant, unresponsive or ineligible for treatment with approved JAK inhibitor drugs

Trial locations

Dose escalation: Australia (2 sites) and South Korea (4 sites)

Dose expansion: Australia, Korea, Taiwan, USA

Commercial partners involved

No commercial partner

Reference: (1) doi.org/10.1002/ajh.23409

AUTHORISED FOR RELEASE TO ASX BY:

Pharmaxis Ltd Disclosure Committee. Contact: David McGarvey, Chief Financial Officer and Company Secretary: T +61 2 9454 7203, E david.mcgarvey@pharmaxis.com.au

Join the Pharmaxis mailing listhere

Follow us on LinkedInand Twitter

About Pharmaxis

Pharmaxis Ltd is an Australian clinical stage drug development company developing drugs for inflammatory and fibrotic diseases, with a focus on myelofibrosis. The company has a highly productive drug discovery engine built on its expertise in the chemistry of amine oxidase inhibitors, with drug candidates in clinical trials. Pharmaxis has also developed two respiratory products which are approved and supplied in global markets, generating ongoing revenue.

Pharmaxis is developing its drug PXS-5505 for the bone marrow cancer myelofibrosis which causes a build up of scar tissue that leads to loss of production of red and white blood cells and platelets. The US Food and Drug Administration has granted Orphan Drug Designation to PXS-5055 for the treatment of myelofibrosis and permission under an Investigational Drug Application (IND) to progress a phase 1c/2 clinical trial that began recruitment in Q1 2021. PXS5505 is also being investigated as a potential treatment for other cancers such as liver and pancreatic cancer.

Other drug candidates being developed from Pharmaxis' amine oxidase chemistry platform are targeting fibrotic diseases such as kidney fibrosis, NASH, pulmonary fibrosis and cardiac fibrosis; fibrotic scarring from burns and other trauma; and inflammatory diseases such as Duchenne Muscular Dystrophy.

Pharmaxis has developed two products from its proprietary spray drying technology that are manufactured and exported from its Sydney facility; Bronchitol for cystic fibrosis, which is approved and marketed in the United States, Europe, Russia and Australia; and Aridol for the assessment of asthma, which is approved and marketed in the United States, Europe, Australia and Asia.

Pharmaxis is listed on the Australian Securities Exchange (PXS). Its head office, manufacturing and research facilities are in Sydney, Australia. http://www.pharmaxis.com.au

About PXS-5505

PXS-5505 is an orally taken drug that inhibits the lysyl oxidase family of enzymes, two members LOX and LOXL2 are strongly upregulated in human myelofibrosis. In pre-clinical models of myelofibrosis PXS-5505 reversed the bone marrow fibrosis that drives morbidity and mortality in myelofibrosis and reduced many of the abnormalities associated with this disease. It has already received IND approval and Orphan Drug Designation from the FDA.

Myelofibrosis is a disorder in which normal bone marrow tissue is gradually replaced with a fibrous scar-like material. Over time, this leads to progressive bone marrow failure. Under normal conditions, the bone marrow provides a fine network of fibres on which the stem cells can divide and grow. Specialised cells in the bone marrow known as fibroblasts make these fibres.

In myelofibrosis, chemicals released by high numbers of platelets and abnormal megakaryocytes (platelet forming cells) over-stimulate the fibroblasts. This results in the overgrowth of thick coarse fibres in the bone marrow, which gradually replace normal bone marrow tissue. Over time this destroys the normal bone marrow environment, preventing the production of adequate numbers of red cells, white cells and platelets. This results in anaemia, low platelet counts and the production of blood cells in areas outside the bone marrow for example in the spleen and liver, which become enlarged as a result.

Myelofibrosis can occur at any age but is usually diagnosed later in life, between the ages of 60 and 70 years. The cause of myelofibrosis remains largely unknown. It can be classified as either JAK2 mutation positive (having the JAK2 mutation) or negative (not having the JAK2 mutation).

Source: Australian Leukemia Foundation: https://www.leukaemia.org.au/disease-information/myeloproliferative-disorders/types-of-mpn/primary-myelofibrosis/

Forward-looking statements

Forwardlooking statements in this media release include statements regarding our expectations, beliefs, hopes, goals, intentions, initiatives or strategies, including statements regarding the potential of products and drug candidates. All forward-looking statements included in this media release are based upon information available to us as of the date hereof. Actual results, performance or achievements could be significantly different from those expressed in, or implied by, these forward-looking statements. These forward-looking statements are not guarantees or predictions of future results, levels of performance, and involve known and unknown risks, uncertainties and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this document. For example, despite our efforts there is no certainty that we will be successful in developing or partnering any of the products in our pipeline on commercially acceptable terms, in a timely fashion or at all. Except as required by law we undertake no obligation to update these forward-looking statements as a result of new information, future events or otherwise.

CONTACT:

Media: Felicity Moffatt: T +61 418 677 701, E felicity.moffatt@pharmaxis.com.au

Investor relations:Rudi Michelson (Monsoon Communications) T +61 411 402 737, E rudim@monsoon.com.au

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Pharmaxis Cleared To Progress To Phase 2 Bone Marrow Cancer Trial - WAGM

Cardiac Stem Cells Comments Off on Pharmaxis Cleared To Progress To Phase 2 Bone Marrow Cancer Trial – WAGM | October 5th, 2021

Trained as a chemist, biophysicist, internist, and cardiologist, Mark Yeager is eager to propel the Frost Institute for Chemistry and Molecular Science into a leading research center.

Even in his youth Mark Yeager could picture the door to his future. Scuffed, chipped, and almost black from layers of varnish, the old, wooden door had a frosted window with five words stenciled in glossy black: Laboratory of Dr. Mark Yeager.

Yet Yeager, the inaugural executive director of the University of Miamis Frost Institute for Chemistry and Molecular Science (FICMS), is quite happy that his new lab in the 94,000-square-foot building slated to open late next year wont even have a door. The $60 million facilitys open floor plan was designed to encourage the free flow of people and ideasand help transform the University into one of the worlds premier research centers for improving the health of humans and that of our planet.

That is the vision, but its not a fantastical vision, said Yeager, a distinguished biophysicist and cardiologist whose top priority is attracting a diverse and elite group of scientists as the institutes first faculty. It is achievable, and it will happen because the University has not wavered in its commitment to elevate STEM (science, technology, engineering, and mathematics) to advance scientific discovery. Theres something going on here thats organic and alive and excitingand Im thrilled to be part of it.

Yeager, whose own groundbreaking research focuses on the molecular causes of heart disease and viral infections, trained as a chemist at Carnegie-Mellon University, as a physician and biophysicist at Yale University and as an internist and cardiologist at Stanford University. He spent two decades at Scripps Research in California, where he established his first independent laboratory, served as the director of research in cardiology, and helped launch the Skaggs Clinical Scholars Program in Translational Research. He has also served as a consultant and scientific and clinical advisor to several biotech companies.

Now he is transitioning to the University from the University of Virginia School of Medicine (UVA), where he chaired the Department of Molecular Biophysics and Biochemistry for nearly a dozen years and helped establish the Sheridan G. Snyder Translational Research Building. At UVA, he also established one of the nations five regional centers for cryo-electron microscopy (cryoEM)the technique he advanced for flash-freezing, imaging, and studying proteins and other macromolecules in their near-natural state.

It is exciting to see the progress being made on the evolution of our Frost Institutes, starting with Data Science and Computing and now the emergence of Chemistry and Molecular Science. We are fortunate to have Mark overseeing our Frost Institute for Chemistry and Molecular Science and working across the entire institutionhis interdisciplinary knowledge and perspective on chemistry are essential for our success, said Jeffrey Duerk, executive vice president for academic affairs and provost. Mark brings a wealth of knowledge and experience to the University of Miami and we are looking forward to his impactful leadership continuing as we move forward.

Yeager said he knew he was making the right career move on his first visit to the University last November. Although the COVID-19 pandemic had curtailed in-person learning and suspended new construction, he heard the unmistakable sound of heavy equipment as he walked past the royal palms and fountain at the end of Memorial Drive, where the five-story FICMS now stands.

I could see an excavation area and heard a cacophony of construction noise where I had a hunch the institute should be, he recalled. That told me that the University was all in. They had made this commitment to fortify STEM and to do transformational science and nothing was going to stop them. In spite of the pandemic, it was all systems go.

The Universitys longtime benefactors, Phillip and Patricia Frost, enabled that commitment in 2017, when they announced their landmark $100 million gift to establish the Frost Institutes for Science and Engineering, now a key initiative of the Roadmap to Our New Centurythe strategic plan guiding the University toward its centennial mark. The umbrella organization for a group of multidisciplinary research centers patterned after the National Institutes of Health and its network of affiliated institutes, the Frost Institutes were envisioned to translate interdisciplinary research into solutions for real-world problems.

Though Yeager officially started his new role on June 1, he has been heavily involved in planning the FICMS' interior for months. He recently placed a $20 million order to equip the facility with five different electron microscopy instruments that chemists, molecular scientists, and engineers will use to explore the molecular structure of exquisitely beam-sensitive soft materials like proteins, hard materials such as metal alloys, as well as nanomaterials comprised of soft and hard components. Along with the buildings state-of-the-art technology and the Universitys research infrastructure, hes confident its location in the heart of the Coral Gables campus will help him recruit a diverse and elite group of scientists who are exploring challenging avenues of impactful researchsomething he has been driven to do almost his entire life.

An occasional songwriter, guitar player, and jogger who in his younger days ran 18 marathons, Yeager was always fascinated by scientific discoveries that illuminated unknown and unseen worlds. A child of the Sputnik era who began entering science fairs in junior high, he began forging his own career as a physician-scientist while in high school in Colorado Springs, Colorado, where his father, an agricultural economist, settled his family after a number of job-related moves.

Inspired by an experiment in Scientific American magazine, he convinced physicians in the therapeutic radiology department at Penrose Hospital to irradiate his fruit flies so he could compare the effects of administering different doses of radiation on their eye pigments. Delivered in Styrofoam cups, his experiments on what is now called dose fractionationand used to reduce tissue damage during cancer treatmentswon him first place in the U.S. Department of Agricultures 1967 International Science Fair and a research stint in an insect toxicology lab in Berkeley, California.

The following summer, when Yeager returned to Penrose Hospital to work as an orderly, he realized that he loved patient care as much as laboratory research and began plotting how he could pursue both careers.

I just got incredible satisfaction from helping patients get out of bed and into a wheelchair, transfer to a gurney, learn to use crutches, recalled Yeager, who joins the University as one of its 100 Talents for 100 Years, a Roadmap initiative to add 100 new endowed chairs to the faculty by the Universitys 2025 centennial. But I also loved chemistry. I loved physics. I loved too many things.

After earning his undergraduate degree in chemistry from Carnegie-Mellon, he was accepted to the Medical Scientist Training Program at Yale University, where, along with his medical degree, he earned his masters degree and doctorate in molecular biophysics and biochemistry. There, he encountered the first of many trailblazing scientists, including two future Nobel laureates, who would influence his lifes work. His Ph.D. advisor, Lubert Stryer, was particularly influential. Stryer authored a premier textbook of biochemistry, pioneered fluorescence-based techniques to explore the motions of biological macromolecules, and made fundamental discoveries on the molecular basis of vision. Yeagers graduate work on rhodopsin, a photoreceptor membrane protein, triggered his fascination with elucidating the molecular bases for such diseases as sudden cardiac death, heart attacks, HIV-1, and other viral infections.

Yeager completed his medical residency and specialized fellowship training in cardiovascular medicine at Stanford University Medical Center, where he managed the pre- and post-operative care of heart transplant patients and wrote 13 chapters in the book Handbook of Difficult Diagnoses.

He also continued exploring cellular biology in the laboratory of Nigel Unwin, who had collaborated with future Nobel laureate Richard Henderson to pioneer the use of cryoEM to determine the molecular structure of membrane proteinsand inspired Yeagers groundbreaking research on gap junction channels. The electrical conduits that connect every cell in the body to its neighbor, gap junction channels play a critical role in maintaining the normal heartbeat.

That research, which Yeager continued at Scripps and at UVA, explained how gap junction channels behave in their normal state, and during an injured state, such as a heart attack. His quest to answer another question particularly relevant todayhow viruses enter host cells, replicate, and assemble infectious particlesis exemplified by his breakthrough research on the assembly, structure, and maturation of HIV-1, the virus that causes AIDS.

Today, those insights, which Yeager humbly calls a few bricks in the edifice of science, hold important clues for developing new, more effective therapies to prevent HIV-1 infection, repair injured tissue, and treat cancer and cardiovascular diseasethe kind of impactful research that the FICMS was designed to advance with collaborative partners across the University, and beyond.

As a pioneer in the field of cryo-transmission electron microscopy, a forefront technology in materials and biological research, Marks expertise and knowledge will position the University as aleader in these cutting-edge fields, said Leonidas Bachas, dean of the College of Arts and Sciences who served as the initial interim director of the FICMS. We look forward to having him lead the Frost Institute for Chemistry and Molecular Science as we continue to advance the sciences, innovate, and expand research collaborations with our faculty and industry partners.

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Distinguished physician-scientist takes the helm of first Frost Institute - University of Miami

Cardiac Stem Cells Comments Off on Distinguished physician-scientist takes the helm of first Frost Institute – University of Miami | October 5th, 2021

NEW YORK, Aug. 30, 2021 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB), global leader in allogeneic cellular medicines for inflammatory diseases, today reported operational highlights and financial results for the fourth quarter and full-year ended June 30, 2021 (FY2021).

During this calendar year we made significant progress in both regulatory and clinical outcomes for our lead product candidate, remestemcel-L, after experiencing a disappointing set-back last year said Silviu Itescu, Chief Executive of Mesoblast. We are pleased with recent recommendations by FDAs CBER to meet with the review team and address remaining CMC items for remestemcel-L in the treatment of steroid-refractory acute graft versus host disease in children. Additionally, our most recent meeting with the FDA has provided clarity on the pathway towards an emergency use authorization for remestemcel-L in the treatment of COVID ARDS.

Operational Highlights

Remestemcel-L Outcome of recent meeting with FDA on regulatory pathway for emergency use authorization in the treatment of COVID-19 ARDS:

Remestemcel-L in the treatment of steroid-refractory acute graft versus host disease (SR-aGVHD) in children:

Rexlemestrocel-L in the treatment of chronic heart failure and chronic low back pain:

Manufacturing

Financial Highlights

DETAILED CLINICAL ACTIVITIES FOR THE FISCAL YEAR FY2021

Remestemcel-L

Acute Respiratory Distress Syndrome due to COVID-19

Mesoblast recently presented results from the randomized controlled trial of remestemcel-L in 222 ventilator-dependent COVID-19 patients with moderate/severe acute respiratory distress syndrome (ARDS) at the biennial Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases conference hosted by the University of Vermont, Burlington, VT, and at the International Society for Cell & Gene Therapy (ISCT) Scientific Signatures Series event on Cell and Gene-Based Therapies in Lung Diseases and Critical Illnesses.

The presented data included improved respiratory function in patients treated with remestemcel-L, as well as 90-day survival outcomes showing remestemcel-L significantly reduced mortality by 48% at 90 days compared to controls in a pre-specified exploratory analysis of 123 treated patients under 65 years old. The trial had been halted after the third interim analysis since the 30-day primary endpoint would not be attained.

Key presentation findings were:

Mesoblast plans to move forward with an additional Phase 3 trial in COVID-19 ARDS with the next step being to agree with the FDA the final protocol and potency assay.

Inflammatory Bowel Disease Crohns Disease and Ulcerative Colitis

A randomized, controlled study of remestemcel-L delivered by an endoscope directly to areas of inflammation and tissue injury in up to 48 patients with medically refractory Crohns disease and ulcerative colitis commenced at Cleveland Clinic in October 2020. The investigator-initiated study is the first in humans using local cell delivery in the gut and will enable Mesoblast to compare clinical outcomes using this delivery method with results from an ongoing randomized, placebo-controlled trial in patients with biologic-refractory Crohns disease where remestemcel-L was administered intravenously.

Rexlemestrocel-L

Chronic Heart Failure

The results from the landmark DREAM-HF randomized controlled trial in 537 treated patients with chronic heart failure with reduced left ventricular ejection fraction (HFrEF) who received rexlemestrocel-L (REVASCOR) or control sham, demonstrated that a single dose of rexlemestrocel-L resulted in substantial and durable reductions in heart attacks, strokes, and cardiac deaths. The trials primary endpoint of reduction in volume overload related hospitalizations was not achieved. The results of this trial identify New York Heart Association (NYHA) class II HFrEF patients as the optimal target population for greatest rexlemestrocel-L treatment effect, and therefore a focus for developing rexlemestrocel-L in the largest market in heart failure.

The incidence of heart attacks and strokes were reduced by 60% over a median follow-up period of 30 months following a single dose of rexlemestrocel-L in the entire population of 537 treated patients. The incidence of death from cardiovascular causes was reduced by 60% in the 206 patients with NYHA class II disease, a significant reduction which was evident in both ischemic and non-ischemic subgroups as well as diabetic and nondiabetic patients.

The results also show that the NYHA class II patients in the control group, following an initial period of approximately 20 months of disease stability, progressed to cardiac death rates in-line with NYHA class III patients. NYHA class II patients treated with a single dose of rexlemestrocel-L did not show such cardiac death progression.

The combination of the three pre-specified outcomes of cardiac death, heart attack or stroke into a single composite outcome - called the three-point major adverse cardiovascular events (MACE) is a well-established endpoint used by the FDA to determine cardiovascular risk. Rexlemestrocel-L reduced this three-point MACE by 30% compared to controls across the entire population of 537 treated patients. In the NYHA class II subgroup of 206 patients, rexlemestrocel-L reduced the three-point MACE by 55% compared to controls.

Mesoblast expects feedback from the FDA in the next quarter on the potential pathway to US regulatory approval for rexlemestrocel-L in patients with chronic heart failure.

Chronic Low Back Pain due to Degenerative Disc Disease

The results from the randomized controlled trial of its allogeneic mesenchymal precursor cell (MPC) therapy rexlemestrocel-L in 404 enrolled patients with chronic low back pain (CLBP) due to degenerative disc disease (DDD) refractory to conventional treatments indicate that a single injection of rexlemestrocel-L+hyaluronic acid (HA) carrier may provide a safe, durable, and effective opioid-sparing therapy for patients with chronic inflammatory back pain due to degenerative disc disease, and that greatest benefits are seen when administered earlier in the disease process before irreversible fibrosis of the intervertebral disc has occurred. The trial's composite outcomes of pain reduction together with functional responses to treatment were not met by either MPC group.

The rexlemestrocel-L+HA treatment group achieved substantial and durable reductions in CLBP compared to control through 24 months across the entire evaluable study population (n=391) compared with saline controls. Greatest pain reduction was observed in the pre-specified population with CLBP of shorter duration than the study median of 68 months (n=194) and subjects using opioids at baseline (n=168) with the rexlemestrocel-L+HA group having substantially greater reduction at all time points (1, 3, 6, 12, 18 and 24 months) compared with saline controls. There was no appreciable difference in the safety of MPC groups compared to saline control over the 24-month period of follow-up in the entire study population. In subjects using opioids at baseline, the MPC+HA demonstrated a reduction in the average opioid dose over 24 months, while saline control subjects had essentially no change.

There is a significant need for a safe, efficacious, and durable opioid-sparing treatment in patients with chronic low back pain due to severely inflamed degenerative disc disease. Mesoblast has filed a request and expects to receive feedback from the FDA on the pathway to US regulatory approval in patients with chronic low back pain due to degenerative disc disease.

Intellectual Property

Mesoblast has an extensive patent portfolio with over 1,000 patents and patent applications across 77 patent families, and patent terms extending through 2041. These patents cover composition of matter, manufacturing, and therapeutic applications of mesenchymal lineage cells, and provide strong commercial protection for our products in all major markets, including the United States, Europe, Japan and China. During the fiscal year Mesoblast has significantly expanded its patent portfolio, focusing on areas of its strategic commercial interests.

Licensing agreements with JCR, Grnenthal, Tasly and Takeda highlight the strength of Mesoblast's extensive intellectual property portfolio covering mesenchymal lineage cells. Mesoblast will continue to use its patents to prosecute its commercial rights as they relate to its core strategic product portfolio. When consistent with the Companys strategic objectives, it may consider providing third parties with commercial access to its patent portfolio.

DETAILED FINANCIAL RESULTS

Financial Results for the Year Ended June 30, 2021 (FY2021)

In August we entered into a contractual amendment to extend the interest-only period of its current senior debt facility to at least January 2022 and as a result no loan repayments will be required prior to January 2022. Mesoblast is in active discussions to refinance the facility.

We expect to recognize the existing US$21.9 million of remestemcel-L pre-launch inventory on the balance sheet if we receive FDA approval.

As a result of the above and other remeasurements on revaluation of assets and liabilities, the loss after tax for FY2021 was US$98.8 million compared to US$77.9 million for FY2020. The net loss attributable to ordinary shareholders was 16.33 US cents per share for FY2021, compared with 14.74 US cents per share for FY2020.

Conference Call

There will be a webcast today, beginning at 7.00pm EDT (Monday, August 30, 2021); 9.00am AEST (Tuesday, August 31). It can be accessed via:https://webcast.boardroom.media/mesoblast-limited/20210826/NaN61036c41df5665001c97fc67

The archived webcast will be available on the Investor page of the Companys website: http://www.mesoblast.com

About Mesoblast

Mesoblast is a world leader in developing allogeneic (off-the-shelf) cellular medicines for the treatment of severe and life-threatening inflammatory conditions. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of late-stage product candidates which respond to severe inflammation by releasing anti-inflammatory factors that counter and modulate multiple effector arms of the immune system, resulting in significant reduction of the damaging inflammatory process.

Mesoblast has a strong and extensive global intellectual property portfolio with protection extending through to at least 2041 in all major markets. The Companys proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

Mesoblast has completed Phase 3 trials of rexlemestrocel-L for advanced chronic heart failure and chronic low back pain. Remestemcel-L is being developed for inflammatory diseases in children and adults including steroid refractory acute graft versus host disease and moderate to severe acute respiratory distress syndrome. Two products have been commercialized in Japan and Europe by Mesoblasts licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see http://www.mesoblast.com, LinkedIn: Mesoblast Limited and Twitter: @Mesoblast

References / Footnotes

Forward-Looking Statements

This announcement includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements should not be read as a guarantee of future performance or results, and actual results may differ from the results anticipated in these forward-looking statements, and the differences may be material and adverse. Forward-looking statements include, but are not limited to, statements about the initiation, timing, progress and results of Mesoblasts preclinical and clinical studies, and Mesoblasts research and development programs; Mesoblasts ability to advance product candidates into, enroll and successfully complete, clinical studies, including multi-national clinical trials; Mesoblasts ability to advance its manufacturing capabilities; the timing or likelihood of regulatory filings and approvals, manufacturing activities and product marketing activities, if any; the commercialization of Mesoblasts product candidates, if approved; regulatory or public perceptions and market acceptance surrounding the use of stem-cell based therapies; the potential for Mesoblasts product candidates, if any are approved, to be withdrawn from the market due to patient adverse events or deaths; the potential benefits of strategic collaboration agreements and Mesoblasts ability to enter into and maintain established strategic collaborations; Mesoblasts ability to establish and maintain intellectual property on its product candidates and Mesoblasts ability to successfully defend these in cases of alleged infringement; the scope of protection Mesoblast is able to establish and maintain for intellectual property rights covering its product candidates and technology; estimates of Mesoblasts expenses, future revenues, capital requirements and its needs for additional financing; Mesoblasts financial performance; developments relating to Mesoblasts competitors and industry; and the pricing and reimbursement of Mesoblasts product candidates, if approved. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblasts actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

Release authorized by the Chief Executive.

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Operational Highlights and Financial Results for the Year Ended June 30, 2021 - GlobeNewswire

Cardiac Stem Cells Comments Off on Operational Highlights and Financial Results for the Year Ended June 30, 2021 – GlobeNewswire | September 1st, 2021

The increasing prevalence of new coronavirus variants is raising questions about how well protected those who've already had their COVID-19 shots are against evolving forms of the SARS-CoV-2 virus. Here, microbiology and infectious disease specialist William Petri of the University of Virginia answers some common questions about COVID-19 booster shots.

1. What is a booster shot?Boosters are an extra dose of a vaccine given to maintain vaccine-induced protection against a disease. They are commonly used to bolster many vaccines because immunity can wear off over time. For example, the flu vaccine needs a booster every year, and the diphtheria and tetanus vaccine every 10 years.

Boosters are often identical to the original vaccine. In some cases, however, the booster shot has been modified to enhance protection against new viral variants. The seasonal flu vaccine, most notably, requires an annual booster because the flu virus changes so rapidly.

3. Why aren't booster shots recommended for everyone yet?While vaccine-induced immunity may not last forever, it is not clear when a booster will be needed.

Encouragingly, all of the currently authorized COVID-19 vaccines induce a robust immune memory against the coronavirus. The vaccine teaches your immune system's memory B cells to produce antibodies when you're exposed to the virus. Researchers have detected high levels of memory B cells in the lymph nodes of people who received the Pfizer vaccine for at least 12 weeks after they got the shot.

Studies also suggest that authorized COVID-19 vaccines are continuing to offer protection even against emerging strains of the coronavirus. Among one study's participants, the Johnson & Johnson vaccine had 73% and 82% efficacy 14 days and 28 days post shot, respectively, at warding off severe disease from the beta variant. Another study found the Pfizer vaccine to be 88% effective against the delta variant.

4. How will I know if I need a booster?You may need to wait for an outbreak in people who have been vaccinated. Researchers are still figuring out the best way to measure the strength of someone's vaccine-induced immunity. The COVID-19 vaccines have been so effective that there are not many failures to test.

The best candidate to measure are certain antibodies the vaccine induces the immune system to make. They recognize the spike protein that allows the coronavirus to enter and infect cells. Evidence supporting the importance of anti-spike antibodies includes a study showing that the somewhat more effective mRNA vaccines like Pfizer and Moderna generate higher antibody levels in the blood than the adenovirus vector vaccines like Johnson & Johnson and AstraZeneca. In a preliminary study that has not yet been peer-reviewed, anti-spike antibody levels were lower in people who caught COVID-19 after they were vaccinated with the Oxford-AstraZeneca vaccine.

Medical workers would love to be able to give patients a blood test that would tell them how well protected they are or aren't against COVID-19. That would be a clear indication as to whether a booster shot is needed.

But until researchers know for sure how to measure vaccine-induced immunity, the next indication that boosters may be needed are breakthrough infections in older adults who have already been vaccinated. People over the age of 80 make lower levels of antibodies after vaccination, so their immunity may wane sooner than that of the general population. The elderly would also most likely be the most susceptible to new viral variants that evade the protection current vaccines provide.

5. Who does the FDA and CDC recommend get a third shot?An extra shot may be necessary for certain immunocompromised people. In one study, 39 of 40 kidney transplant recipients and a third of dialysis patients failed to make antibodies after vaccination. Another study identified 20 patients with rheumatic or musculoskeletal diseases on medications that suppress the immune system who also did not have detectable antibodies. Both of these studies were done after patients received the full vaccine dose.

Currently, the CDC recommends that the following people consider getting a third dose:

Those who are immunocompromised may wonder if the vaccine they received is successfully generating immunity in their body. A preliminary study that has not yet been peer-reviewed did find that a test that specifically targets the anti-spike antibodies the vaccines trigger may be helpful in determining whether the vaccine worked. But for now, the FDA does not recommend antibody tests to assess immunity.

6. Does my third dose need to match my first two?Likely not. Recent research has shown that mRNA vaccines, like Pfizer and Moderna, can be mixed with adenovirus-based vaccines like AstraZeneca with comparable results.

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The Covid booster shot is not for everyone. It's only meant for severely immunocompromised people - ETHealthworld.com

Cardiac Stem Cells Comments Off on The Covid booster shot is not for everyone. It’s only meant for severely immunocompromised people – ETHealthworld.com | August 19th, 2021

Abstract: Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $2. 3 Billion by 2026 . Induced pluripotent stem cells (iPSCs) hold tremendous clinical potential to transform the entire therapeutic landscape by offering treatments for various medical conditions and disorders.

New York, Aug. 05, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Induced Pluripotent Stem Cell (iPSC) Industry" - https://www.reportlinker.com/p05798831/?utm_source=GNW These cells are derived from somatic cells like blood or skin cells that are genetically reprogrammed into embryonic stem cell-like state for developing an unlimited source of a diverse range of human cells for therapeutic applications. The global market is propelled by increasing demand for these cells, rising focus on researchers in the field, and their potential application in treatment of various diseases. The market growth is supplemented by rising prevalence of several chronic disorders such as diabetes, heart disease, stroke and cancer. Moreover, increasing awareness about stem cells and associated research, potential clinical applications and rising financial assistance by governments and private players are expected to contribute significantly to the market expansion. The iPSC technique is anticipated to find extensive adoption in the pharmaceutical industry for developing efficient cell sources like iPSC-derived functional cells to support drug screening and toxicity testing.

Amid the COVID-19 crisis, the global market for Induced Pluripotent Stem Cell ((iPSC) estimated at US$1.6 Billion in the year 2020, is projected to reach a revised size of US$2.3 Billion by 2026, growing at a CAGR of 6.6% over the analysis period. Vascular Cells, one of the segments analyzed in the report, is projected to record a 7.2% CAGR and reach US$835.8 Million by the end of the analysis period. After a thorough analysis of the business implications of the pandemic and its induced economic crisis, growth in the Cardiac Cells segment is readjusted to a revised 7.9% CAGR for the next 7-year period. The demand for iPSC-derived cardiac cells is attributed to diverse applications including cardiotoxicity testing, drug screening and drug validation along with metabolism studies and electrophysiology applications.

The U.S. Market is Estimated at $767.1 Million in 2021, While China is Forecast to Reach $82.4 Million by 2026

The Induced Pluripotent Stem Cell ((iPSC) market in the U.S. is estimated at US$767.1 Million in the year 2021. China, the world`s second largest economy, is forecast to reach a projected market size of US$82.4 Million by the year 2026 trailing a CAGR of 8.5% over the analysis period. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 5.5 % and 6.8% respectively over the analysis period. Within Europe, Germany is forecast to grow at approximately 6.5% CAGR. North America leads the global market, supported by continuing advances related to iPSC technology and access to functional cells used in pre-clinical drug screening. The market growth is supplemented by increasing insights into the iPSC platform along with high throughput analysis for drug toxicity. The iPSC market in Asia-Pacific is estimated to post a fast growth due to increasing R&D projects across countries like Australia, Japan and Singapore.

Neuronal Cells Segment to Reach $336.9 Million by 2026

In the global Neuronal Cells segment, USA, Canada, Japan, China and Europe will drive the 6.4% CAGR estimated for this segment. These regional markets accounting for a combined market size of US$202.9 Million in the year 2020 will reach a projected size of US$308 Million by the close of the analysis period. China will remain among the fastest growing in this cluster of regional markets. Led by countries such as Australia, India, and South Korea, the market in Asia-Pacific is forecast to reach US$19.8 Million by the year 2026. Select Competitors (Total 51 Featured)

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Axol Bioscience Ltd.

Cynata Therapeutics Limited

Evotec SE

Fate Therapeutics, Inc.

FUJIFILM Cellular Dynamics, Inc.

Ncardia

Pluricell Biotech

REPROCELL USA, Inc.

Sumitomo Dainippon Pharma Co., Ltd.

Takara Bio, Inc.

Thermo Fisher Scientific, Inc.

ViaCyte, Inc.

Read the full report: https://www.reportlinker.com/p05798831/?utm_source=GNW

I. METHODOLOGY

II. EXECUTIVE SUMMARY

1. MARKET OVERVIEW Influencer Market Insights Impact of Covid-19 and a Looming Global Recession Induced Pluripotent Stem Cells (iPSCs) Market Gains from Increasing Use in Research for COVID-19 Studies Employing iPSCs in COVID-19 Research Stem Cells, Application Areas, and the Different Types: A Prelude Applications of Stem Cells Types of Stem Cells Induced Pluripotent Stem Cell (iPSC): An Introduction Production of iPSCs First & Second Generation Mouse iPSCs Human iPSCs Key Properties of iPSCs Transcription Factors Involved in Generation of iPSCs Noteworthy Research & Application Areas for iPSCs Induced Pluripotent Stem Cell ((iPSC) Market: Growth Prospects and Outlook Drug Development Application to Witness Considerable Growth Technical Breakthroughs, Advances & Clinical Trials to Spur Growth of iPSC Market North America Dominates Global iPSC Market Competition Recent Market Activity Select Innovation/Advancement

2. FOCUS ON SELECT PLAYERS Axol Bioscience Ltd. (UK) Cynata Therapeutics Limited (Australia) Evotec SE (Germany) Fate Therapeutics, Inc. (USA) FUJIFILM Cellular Dynamics, Inc. (USA) Ncardia (Belgium) Pluricell Biotech (Brazil) REPROCELL USA, Inc. (USA) Sumitomo Dainippon Pharma Co., Ltd. (Japan) Takara Bio, Inc. (Japan) Thermo Fisher Scientific, Inc. (USA) ViaCyte, Inc. (USA)

3. MARKET TRENDS & DRIVERS Effective Research Programs Hold Key in Roll Out of Advanced iPSC Treatments Induced Pluripotent Stem Cells: A Giant Leap in the Therapeutic Applications Research Trends in Induced Pluripotent Stem Cell Space EXHIBIT 1: Worldwide Publication of hESC and hiPSC Research Papers for the Period 2008-2010, 2011-2013 and 2014-2016 EXHIBIT 2: Number of Original Research Papers on hESC and iPSC Published Worldwide (2014-2016) Concerns Related to Embryonic Stem Cells Shift the Focus onto iPSCs Regenerative Medicine: A Promising Application of iPSCs Induced Pluripotent: A Potential Competitor to hESCs? EXHIBIT 3: Global Regenerative Medicine Market Size in US$ Billion for 2019, 2021, 2023 and 2025 EXHIBIT 4: Global Stem Cell & Regenerative Medicine Market by Product (in %) for the Year 2019 EXHIBIT 5: Global Regenerative Medicines Market by Category: Breakdown (in %) for Biomaterials, Stem Cell Therapies and Tissue Engineering for 2019 Pluripotent Stem Cells Hold Significance for Cardiovascular Regenerative Medicine EXHIBIT 6: Leading Causes of Mortality Worldwide: Number of Deaths in Millions & % Share of Deaths by Cause for 2017 EXHIBIT 7: Leading Causes of Mortality for Low-Income and High -Income Countries Growing Importance of iPSCs in Personalized Drug Discovery Persistent Advancements in Genetics Space and Subsequent Growth in Precision Medicine Augur Well for iPSCs Market EXHIBIT 8: Global Precision Medicine Market (In US$ Billion) for the Years 2018, 2021 & 2024 Increasing Prevalence of Chronic Disorders Supports Growth of iPSCs Market EXHIBIT 9: Worldwide Cancer Incidence: Number of New Cancer Cases Diagnosed for 2012, 2018 & 2040 EXHIBIT 10: Number of New Cancer Cases Reported (in Thousands) by Cancer Type: 2018 EXHIBIT 11: Fatalities by Heart Conditions: Estimated Percentage Breakdown for Cardiovascular Disease, Ischemic Heart Disease, Stroke, and Others EXHIBIT 12: Rising Diabetes Prevalence Presents Opportunity for iPSCs Market: Number of Adults (20-79) with Diabetes (in Millions) by Region for 2017 and 2045 Aging Demographics Add to the Global Burden of Chronic Diseases, Presenting Opportunities for iPSCs Market EXHIBIT 13: Expanding Elderly Population Worldwide: Breakdown of Number of People Aged 65+ Years in Million by Geographic Region for the Years 2019 and 2030 Growth in Number of Genomics Projects Propels Market Growth EXHIBIT 14: Genomic Initiatives in Select Countries EXHIBIT 15: New Gene-Editing Tools Spur Interest and Investments in Genetics, Driving Lucrative Growth Opportunities for iPSCs: Total VC Funding (In US$ Million) in Genetics for the Years 2014, 2015, 2016, 2017 and 2018 Launch of Numerous iPSCs-Related Clinical Trials Set to Benefit Market Growth EXHIBIT 16: Number of Induced Pluripotent Stem Cells based Studies by Select Condition: As on Oct 31, 2020 iPSCs-based Clinical Trial for Heart Diseases Induced Pluripotent Stem Cells for Stroke Treatment ?Off-the-shelf? Stem Cell Treatment for Cancer Enters Clinical Trial iPSCs for Hematological Disorders Market Benefits from Growing Funding for iPSCs-Related R&D Initiatives EXHIBIT 17: Stem Cell Research Funding in the US (in US$ Million) for the Years 2016 through 2021 Human iPSC Banks: A Review of Emerging Opportunities and Drawbacks EXHIBIT 18: Human iPSC Banks Worldwide: An Overview EXHIBIT 19: Cell Sources and Reprogramming Methods Used by Select iPSC Banks Innovations, Research Studies & Advancements in iPSCs Key iPSC Research Breakthroughs for Regenerative Medicine Researchers Develop Novel Oncogene-Free and Virus-Free iPSC Production Method Scientists Study Concerns of Genetic Mutations in iPSCs iPSCs Hold Tremendous Potential in Transforming Research Efforts Researchers Highlight Potential Use of iPSCs for Developing Novel Cancer Vaccines Scientists Use Machine Learning to Improve Reliability of iPSC Self-Organization STEMCELL Technologies Unveils mTeSR? Plus Challenges and Risks Related to Pluripotent Stem Cells A Glance at Issues Related to Reprogramming of Adult Cells to iPSCs A Note on Legal, Social and Ethical Considerations with iPSCs

4. GLOBAL MARKET PERSPECTIVE Table 1: World Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 2: World 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets for Years 2020 & 2027

Table 3: World Current & Future Analysis for Vascular Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 4: World 7-Year Perspective for Vascular Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 5: World Current & Future Analysis for Cardiac Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 6: World 7-Year Perspective for Cardiac Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 7: World Current & Future Analysis for Neuronal Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 8: World 7-Year Perspective for Neuronal Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 9: World Current & Future Analysis for Liver Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 10: World 7-Year Perspective for Liver Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 11: World Current & Future Analysis for Immune Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 12: World 7-Year Perspective for Immune Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 13: World Current & Future Analysis for Other Cell Types by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 14: World 7-Year Perspective for Other Cell Types by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 15: World Current & Future Analysis for Cellular Reprogramming by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 16: World 7-Year Perspective for Cellular Reprogramming by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 17: World Current & Future Analysis for Cell Culture by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 18: World 7-Year Perspective for Cell Culture by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 19: World Current & Future Analysis for Cell Differentiation by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 20: World 7-Year Perspective for Cell Differentiation by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 21: World Current & Future Analysis for Cell Analysis by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 22: World 7-Year Perspective for Cell Analysis by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 23: World Current & Future Analysis for Cellular Engineering by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 24: World 7-Year Perspective for Cellular Engineering by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 25: World Current & Future Analysis for Other Research Methods by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 26: World 7-Year Perspective for Other Research Methods by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 27: World Current & Future Analysis for Drug Development & Toxicology Testing by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 28: World 7-Year Perspective for Drug Development & Toxicology Testing by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 29: World Current & Future Analysis for Academic Research by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 30: World 7-Year Perspective for Academic Research by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 31: World Current & Future Analysis for Regenerative Medicine by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 32: World 7-Year Perspective for Regenerative Medicine by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 33: World Current & Future Analysis for Other Applications by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 34: World 7-Year Perspective for Other Applications by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

III. MARKET ANALYSIS

UNITED STATES Table 35: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 36: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 37: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 38: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 39: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 40: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

CANADA Table 41: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 42: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 43: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 44: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 45: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 46: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

JAPAN Table 47: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 48: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 49: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 50: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 51: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 52: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

CHINA Table 53: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 54: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 55: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 56: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 57: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 58: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

EUROPE Table 59: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - France, Germany, Italy, UK and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 60: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - Percentage Breakdown of Value Sales for France, Germany, Italy, UK and Rest of Europe Markets for Years 2020 & 2027

Table 61: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 62: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 63: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 64: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 65: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 66: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

FRANCE Table 67: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 68: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 69: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 70: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 71: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 72: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

GERMANY Table 73: Germany Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

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Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $2.3 Billion by 2026 - Yahoo Finance UK

Cardiac Stem Cells Comments Off on Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $2.3 Billion by 2026 – Yahoo Finance UK | August 6th, 2021

The future is quite bright for multiple myeloma. We are really homing in on the best regimen for frontline therapy in transplant-eligible and -ineligible [patient populations], Martin said. We are also closer with our recommendations to figuring out how to treat early-relapsed multiple myeloma. We have a variety of novel drugs that are approved for use to treat [patients with] late relapse. That [setting] has been our unmet medical need, [historically].

Martin, a clinical professor of medicine in the Adult Leukemia and Bone Marrow Transplantation Program; associate director of the Myeloma Program; and co-leader of the Cancer Immunology and Immunotherapy Program at the Helen Diller Family Comprehensive Cancer Center of the University of California, San Francisco; added that there are several very exciting therapies under investigation in clinical trials, including BiTEs. [These therapies] are showing unprecedented responses in very refractory patients, [including] the triple-class exposed patients, which is amazing.

He spoke with OncLive during an Institutional Perspectives in Cancer webinar on multiple myeloma. He chaired the virtual meeting which covered updates in frontline, early-, and late-relapsed multiple myeloma, immunotherapy in multiple myeloma, and frontline and relapsed/refractory amyloidosis.

Martin discussed the latest news in frontline, early relapsed, and heavily pretreated multiple myeloma, including the growing promise of quadruplets, emerging targets beyond BCMA, and the potential emergence of quadruplets, venetoclax (Venclexta), and antiviral therapy in amyloidosis.

Martin: For frontline therapy in multiple myeloma, we break [our algorithm] up [according to] patients who are fit and [unfit. Patients who are fit] can likely go to stem cell transplant. A quadruplet is going to be where we are headed, and it is going to be [a quadruplet using] the 3 different classes of drugs: a monoclonal antibody, an immunomodulatory drug [IMiD], and a proteasome inhibitor [PI], together with a steroid. [The combination of] those 4 classes of drugs [were evaluated] in the GRIFFIN [NCT02874742] and Cassiopeia trials [NCT02541383]. The GRIFFIN trial looked at daratumumab [Darzalex], lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone, whereas the Cassiopeia trial looked at daratumumab, thalidomide [Thalomid], and dexamethasone. Both [trials] showed spectacular early responses for induction therapy to [the respective] quadruplets.

Another study looked at daratumumab [plus] carfilzomib [Kyprolis], lenalidomide, and dexamethasone [KRd]. That trial too showed unprecedented early responses as frontline therapy. More studies are looking at other CD38[-directed monoclonal antibodies], like isatuximab-irfc [Sarclisa], together with lenalidomide, as well as KRd.

These quadruplets are showing fast and deep responses after 4 cycles [of treatment]. For patients who are transplant eligible, [treatment with a quadruplet] prepares them for transplant quite well. They can go into transplant with a nice, deep response and, hopefully, [derive] a deeper response after remission.

The question exists of whether the quadruplets and other therapies may take away the need for autologous stem cell transplant. Right now, transplant is still part of frontline therapy and is especially useful in patients who have high-risk disease.

In the transplant-ineligible population, the MAIA trial [NCT02252172] looked at daratumumab plus lenalidomide and dexamethasone vs lenalidomide and dexamethasone. The triplet has shown a median progression-free survival [PFS] approaching 60 months; that is just amazing for frontline therapy. We will see if quadruplets are needed in the transplant-ineligible setting.

We have several trials testing quadruplet therapy in the transplant-eligible population. Both daratumumab and isatuximab are being combined with IMiDs, PIs, and dexamethasone in a randomized fashion [vs triplet therapy]. We will see what the winner is. It will be interesting as we move forward, but right now, if we start that triplet therapy, we expect a PFS of 60 months, which is just amazing.

When we think about early relapse, what becomes important is what patients were on when they became relapsed or refractory. If they were on an IMiD, most of the time it was lenalidomide as maintenance therapy. We would then consider that patient lenalidomide refractory. In that scenario, we would use a CD38[-directed monoclonal antibody] plus pomalidomide [Pomalyst] and dexamethasone or a CD38[-directed monoclonal antibody] plus a PI and dexamethasone.

The data with daratumumab plus pomalidomide and dexamethasone, as well as isatuximab plus pomalidomide and dexamethasone, are quite good. Truthfully, my favorite [approach] is that if the patient is on an IMiD, I give an antibody together with a PI. The IKEMA [NCT03275285] and CANDOR [NCT03158688] studies have shown deep and durable responses with a CD38[-directed monoclonal antibody] plus carfilzomib and dexamethasone in the early-relapsed setting.

The CANDOR study showed a PFS of about 28 months. We still need longer follow-up from the IKEMA study to see what the PFS is going to be, but it is certainly going to be at least 28 months. Specifically, [in the IKEMA] study we showed that 30% of patients had achieved minimal residual disease [MRD] negativity with the triplet combination in the early-relapsed setting. Its unprecedented to see these deep responses with evidence of MRD negativity.

If patients have not received a CD38[-directed monoclonal antibody] as part of frontline therapy, that is what the first component should be to add for first relapse. The other regimens, which weve used before and are good, include pomalidomide, bortezomib, and dexamethasone, or pomalidomide, carfilzomib, and dexamethasone. There are multiple other choices, but those are my favorites.

In early-to-mid relapse, we usually use a ping-pong approach where we go back and forth between the categories of agents. Eventually, after 2 or 3 lines of therapy, patients have been exposed to what I call the big 5, which are lenalidomide, bortezomib, carfilzomib, pomalidomide, and a CD38-directed antibody. This is a setting which had been our unmet medical need.

We now have 3 agents that are FDA approved for that group of patients. We have selinexor [Xpovio] plus dexamethasone, which was approved based on the STORM trial [NCT02336815]. That doublet can be used in the [originally indicated] twice-weekly [dose], or given once weekly, which is much better tolerated. Often, we combine [selinexor] with another agent, such as bortezomib, carfilzomib, pomalidomide, or, even, daratumumab, so it is a kind of pick-your-partner [agent] in that regard. There are toxicities associated with selinexor, and we must follow patients closely. We cant just give them the therapy and see them in 4 weeks. We must follow their sodium closely because some patients need salt replacement, hydration, and anti-emetics.

The second [agent approved for triple-class refractory multiple myeloma] is belantamab mafodotin-blmf [Blenrep], which is an antibody-drug conjugate that targets BCMA. The poison is MMAF, which is associated with thrombocytopenia and ocular toxicity. We found that when belantamab mafodotin is used as a single agent without a steroid, the response rate was just over 30%. Patients who respond have durable responses upward of 10 or 12 months. We just have to watch patients for ocular toxicity because [belantamab mafodotin] can cause keratitis on the surface of the eye. Patients must see an ophthalmologist before each dose of belantamab mafodotin, which is dosed every 3 weeks. In my experience, [keratitis] usually occurs after the second or third dose. Most patients respond after the first or second dose, so we can see if the patient responds, and then continue or modify the regimen. We can lengthen the dose out to every 4 weeks or every 6 weeks or drop the dose from 2.5 mg/kg to 1.9 mg/kg.

Lastly, we have a new drug called melphalan flufenamide [melflufen; Pepaxto], which is a lipophilic, alkylator-based therapy. The lipophilic component gets the drug fast into cells, but it can be cleaved off the alkylator by aminopeptidases. In fact, normal cells dont have many aminopeptidases, so [melflufen] gets in and out of normal cells relatively quickly; however, the drug gets in myeloma cells, the lipophilic component is cleaved off, and the alkylator gets trapped inside the cell. [Melflufen] is [administered as] one flat dose of 40 mg every 4 weeks with weekly dexamethasone. It is tolerable; the big adverse effect [AE] is blood count suppression. Weve seen response rates in the 25% to 30% range.

The newest [therapy] on the block in what is available for patients who have had 4 prior lines of therapy is the CAR T-cell therapy ide-cel. It is BCMA directed, the original vector was known as bb2121. It is now FDA approved.

The rollout [of ide-cel] has been a little slow in terms of slot allocation, and it has been difficult for centers across the country to get patients on slots. We are hoping that the slot availability will increase over the next few months.

That said, for patients who are triple-class refractory and have had 4 prior lines of therapy, [ide-cel] is a perfect therapy. The CAR T cells have to be done at a licensed CAR T-cell center, of which there are only about 70 in the United States. That comes with some overhead because patients must move to the center and remain there for the first 30 days of therapy because of the significant toxicities associated with CAR T-cell therapy. [These AEs] are mostly cytokine release syndrome [CRS], which happens 80% to 90% of the time, and some neurotoxicity, which is reported in around 15% to 20% of patients. Patients must be followed closely and require initial hospitalization between 7 to 14 days. Then, patients must stay local [for follow-up].

There is a lot of overhead, but it is a one-and-done treatment. We collect their T cells, give them lymphodepletion, give them back the T cells, and patients are off therapy. The median PFS for ide-cel is about 12 months, so hopefully patients get 12 months of free time where they dont need therapy and have truly good quality of life, which is quite nice.

The nice thing about immunotherapy is that multiple targets are being investigated. BCMA was our first target, but we have others, such as GPRC5D and FcRH5. We have multiple different CAR T-cell therapies currently in research studies to try to build upon ide-cel.

We also have BiTEs, in which one arm binds to BCMA or whatever the target is on the myeloma cell, and the other arm looks for the immune cell in the local environment. Most of the other arms bind to CD3 on T cells to activate the T cells. [BiTEs] are a little bit different in terms of how they bind to the myeloma cell and how much they activate the T cell by binding to CD3.

That said, in the early research, most of these therapeutics as single agents have shown response rates on the order of 60% to 80%. Thats, again, unprecedented for single agents. These therapeutics are quite impressive in terms of response rates, but they are also associated with CRS and mild neurotoxicity. They require initial dosing in the hospital and patients are usually hospitalized for 7 to 10 days for step-up dosing. After that, [treatment] can be done in the outpatient setting with intermittent dosing. BiTEs vary from dosing weekly and then less frequently to every 3 weeks. Coming back to the center every 3 weeks is reasonable, even for patients who live outside the research center.

In San Francisco, we have patients coming in every 3 weeks to get their therapy and then they head back home, which is nice. However, it is ongoing therapy and patients must continue their therapy rather than receive a one-and-done treatment. This is because BiTEs are off-the-shelf products. There is not a collection and manufacturing step. These drugs are going to be given in the community eventually once they are approved. These drugs will be used in many more patients compared with CAR T-cell therapy just because of the logistics of CAR T-cell therapies, so BiTEs are exciting.

These advances [observed in multiple myeloma] have also spilled over to amyloidosis. We now have great frontline therapy for amyloidosis, as well as many irons in the fire [evaluating] ways we can treat relapsed amyloidosis. Weve had a troubled past [with] antiviral therapy in amyloidosis. However, there is renewed interest in this and, certainly, there are patients with amyloidosis who would benefit from antiviral therapy.

There is a lot of work going on in amyloidosis currently. The ANDROMEDA study [NCT03201965] has shown in randomized fashion that daratumumab plus bortezomib, cyclophosphamide, and dexamethasone [VCd] results in better organ response rates and PFS vs VCd alone, which had really been our standard therapy in amyloidosis. Going forward, patients with amyloidosis should receive this quadruplet as frontline therapy.

Patients with amyloidosis also have a high incidence of 11;14 translocations [t11;14]. Some case reports [have read out] of patients being treated with venetoclax. Ongoing research avenues are going to further investigate venetoclax with or without the combination of other drugs. Venetoclax will have a strong response rate in patients with amyloidosis and will be used for initial relapse. Eventually, [venetoclax] might be used in patients with t11;14, but those studies are being done. Approval for that is a long way down the road.

Also down the road for amyloidosis are BiTEs. BCMA is on the surface of plasma cells in amyloidosis, also, [as in multiple myeloma]. There is also a renewed interest in antiviral therapy in amyloidosis. The amyloid proteins deposit in the cell and cause significant organ toxicity, especially in the [heart] and kidneys. Antiviral therapy may enhance and quicken organ responses to improve survival for patients, including those with severe cardiac amyloidosis.

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Emerging Quadruplets, Novel Targets, and Immunotherapy Advances Personalized Medicine in Multiple Myeloma - OncLive

Cardiac Stem Cells Comments Off on Emerging Quadruplets, Novel Targets, and Immunotherapy Advances Personalized Medicine in Multiple Myeloma – OncLive | July 22nd, 2021

Cardiovascular disease, any of the diseases, whether congenital or acquired, of the heart and blood vessels. Among the most important are atherosclerosis, rheumatic heart disease, and vascular inflammation. Cardiovascular diseases are a major cause of health problems and death.

This micrograph shows a cross section of a coronary artery narrowed by an atherosclerotic plaque (purplish matter inside the artery). The extensive buildup of plaque impedes the flow of blood through the artery and to the heart's tissues.

Britannica Quiz

44 Questions from Britannicas Most Popular Health and Medicine Quizzes

How much do you know about human anatomy? How about medical conditions? The brain? Youll need to know a lot to answer 44 of the hardest questions from Britannicas most popular quizzes about health and medicine.

Life depends on the functioning of the heart; thus, the heart is involved in all death, but this does not account for its prominence in causing death. To some degree, as medical science advances, more people are saved from other illnesses only to die from one of the unsolved and uncontrolled disorders of the cardiovascular system. Some forms of cardiovascular diseases are becoming less frequent causes of death, and continued research and preventive measures may provide even greater benefits. However, changes in lifestyle and diet, including the adoption of more sedentary lifestyles and the consumption of fried foods and foods high in sugar, have resulted in increases in the incidence of otherwise preventable cardiovascular-related illness and death.

Heart disease as such was not recognized in non-technological cultures, but the beating heart and its relationship to death have always been appreciated. Sudden death, now usually attributed to heart disease, was recognized as early as the 5th century bce by the Greek physician Hippocrates and was noted to be more common in the obese. The role of disease in affecting the heart itself did not become apparent until the 17th century, when examination of the body after death became acceptable.

Gradually, the involvement of the heart valves, the blood vessels, and the heart muscle was observed and categorized in an orderly fashion. The circulation of the blood through the heart was described in 1628 by the British physician William Harvey. The recognition of the manifestations of heart failure came later, as did the ability to diagnose heart ailments by physical examination through the techniques of percussion (thumping), auscultation (listening) with the stethoscope, and other means. It was not until early in the 20th century that the determination of arterial blood pressure and the use of X-rays for diagnosis became widespread.

In 1912 James Bryan Herrick, a Chicago physician, first described what he called coronary thrombosis (he was describing symptoms actually caused by myocardial infarction). Angina pectoris had been recorded centuries earlier. Cardiovascular surgery in the modern sense began in the 1930s, and open-heart surgery began in the 1950s.

The exact incidence of heart disease in the world population is difficult to ascertain, because complete and adequate public health figures for either prevalence or related deaths are not available. Nonetheless, in the 21st century, in many parts of the world, cardiovascular disease was recognized as a leading cause of death. In the more technologically developed countries of the worldsuch as the United Kingdom and most continental European countriesarteriosclerotic heart disease (heart disease resulting from thickening and hardening of the artery walls) was one of the most common forms of cardiovascular disease. In the early 21st century in the United States, an estimated one-half of the adult population was affected by some form of cardiovascular disease; while heart disease and stroke accounted for a significant proportion of this disease burden, high blood pressure was the most common condition. In other areas of the world, such as the countries of Central Africa, other forms of heart disease, often nutritional in nature, were a common cause of death. In Asia and the islands of the Pacific, hypertensive cardiovascular disease, disease involving high blood pressure, constituted a major health hazard.

The hearts complicated evolution during embryological development presents the opportunity for many different types of congenital defects to occur. Congenital heart disease is one of the important types of diseases affecting the cardiovascular system, with an incidence of about 8 per 1,000 live births. In most patients the causes appear to fit in the middle of a continuum from primarily genetic to primarily environmental.

Of the few cases that have a genetic nature, the defect may be the result of a single mutant gene, while in other cases it may be associated with a chromosomal abnormality, the most common of which is Down syndrome, in which about 50 percent of afflicted children have a congenital cardiac abnormality. In the even smaller number of cases of an obvious environmental cause, a variety of specific factors are evident. The occurrence of rubella (German measles) in a woman during the first three months of pregnancy is caused by a virus and is associated in the child with patent ductus arteriosus (nonclosure of the opening between the aorta and the pulmonary artery). Other viruses may be responsible for specific heart lesions, and a number of drugs, including antiepileptic agents, are associated with an increased incidence of congenital heart disease.

In most cases, congenital heart disease is probably caused by a variety of factors, and any genetic factor is usually unmasked only if it occurs together with the appropriate environmental hazard. The risk of a sibling of a child with congenital heart disease being similarly affected is between 2 and 4 percent. The precise recurrence can vary for individual congenital cardiovascular lesions.

Prenatal diagnosis of congenital cardiovascular abnormalities is still at an early stage. The most promising technique is ultrasonography, used for many years to examine the fetus in utero. The increasing sophistication of equipment has made it possible to examine the heart and the great vessels from 16 to 18 weeks of gestation onward and to determine whether defects are present. Amniocentesis (removal and examination of a small quantity of fluid from around the developing fetus) provides a method by which the fetal chromosomes can be examined for chromosomal abnormalities associated with congenital heart disease. In many children and adults the presence of congenital heart disease is detected for the first time when a cardiac murmur is heard. A congenital cardiovascular lesion is rarely signaled by a disturbance of the heart rate or the heart rhythm.

Congenital cardiac disturbances are varied and may involve almost all components of the heart and great arteries. Some may cause death at the time of birth, others may not have an effect until early adulthood, and some may be associated with an essentially normal life span. Nonetheless, about 40 percent of all untreated infants born with congenital heart disease die before the end of their first year.

Congenital heart defects can be classified into cyanotic and noncyanotic varieties. In the cyanotic varieties, a shunt bypasses the lungs and delivers venous (deoxygenated) blood from the right side of the heart into the arterial circulation. The infants nail beds and lips have a blue colour due to the excess deoxygenated blood in the system. Some infants with severe noncyanotic varieties of congenital heart disease may fail to thrive and may have breathing difficulties.

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cardiovascular disease | Symptoms, Causes, Treatment ...

Cardiac Stem Cells Comments Off on cardiovascular disease | Symptoms, Causes, Treatment … | July 7th, 2021

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved an expanded label for KEYTRUDA, Mercks anti-PD-1 therapy, as monotherapy for the treatment of patients with locally advanced cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation. This approval is based on data from the second interim analysis of the Phase 2 KEYNOTE-629 trial, in which KEYTRUDA demonstrated an objective response rate (ORR) of 50% (95% CI, 36-64) (n=54), including a complete response rate of 17% and a partial response rate of 33% in the cohort of patients with locally advanced disease. Among the 27 responding patients, 81% had a duration of response (DOR) of six months or longer, and 37% had a DOR of 12 months or longer. In June 2020, KEYTRUDA was granted its first indication in cSCC, as monotherapy for the treatment of patients with recurrent or metastatic disease that is not curable by surgery or radiation.

This approval is great news for these patients and further demonstrates Mercks commitment to the skin cancer community. KEYTRUDA has shown meaningful efficacy in patients with locally advanced or recurrent or metastatic cutaneous squamous cell carcinoma that cannot be cured by surgery or radiation, said Dr. Vicki Goodman, vice president, clinical research, Merck Research Laboratories. This expanded indication reinforces the role of KEYTRUDA in this cancer type, which is the second most common form of non-melanoma skin cancer.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see Selected Important Safety Information below.

Data Supporting the Approval

The approval was based on data from KEYNOTE-629 (ClinicalTrials.gov, NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial that enrolled patients with recurrent or metastatic cSCC or locally advanced cSCC. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression.

Patients received KEYTRUDA 200 mg intravenously every three weeks until documented disease progression, unacceptable toxicity or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status.

Assessment of tumor status was performed every six weeks during the first year and every nine weeks during the second year. The major efficacy outcome measures were ORR and DOR as assessed by blinded independent central review (BICR) according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

Among the 54 patients with locally advanced cSCC treated, the study population characteristics were: median age of 76 years (range, 35 to 95), 80% age 65 or older; 72% male; 83% white, 13% race unknown; 41% Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 and 59% ECOG PS of 1. Twenty-two percent received one or more prior lines of therapy; 63% received prior radiation therapy.

The ORR was 50% (95% CI, 36-64), including a complete response rate of 17% and a partial response rate of 33%, for patients treated with KEYTRUDA. After a median follow-up of 13.4 months, the median DOR had not yet been reached (range, 1.0+ to 17.2+ months). Among the 27 responding patients, 81% had a DOR of six months or longer, and 37% had a DOR of 12 months or longer.

Among the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629, the median duration of exposure to KEYTRUDA was 6.9 months (range, 1 day to 28.9 months). Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2,799 patients with melanoma or non-small cell lung cancer treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%).

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,500 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or mUC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

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FDA Approves Expanded Indication for Merck's KEYTRUDA (pembrolizumab) in Locally Advanced Cutaneous Squamous Cell Carcinoma (cSCC) - Business Wire

Cardiac Stem Cells Comments Off on FDA Approves Expanded Indication for Merck’s KEYTRUDA (pembrolizumab) in Locally Advanced Cutaneous Squamous Cell Carcinoma (cSCC) – Business Wire | July 7th, 2021

Clinical trial data supporting the safety of the CRISPR-Cas9 genomic editing tool was presented on Monday by Intellia Therapeutics (NASDAQ:NTLA) for its lead product, NTLA-2001. The data was highly encouraging. However, despite NTLA-2001's positive early results as a potential treatment for the rare disease transthyretin (TTR) amyloidosis, there's still a long way to go before Intellia could bring it to market.

In transthyretin amyloidosis, cells in the liver produce misfolded TTR proteins, which accumulate throughout the body, causing debilitating complications that can involve the digestive system, nervous system, and heart. Once symptoms appear, they grow progressively worse, and the disease leads to death within a median of 4 to 17 years among patients with nervous system involvement, and 2 to 6 years among patients with cardiac involvement.

NTLA-2001 edits the genes in those liver cells, removing the segment that produces those lethal misfolded proteins.

Worldwide, an estimated 250,000-550,000 people suffer from some form of amyloidosis.

IMAGE SOURCE: GETTY IMAGES.

An interim readout from Intellia's ongoing phase 1 trial found that a single high-dose infusion of NTLA-2001 led to an 87% mean reduction in the amount of misfolded TTR in patients' bloodstreams, with a maximum reduction of 96% by day 28 in one patient. Encouragingly, no serious adverse events were observed in the six study participants. While this is a small pilot study, in previous studies of NTLA-2001 in mice, the maximum reductions in TTR persisted for 12 months after a single treatment.

All of this data provides an early indication that CRISPR gene therapies are safe and efficacious as treatments for at least some genetic diseases.

There are other treatments on the market for TTR amyloidosis, but one thing that would set CRISPR apart is the relative simplicity of administering it. And that factor could lead insurers to favor CRISPR treatments for certain rare and debilitating diseases such as TTR amyloidosis and hemophilia.

For example, Alnylam's (NASDAQ:ALNY) RNA-silencing therapy Onpattro requires an infusion every three weeks at a clinician's office. Ionis Pharmaceuticals' (NASDAQ:IONS) Tegsedi requires regular injections, though they can be self-administered. Both are priced in the neighborhood of $345,000 per year, and Onpattro comes with the additional costs associated with going to a medical office and having an infusion set up. Then there is Pfizer's (NYSE:PFE) once-daily oral medication Vyndamax, which costs $225,000 annually.

As a one-time infusion, gene therapy may become a compelling option for both patients and insurers, particularly given the high prices of currently available treatments. Though TTR amyloidosis treatments are a niche market, in 2020, Onpattro generated sales of $306 million, Tegsedi just under $70 million, and Vyndamax $429 million. Assuming that Intellia charges more for NTLA-2001 -- a one-time treatment with bluebird bio's (NASDAQ:BLUE) gene therapy for beta-thalassemia, Zynteglo, costs about $1.8 million -- TTR amyloidosis treatment could easily become a multibillion-dollar addressable market for the biotech.

Notably, CRISPR therapy for TTR amyloidosis may also put less stress on the healthcare system than the lentivirus and adenovirus gene therapies that are further along in clinical trials. Consider, for instance, Zynteglo, which requires a significant amount of effort and processing prior to treatment. First, physicians must extract stem cells from the patient, which must then be transported to and treated by bluebird bio. In the meantime, the patient undergoes "myeloablative conditioning" -- essentially knocking down the patient's bone marrow in preparation for a transplant of the edited stem cells, which will contain a repaired version of the gene that (when mutated) causes beta-thalassemia. This complicated process requires treatment at a qualified transplant center.

By comparison, for TTR amyloidosis, NTLA-2001 requires pre-medication with steroids and antihistamines. That's it. No prolonged patient preparation at the hospital. No bone marrow suppression. No shipping the patient's stem cells to a lab. The relative simplicity of administering CRISPR therapies is just one reason for the degree of excitement they are generating.

It may also give them a lower total cost of treatment than current gene therapies, which could make these therapies more palatable to insurers. If NTLA-2001 pans out, we may see a new biotech boom, with Intellia leading the charge.

Before investors get their hopes up too much, remember that these results were from a six-person, phase 1 trial, and that Intellia now holds a market cap of roughly $11 billion. In fact, its valuation rose by about $2.8 billion in a single trading session after the interim trial data was made public. That gain was more than the current $2.1 billion market cap of bluebird bio, which already has an approved gene therapy on the market as well as a CAR-T therapy, and has two more candidates in phase 3 trials.

For further context, bluebird bio announced phase 1 results for Zynteglo in December 2014. While Zynteglo was approved for use in the EU in late 2019, bluebird bio faced some backlash on pricing, and the company isn't selling it in Germany because the two sides could not agree on pricing.

Moreover, the NTLA-2001 study excluded patients who had previously received RNA-silencing therapy, and none of these patients had previously taken Vyndamax either. How previous treatments will affect the way patients respond to NTLA-2001 is not yet known. And with hundreds of millions of dollars in revenue annually on the line, it is doubtful that Alynam, Ionis, or Pfizer will surrender this market without a fight.

In sum, Intellia will still need to conduct several years of trials, leap many regulatory hurdles, and outmaneuver an array of rivals stand before it can declare the CRISPR-Cas9 platform a winner. Not only that, but -- recognizing that future studies won't be cheap -- Intellia has already proposed another public offering of $400 million worth of common stock this week, diluting its current shareholders.

So while long-term Intellia shareholders have reason to celebrate, let bluebird bio serve as a cautionary tale. That biotech was once flying high on positive trial data, hitting a market cap of around $15.5 billion in March 2018. Since then, its shares have nose-dived by more than 80%. This despite the fact that it now has two approved therapies and two more candidates in phase 3 trials.

As such, I would be concerned about investing new money in Intellia now. I suspect it will soon reach its peak for the foreseeable future. Biotech investing can be gut-wrenchingly fickle, and investors may want to consider taking a basket approach to high-risk clinical-stage biotechs, rather than investing too heavily in a single player.

This article represents the opinion of the writer, who may disagree with the official recommendation position of a Motley Fool premium advisory service. Were motley! Questioning an investing thesis -- even one of our own -- helps us all think critically about investing and make decisions that help us become smarter, happier, and richer.

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2 Reasons to Buy Intellia -- and 1 Big Reason Why I Won't - The Motley Fool

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Global Autologous Stem Cell Based Therapies Market 2021 Outlook and Study of Top Players Regeneus, Mesoblast, Pluristem Therapeutics Inc, US STEM...

Cardiac Stem Cells Comments Off on Global Autologous Stem Cell Based Therapies Market 2021 Outlook and Study of Top Players Regeneus, Mesoblast, Pluristem Therapeutics Inc, US STEM… | July 7th, 2021

Why is the Development of Disease-Modifying Osteoarthritis Drugs (DMOADs) Required?Disease Burden

Osteoarthritis (OA) is the most prevalent arthritis globally and represents a major challenge for twenty-first century health care systems.1,2 The Global Burden of Disease 2020 report showed an increase of 9.3% and 8.2% in the age-standardized OA point prevalence and annual incidence rate from 1990 to 2017.3 The prevalence rises with increasing age; in the USA (United States of America), OA was found in 13.9% of adults aged 25 years and 33.6% for those aged 65 years respectively in 2005.4 The lifetime risk of having symptomatic knee OA is about 40% in men and 47% in women, and the risk increases to 60.5% among obese persons.5 By the year 2040, an estimated 25.9% of the total adult population will have doctor-diagnosed arthritis in the USA.6

Globally, 80% of patients with OA suffer from limitations in movement, and 25% from difficulty in performing their major daily activities of life; representing a significant impact of OA on functional impairment and disability.7 In terms of economic burden, mean per-person earnings losses caused by OA were, on average, 7548 US$ per year from 2008 to 2011.8 The mean all-cause health care utilization of working-age patients with OA is $14,521 US$ per year.9 The socio-economic costs of OA were reported to range between 0.25% and 0.50% of a countrys GDP.10 In an individual patient data meta-analysis, the pooled estimate for premature mortality revealed a 23% increased risk (95% CI 1.07, 1.42) in patients with knee OA and a 20% increased risk (95% CI 1.04, 1.37) in hip OA.11

Current OA treatment options are focused on symptomatic improvement in pain and joint function and include paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, and intra-articular medications such as steroids and hyaluronic acids.14 Surgical treatments are typically indicated only for patients with end-stage OA, as a last resort. Recently, paracetamol and opioids are only conditionally or not recommended by several scientific organisations,12,13 highlighting the importance of finding new effective treatments for OA. In addition, outcomes for patients with OA are usually suboptimal and patients remain vulnerable to the clinical consequences of the disease on pain and physical function.14

OA was previously regarded as a degenerative disorder resulting from cartilage damage;15 however, the development and utilization of modern imaging methods revealed that it results from the failure of the joint organ with a heterogeneous involvement of the whole joint structures, including cartilage damage, subchondral bone remodeling, synovial inflammation and osteophyte development.16 Therefore, OA can be defined as a complex heterogeneous syndrome with multiple joint tissue involvement of varying severity. In part as a consequence, it is a huge challenge to develop a single one size fits all therapy that may be suitable and effective for all patients with OA.17

The central hallmark in the pathologic process of OA disease is the progressive deterioration in the biological, structural and mechanical properties and function of the joint tissues, and an effective medical treatment should possess the ability to delay these processes or ideally even halt them completely. Such pharmaceutical agents that will alter the natural history of disease progression by arresting joint structural change and ameliorating symptoms, either by reducing pain or improving physical function are termed as DMOADs.18

Currently, regulatory bodies such as US Food and Drug Administration (FDA)19 and the European Medicines Agency (EMA)20 have not approved any drug as an effective DMOAD, as the approval guide requires a potential DMOAD to demonstrate a slowing in the loss of knee or hip joint space width (JSW) on x-ray with associated symptomatic improvement.17 Therefore, current OA trials for DMOAD development pipeline need to meet both clinically meaningful symptom improvement with concomitant structural benefits according to US FDAs published draft industry guidance on structural endpoints for OA published in 2018.18

Because OA is characterised by its extraordinary inter-patient variability in clinical and structural manifestations, identification of patient/disease subtypes appropriate for targeted therapy is probably one of the promising ways forward in drug development research.21,22 In addition, structural changes in OA result from complex interactions among different pathobiological pathways, which implicate a variety of catabolic factors and cytokines in the different joint tissues (molecular cross-talk).23 Therefore, a new model of classifying OA based on pathophysiological disease subtypes is needed.

These subtypes can be clinical phenotypes or molecular/mechanistic endotypes.24 A clinical phenotype can be defined as a group of observable traits (ie aetiologic factors, risk factors) that can identify and characterize a subtype in a defined population.25,26 In other words, these subgroups of patients have similar clinically observable characteristics for better identifying individuals who are at higher risk of progression (prognostic) or who are more likely to respond to a specific intervention (prescriptive).27,28

An endotype is a disease subtype defined by distinct pathophysiologic mechanisms, including cellular, molecular and biomechanical signalling pathways.29 Therefore, the endotype is distinct from a phenotype, and indicates the presence of a well-defined molecular mechanism. A given clinical phenotype of OA may comprise overlapping molecular endotypes (ie, different mechanisms giving rise to the same manifestation at varying degrees during different phases of the disease).24

From the point of view of targeted drug discovery, where identifying and directing the right pathobiological mechanism and structural manifestations of disease is key for success, drug development in OA should be based on the endotypes as the basis of the main drivers of OA disease.30 In this review, we will, therefore, focus on currently ongoing phase 2 and 3 clinical trials of active drug development (Figure 1) related to three main molecular/mechanistic endotypes: 1) Cartilage-driven endotype, 2) Bone-driven endotype, 3) Inflammation-driven endotype. While each drug has been assigned to and is discussed under one endotype based on its predominant activity, a particular therapeutic may have broader endotype-effects and where present, these are duly noted.

Figure 1 Active drugs related to the three main molecular or mechanistic OA endotypes (phase 2 and 3).

One author (WMO) conducted electronic and manual searches on the https://clinicaltrials.gov/ for identifying ongoing phase 2/3 clinical trials in active drug development pipelines, as well as electronic database searches in the PubMed and Embase via Ovid for published reports of phase-2/3 clinical trials results from the inception of these databases to 31st March 2021 using the following MESH or keywords: osteoarthritis OR osteoarthrosis AND DMOAD/ OR structure modification OR disease-modifying osteoarthritis drugs/.

Cartilage damage is considered as a central part of OA disease process, which involves a variety of catabolic and reparative mechanisms at the molecular level. The pharmaceutical drugs in phase 2 and 3 stages of development for cartilage-driven endotype are summarized in Table 1.

Matrix-degrading enzymes in the joint such as collagenases and aggrecanases are responsible for proteolysis of extracellular matrix components such as type II collagen and aggrecan, which is the most abundant proteoglycan in cartilage.31 Proteinases such as matrix metalloproteinase 13 (MMP13) and ADAMTS5 (a Disintegrin And Metalloproteinase with ThromboSpondin-motif-5) are involved in cartilage destruction and progression of cartilage damage in OA pre-clinical models.32,33 The potential benefits of MMP inhibitors in preserving the OA joint have been investigated. However, in patients with knee OA, broad-spectrum MMP inhibitors such as PG-116800 showed reversible musculoskeletal toxicities in a dose-dependent manner without clinical benefits, leading to the termination of further development of this drug.34

S201086/GLPG1972 is a potent and highly selective active site inhibitor of ADAMTS5. It possesses an excellent selectivity profile in animal models and high stability in dog and human liver microsomes and hepatocytes.35 Phase-1 clinical studies revealed favorable pharmacokinetics as well as a strong and consistent target engagement in both healthy subjects and OA patients (n=171).36 In a phase-2 study (Roccella study) which investigated the efficacy and safety profile of three different once-daily oral doses of GLPG1972/S201086 (n=932), the change in cartilage thickness [in mm (SD)] of central medial tibiofemoral compartment of the target knee via quantitative MRI was 0.116 (0.27) for the placebo group and 0.068 (0.20), 0.097 (0.27) and 0.085 (0.22), for the low, medium and high dose, respectively. There was no statistically significant difference versus placebo in both MRI and clinical outcome measures.37 Another ADAMTS5-targeting agent, M6495 an anti-ADAMTS5 Nanobody (Ablynx), showed an acceptable safety profile and dose-dependent effects in a phase-1 study.38

Sprifermin is a recombinant human fibroblast growth factor 18 (FGF18) which binds to fibroblast growth factor receptor-3 (FGFR-3) in cartilage.39 It stimulates the proliferation of articular chondrocytes and induces hyaline extracellular matrix synthesis in rat OA models.40 At the cellular level, intermittent administration may transiently promote an anabolic effect, while continuous administration may stimulate other signalling pathways, leading to a weaker effect.41

Lohmander et al reported in 2014 that intra-articular (IA) sprifermin administration did not improve medial tibiofemoral cartilage-thickness over 12 months quantified by MRI (n=168) possibly as follow-ups were too short for detection of the full disease-modifying effect of treatment.39 However, a significant dose-dependent response was detected in total and lateral tibiofemoral cartilage-thickness and radiographic JSW over 12 months. The authors speculated that the dynamic loading implicated in predominantly medial tibiofemoral involvement seems to impede attempts to prevent cartilage loss or regenerate cartilage tissue. Sprifermin had no major local or systemic adverse events compared with placebo. Conference abstracts published in 2015 and 2016 reported the structure-modifying effects on cartilage thickness and bone marrow lesions (BMLs) on MRI on 12-month follow-up, using post-hoc analyses of the same study.42,43

In another clinical trial in which Sprifermin was administered up to 300 g for advanced knee OA, it was reported in 2016 that no significant benefits were detected for cartilage outcomes on histology, synovitis, effusion, BMLs on MRI and JSW on X-ray. However, the study was underpowered as MRI was only available in 30 out of 52 patients and the follow-up period was only 24 weeks, which may be too short for capturing the structure-modifying effects.44

In a 5-year, phase 2 dose-finding, multicenter randomized clinical trial [FGF18 Osteoarthritis Randomized Trial with administration of Repeated Doses (FORWARD) study], the effects of Sprifermin on changes in total femorotibial joint cartilage thickness (n=549) on MRI was evaluated at 2-year follow-up (NCT01919164). Hochberg et al reported in 2019 that three once-weekly IA injection of 100 g sprifermin provided a significant improvement in total femorotibial joint cartilage thickness [0.05 mm (95% CI, 0.03 to 0.07 mm)] for participants administered every 6 months and [0.04 mm (95% CI, 0.02 to 0.06 mm)] for participants administered every 12 months, compared with the placebo saline injection provided every 6 months (0.02 mm).45 No significant improvement in total WOMAC scores was detected, compared with placebo. The most frequently reported treatment-emergent adverse event was arthralgia and showed no difference from the placebo group (43%). An exploratory analysis of the same study at 3 year-follow-up (n=442) reveals significant differences (0.05 mm [95% CI, 0.030.07 mm]) in total femorotibial joint cartilage thickness over MRI between Sprifermin (100 g of Sprifermin every 6 months) and placebo (saline every 6 months).45 However, the clinical significance of a 0.05-mm increase of cartilage thickness in this study remains unclear in terms of reducing risk for knee replacement, delaying time towards knee replacement, or both.46 No significant change in total WOMAC scores in this study may be attributed to using intra-articular saline injections as a control since the IA saline injection may act as an active placebo,47 masking symptomatic benefits. In addition, a large number of patients with low baseline pain and/or high baseline cartilage thickness may result in a potential floor effect on symptoms as 32% of this study had <40/100 points on WOMAC pain score at baseline and 50% had medial minimum joint space width (mJSW) >4.0 mm on baseline X-rays. Therefore, analysis of a more selective subgroup, featuring baseline characteristics associated with rapid structural and symptomatic OA progression should be investigated. In a 2019 ACR conference abstract, it was reported that in a subgroup at risk (n=161) of structural and symptomatic progression with a baseline medial or lateral mJSW between 1.5 and 3.5 mm and WOMAC pain score of 4090 out of 100, WOMAC pain was significantly improved on 3 year follow-up [8.8 (22.4, 4.9)] in the group administered with the 100 g Sprifermin (n=34) compared with the placebo (n=33)48 suggesting that, in this subgroup, the drug effect reaches the absolute minimal clinically important improvement for the WOMAC pain subscore which ranges 69.49

In a recent 2020 paper using a post-hoc analysis of the same data from the FORWARD study, thinning/thickening scores and ordered values of femorotibial cartilage thickness change on MRI over 24 months were analyzed by applying location-independent (ie not region-specific) analysis methodology in the knee joint.50 With administration of 100g Sprifermin every 6 months cartilage thickening is more than double [856m (717 to 996) vs 356m (313 to 398)] and cartilage thinning almost reduced to [432m (521 to 343) vs 335m (381 to 288)] that in healthy reference subjects from the Osteoarthritis Initiative dataset (n=82). The authors concluded that the finding supported the evidence of substantial structure-protective action of Sprifermin. However, as this is a post-hoc analysis, further study will be required to confirm its structure-modifying effect.

At a molecular level, the regulation of Wnt signalling determines osteoblast and chondrocyte lineage specification and their homeostasis.51 Increased Wnt signaling predisposes MSCs to an osteogenic lineage fate and induces generation of metalloproteinases which can cause cartilage degradation in OA.52 Increased expression and activation of the Wnt pathway in articular cartilage chondrocytes in OA similarly promotes cartilage degradation, while elevated Wnt signalling in subchondral bone enhances bone formation and sclerosis.5355 Therefore, pharmacological modulation of Wnt signaling might have potential benefits in repairing osteochondral dysregulation detected in OA disease process. Moreover, increased Wnt signaling in the synovium may potently lead to the OA progression via increased production of MMPs as well as activation of osteoclast differentiation and enhanced subchondral bone turnover.56,57

Lorecivivint (SM04690) is a small-molecule CLK/DYRK1A inhibitor that blocks Wnt signalling at the transcriptional level.58 It showed induction of chondrogenesis and reduction in cartilage degradation in preclinical studies.5860 In a 52-week, multicenter, phase-2 trial (n=455) (NCT02536833), the primary end point, a significant improvement in the WOMAC pain score compared with placebo at week 13, was not met, compared with IA placebo saline injection, However, at 52-week follow-up, intra-articular administration of 0.07 mg demonstrated a significant benefit in pain and functional scores [between-group difference versus placebo, 8.73, 95% CI (17.44, 0.03) and 10.26, 95% CI (19.82, 0.69)], as well as improvement in mJSW on X-rays [between-group difference versus placebo, +0.39 mm, 95% CI (0.06, 0.72)] in patients with unilateral knee OA. Serious adverse events were reported in 17 (3.7%) patients.61 The most common SAEs included infections and cardiac disorders and were deemed unrelated to the study drug by the investigators.62

Another phase-2 trial evaluated in 700 patients for 24 weeks was completed (NCT03122860) where the 0.07 mg lorecivivint treatment group demonstrated more favorable reductions in both WOMAC indices as compared with placebo.63 Recently, the investigators reported the safety data after the combined analysis of the two trials, which included 848 Lorecivivint-treated and 360 control subjects in total. The incidence of adverse effects or serious adverse effects was similar in treatment (41.3% and 2.4%) and control groups (38.3% and 1.1%), respectively. The most commonly reported AE in both groups was arthralgia (7.6% vs 7.2%).64 Two small phase-2 (NCT03727022, NCT03706521) and three phase-3 (NCT03928184, NCT04385303, NCT04520607) trials are still active.

Transforming growth factor- (TGF-) induces extracellular matrix protein synthesis and modulates cartilage development. A variety of TGF- signalling pathways are crucial for early cartilage growth, maintaining cartilage homeostasis in later life and may also possess anti-inflammatory and immunosuppressive properties.65 Impaired TGF- function in cartilage might be related to an increased susceptibility to OA.66 However, the biological effect of TGF- is under complex control, and may switch from being protective in normal joints to detrimental in OA as a result of changes in the predominant cell-surface receptors and intra-cellular signalling pathways in various joint tissues (cartilage, bone, synovium).67 In addition, osteocyte TGF- signaling could regulate the osteogenic and osteoclastic activity of mesenchymal stem cells and may be associated with the remodeling of subchondral bone in advanced OA.68

TissueGene-C (TG-C) uses a cell-mediated cytokine gene therapy approach and includes non-irradiated allogeneic human chondrocytes and irradiated allogeneic human GP2-293 cells in a ratio of 3:1, retrovirally transduced to promote TGF-beta1 transcription (hChonJb#7 cells).6971 A recent study reported as a possible mechanism of action that TG-C induced an M2 macrophage-dominant pro-anabolic micro-environment in a rat model, thereby providing a beneficial effect on cartilage regeneration.72 At one-year follow-up after a single IA administration, there were significant improvements in pain, sports activities and quality of life but structure-modifying effects on the cartilage were insignificant (n=156).73 In a phase-2 trial (NCT01221441) including 57 patients in the treatment group and 29 patients in the placebo group, the TG-C administration caused less progression (47.9% vs 34.6%; adjusted RR 0.7, 95% CI 0.51.1) of cartilage damage than placebo over 12-months.69 In a phase-3 trial (NCT02072070) which included 163 patients, symptomatic benefit was detected.74

The two pivotal phase-3 trials (NCT03203330, NCT03291470) had been on hold in April 2019 while the regulators were investigating chemistry, manufacturing, and control issues related with the potential mislabeling of ingredients.75 This clinical hold was lifted in April 2020, and trial enrollments have been reinitiated later in 2020.76 Recently, analysis of the safety data from an observational long-term safety follow-up trial showed that there is no evidence to suggest that injection of TG-C was associated with increased risk of cancer nor generated any long-term safety concerns over an average 10 years.71

Senescence is characterized mainly by altered responses to cellular stress and proliferation arrest of cells.77 Senescent cells (SnCs) are a newly implicated factor in the OA pathogenic process78 by promoting pathological age-related deterioration via the production of proinflammatory cytokines, chemokines, extracellular proteases, and growth factors (termed the senescence-associated secretory phenotype (SASP))79 and altering the function of neighbouring cells (termed secondary or paracrine senescence).80 Therefore, senotherapeutics which are directed at SnCs are an emerging therapy for treating diseases related to ageing. Senotherapeutics can be classified into of 3 types: 1) senolytics which kill and destroy SnCs selectively; 2) senomorphics which modulate or even reverse the phenotype of SnCs to those of young cells by blocking SASP; 3) senoinflammation, the immune system-mediated clearance of SnCs.81 Several senolytic pharmaceutical drugs such as Fisetin and UBX0101 are emerging.

Fisetin is a polyphenol extracted from fruits and vegetables and shows potential senolytic and anti-inflammatory activities.82 Fisetin inhibited IL-1-induced MMP13 and ADAMTS5 expression in human OA chondrocytes in vitro, and reduced cartilage damage along with subchondral bone thickening and synovitis in a mouse OA model induced by destabilization of the medial meniscus (DMM).83 Two phase-2 clinical trials (NCT 04210986, NCT04815902) are under investigation in patients with knee OA and estimated to be completed in 2022 and 2025, respectively.

UBX0101 is a small molecule inhibitor of the MDM2/p53 protein interaction, which possesses a potent senolytic candidate. In a preclinical study, UBX0101 improved chondrogenesis in human OA tissue in vitro, and in an anterior cruciate ligament transection (ACLT) OA model in mice UBX0101 attenuated SnCs by stimulating apoptosis, and reduced cartilage damage and joint pain.84 The amount SnCs in human OA synovial tissues positively correlated with knee pain, disease severity and synovitis severity.85 A phase-1 study (n=48) revealed that a single intra-articular injection of UBX0101 at different doses up to 4 mg had a favorable safety profile and dose-dependent, clinically meaningful improvements in pain on Numeric Rating Scale (010) [3.95 (95% CI, 4.74, 3.16)] and WOMAC function [1.05 (95% CI, 1.36,-0.74)] compared with placebo injection. Recently, UNITY Biotechnology announced 12-week data from UBX0101 Phase-2 Clinical Study (NCT04129944) which did not detect a significant change in pain and function in 183 patients with painful knee OA.86 A follow-up observational study of the previous trial (NCT04349956) was terminated in November 2020 due to failure to meet the trial outcomes.

Subchondral change in OA involves an uncoupled remodelling process, which is characterized by both increased osteoblast activation and bone formation but simultaneously macrophage infiltration and osteoclast formation.87 Activation of osteoclasts can result in pain genesis through developing acidic conditions at the osteochondral junction, thereby activating acid-sensing receptors of sensory neurons.88,89 Subchondral bone also undergoes remarkable alterations in both composition and structural organization, leading to adverse effects on the overlying articular cartilage.90 Therefore, targeting the pathways that modify subchondral bone turnover is an attractive option for DMOAD research.89 The pharmaceutical drugs in phase 2 and 3 stages of development for bone-driven endotype are summarized in Table 2.

Table 2 The Registered Phase 2/3 Clinical Trials on Compounds with Potential Disease-Modifying Effects on Subchondral Bone

Cathepsin K is a cysteine protease which induces bone resorption and cartilage damage through the breakdown of key bone matrix proteins.91,92 Cathepsin K knock out mice had attenuated cartilage damage in OA induced by DMM, and inhibition of Cathepsin K in rabbits by daily oral dosing with L-006235 reduced cartilage damage and subchondral bone remodelling in an ACLT model of OA.93,94

MIV-711 is a selective cathepsin K inhibitor, and in a 6-month phase 2 clinical trial (NCT02705625) (n=244), significantly reduced femoral bone disease progression and reduced cartilage loss, although there was no improvement in pain outcome.95 Infrequent musculoskeletal symptoms, infections and rashes were reported. A further 6-month open-level extension study showed the maintenance of structural benefit with symptomatic improvement (n=50).96 However, as most of the participants in the extension sub-study were selected because their symptoms did not worsen, a treatment benefit may be due to positive selection bias.95

Recombinant human PTH, teriparatide, is a 134 amino-acid fragment acquired from human PTH). Its anabolic action on bone production is used for osteoporosis management. In OA, it exhibits the ability to maintain articular cartilage health,97 stimulate the synthesis of extracellular matrix and induce chondrocyte proliferation in pre-clinical injury-induced OA models.98 PTH can increase subchondral bone mineral density, which could exert a negative effect on OA progression. In this sense, PTH could be an excellent drug in OA patients with osteoporosis and low subchondral sclerosis.99 Additionally, intermittent parathyroid hormone treatment attenuates OA pain in a DMM model, in association with inhibiting subchondral sensory innervation, subchondral bone deterioration, and articular cartilage degeneration.100 A phase-2 study is currently ongoing to evaluate the efficacy of PTH in knee OA participants (NCT03072147).

TPX-100 is a novel 23-amino-acid peptide derived from MEPE, a member of the Small Integrin-Binding Ligand, N-linked Glycoprotein (SIBLING) protein family, involved in subchondral bone remodeling.101 TPX-100 provided symptomatic improvements in patellofemoral OA knees administered with 4 weekly 200 mg injections compared with placebo injection in the contralateral knees (n=93), but only 14% of knees showed changes in cartilage thickness/volume measured on MRI over 12 months with no evidence of structural modification. No drug-related SAEs occurred in this study.102 Another 2020 OARSI conference abstract reported a statistically significant decrease in pathologic bone shape change in the femur at both 6 and 12 months using 3D femoral bone shape change.103

Antiresorptive drugs have shown reduction in bone remodeling and improvement in trabecular microarchitecture and bone mineralization. In clinical trials investigating the structure-modifying effects of bisphosphonates (alendronate, risedronate, zoledronic acid), the results are inconsistent across the studies and their outcomes presented a great heterogeneity.17,104 In a recent systematic review including preclinical studies (n=26) over the past two decades (20002020), these drugs showed better chondroprotective effects at high doses with a dose-dependent manner as well as depending on the timing of treatment initiation in relation to OA stage (time-dependency).105 Therefore, these agents may still be of potential benefits in certain OA endotypes with high rates of subchondral bone turnover. This phenotype-dependency has been demonstrated in pre-clinical research, where bisphosphonates are differentially effective in reducing pain and not only bone but also cartilage pathology in OA models with high versus low bone turnover.106109 Recently, clodronate (n=74)110 and neridronate (n=64)111 have been successfully used for the treatment of knee and hand OA, with an interesting efficacy on BMLs, although the sample sizes are small. An individual patient data meta-analysis for examining their efficacy in specific knee OA subtypes is still ongoing.112

In a multicentre, randomised controlled trial involving knee OA patients with significant knee pain and MRI-detected BMLs (n = 223), 2 annual infusions with 5 mg of zoledronic acid (the most potent of all bisphosphonates) did not significantly reduce cartilage volume loss, knee pain or BML size although the study was designed for detecting effects on the bone-driven subgroup with BMLs which may likely have potential benefits from this therapy.113 It was noted that more knee replacement procedures were performed in the zoledronic acid group compared with the placebo group (9% vs 2%) in contrast with other population-based studies.114,115

Another study involving Osteoarthritis Initiative (OAI) female participants (n=346) showed that bisphosphonate therapy may be protective of radiographic knee OA progression in nonoverweight patients with earlystage OA.116 Currently, a Phase 3 study (NCT04303026) to examine its effects in hip OA is ongoing. A phase 2 study examining the effects of another anti-resorptive, denosumab, in hand OA is expected to finish in 2021 (NCT02771860).

Vitamin D has a direct impact on cartilage by inducing proteoglycan synthesis in mature chondrocytes,117 and enhances chondrocyte viability and reduces their inflammatory cytokine synthesis through activating AMPK/mTOR and autophagy.118 Active vitamin D administration reduced cartilage degradation and inflammation in models of OA in mice and rats induced by meniscal injury/meniscectomy and ACLT.118120 Out of two recently published systematic reviews, one review showed the association of vitamin D deficiency with knee OA in patients but inconsistent evidence for its role in the prevention of incidence and progression of radiographic OA,121 while the other argued that inconsistent results may be attributed to factors such as severity of knee OA, baseline level of serum vitamin D, duration of treatment, and vitamin D dosages.122 There is a need for multicentric and well-conducted randomized studies using larger samples to determine its efficacy. A small Phase 4 clinical trial is currently active (NCT04739592).

Synovial inflammation (synovitis) is an important contributing factor to the OA pathogenesis through increased local production of pro-inflammatory cytokines, chemokines, and mediators of joint tissue damage123,124 which may be amenable to a range of anti-inflammatory drugs commonly used in inflammatory rheumatic diseases. The pharmaceutical drugs in phase 2 and 3 stages of development for inflammation-driven endotype are summarized in Table 3.

Diacerein is a purified anthraquinone derivative. It involves an inhibitory action on IL-1 and its signalling pathway, possesses an anticatabolic effect on OA tissues and reduces generation of metalloproteases.125 In animal models of OA (sheep meniscectomy, canine ACLT, rabbit ACLT and partial meniscectomy) diacerein has generally shown limited long-term effect on cartilage composition or pathology, but some evidence of reducing synovitis.126129 In a 2014 Cochrane review, the authors concluded that diacerein demonstrated only a minimal symptomatic improvement in patients with unclear benefits in JSW on X-rays, compared with placebo. Diarrhoea was the main adverse event with an absolute difference of 26%.130

The EMAs Pharmacovigilance Risk Assessment Committee suspended diacerein across Europe in 2013 due to its harms overweighing benefits,131 and then re-evaluated the drug in 2014, suggesting that it remain available with restrictions to limit risks of severe diarrhoea and hepatotoxicity.132 In 2016, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) reported that diacerein had efficacy similar to that of NSAIDs with slower onset of action, suggesting that it might have some benefits for patients with contraindication to NSAID.133

Recently, results of a phase-3 clinical trial (NCT02688400) were reported where the authors explored the comparative efficacy and safety of diacerein vs celecoxib in patients with moderate and severe knee OA using a non-inferiority trial design [(6-months of diacerein 50 mg once daily for 1 month and twice daily thereafter (n = 187), or celecoxib 200 mg once daily (n = 193)]. Diacerein was non-inferior to celecoxib in reducing pain, stiffness, or functional limitations. The diacerein group had a higher number of emergent AEs (26.3%) compared with the celecoxib group (17.4%), mainly due to higher diarrhoea events (10.2% vs 3.7%). One patient in the diacerein group had three SAEs (abdominal pain, elevated transaminase and gamma-glutamyl transferase, collectively suggestive of hepatitis) which resolved spontaneously following drug withdrawal.134

In in vitro and in vivo preclinical studies, interleukin-1 (IL-1), tumor necrosis factor- (TNF-), IL-6, IL-15, IL-17, and IL-18 exhibit pro-inflammatory actions, leading to the initiation and progression of cartilage damage and joint inflammation. So far, IL-1 and TNF- have been the most extensively studied cytokines in pre-clinical research.135,136 Despite this favorable evidence in animal OA models, most clinical trials investigating the disease-modifying effects demonstrated by inhibitors of IL-1 and TNF- in OA patients failed to meet the primary and secondary endpoints such as in cases of Gevokizumab (XOMA-052),137 AMG108,138 Lutikizumab (ABT-981),139,140 anakinra,141 adalimumab142144 and etanercept.145 In a meta-analysis evaluating the efficacy of disease-modifying anti-rheumatic drugs in OA, neither IL1-inhibitors nor TNF-inhibitors possess symptomatic benefits irrespective of the joint site affected or the inflammatory phenotype (erosive or non-erosive OA).146

These failed trial results may suggest the implication of a more complicated interaction among various cytokines in the OA pathogenic process. One of the reasons for failure may be that the clinical trials were designed to detect an effect on symptoms rather than on joint structure, which is conversely the main outcome evaluated in preclinical studies, or that they are underpowered or have not followed participants for long enough to find meaningful structural effects such as proposed in the recent CANTOS trial.147 In a recent exploratory analysis of the CANTOS trial involving patients with elevated high-sensitivity C-reactive protein (hs-CRP) levels 2 mg/L and a history of myocardial infarction (n=10061), IL-1 inhibition using canakinumab may render a substantial reduction of THR/TKR rates as well as OA-related symptoms on an averaged 3.7 years follow-up.147 Although the study had some positives such as a large sample size and long-term follow-up, it was not primarily designed to investigate the DMOAD efficacy of canakinumab and many relevant OA outcomes were missing, necessitating further confirmatory studies.

IL-6 can increase the risk of radiographic OA and associated with knee cartilage damage,148 suggesting the potential role of low-level inflammation in the pathogenesis of OA. IL-6R blockage with tocilizumab contributes to cartilage preservation and increases bone volume in a mouse model of ischemic osteonecrosis,149 and reduced cartilage lesions, osteophyte formation and synovitis in DMM-induced OA in mice.150 However, male IL-6 knock out mice have increased cartilage damage and age-related OA.151 In local joint tissues, IL-6 classic signaling produces structure-protective effects, while trans-signaling leads to catabolic effects.152 This finding might suggest that selective inhibition of IL-6 trans-signaling could be a superior treatment strategy as this may inhibit deleterious IL-6 effects in OA, while maintaining protective IL-6 signaling via the classic pathway.153 Recently, in a phase-3 trial evaluating the efficacy of tocilizumab in hand OA for 12 weeks (n=104), it revealed no more effectiveness than placebo for pain relief (7.9 vs 9.9 on VAS score in the tocilizumab and placebo groups).154

Interleukin-10 (IL-10) is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. It also possesses chondroprotective effects, via reduced production of matrix metalloproteases155 as well as inhibition of chondrocyte apoptosis.156 Therefore, IL-10 could have potential benefits in OA management, both for pain improvement and suppression of the cartilage-damaging processes. Currently, there is a phase-2 clinical trial evaluating the safety and efficacy of a single injection of XT-150 (a plasmid DNA with a variant of human IL-10 transgene) in patients with knee OA (NCT04124042), and it is estimated to be complete in 2022.

In this section, we briefly put forward the reasons for failures in OA clinical trials and possible steps to overcome these barriers (Figure 2).

Figure 2 Reasons for DMOAD trial failures.

The drug will be required to demonstrate symptomatic benefits (pain and/or function) coupled with structural modifications to meet regulatory requirements as a disease-modifying agent.19,20 To date, no agent has been approved by the regulatory agencies.17 Some argue that the improvements in structural change (in the absence of any meaningful symptomatic benefits) should be a meaningful target for approval, in and of itself. However, this is unlikely to meet consumers needs as their primary reason for clinical presentation relates to symptomatic complaints.30

On the other hand, OA is a slowly progressive disease and only 14% of patients with incident OA have measurable disease progression over a 1-year period (Figure 2).157 Therefore, structure-modifying effects using targeted therapy would be optimal to delay or even avoid disease worsening and joint replacement. In OA, symptom-structure discordance is often described.158 Analysis of data from the Osteoarthritis Initiative revealed that changes in bone structure over 2 years do not translate into pain worsening until 4 years,159 suggesting that a structure-modifying drug may need longer follow-up to detect symptomatic benefit. In addition, a variety of disease outcomes using different OA subtypes (genotypes, phenotypes and endotypes) are needed to demonstrate the ability of a structure-modifying drug to directly predict for symptomatic benefits to overcome the regulatory hurdles.18

In addition, FDAs formal recognition of OA as a serious disease paves the way for using surrogate outcome measures for regulatory approval of DMOADs under accelerated approval regulations. However, two challenges need to be addressed: 1) selection/qualification of appropriate surrogate outcome measures, and 2) appropriate designs for post-marketing confirmatory studies. To overcome the first challenge, the Foundation for NIH (FNIH) OA Biomarkers Consortium initiative was established.160 For addressing the second challenge, Kraus et al proposed two major study design scenarios: 1) prospective trial continuation which continue all patients on initial drug allocation into the post-marketing approval trial until a failure threshold is achieved; and 2) separate post-marketing approval study which use different study population administered with active treatment only.161

The imaging standard in OA clinical trials has been radiographically measured mJSW which is notoriously unresponsive to change as well as possessing several other drawbacks such as issues with alignment, positioning and assuming JSW as the composite contribution of changes in other structures in this heterogeneous OA with multiple-tissue involvement.162,163 Therefore, utilization of this insensitive-to-change measure may limit our opportunity to detect any modification in what oftentimes is a slow-moving disease.

In 2015 OARSI published recommendations related to the applications of knee imaging in knee OA trials to set standards and improve quality assurance.164 Although a range of different MRI approaches have been developed to evaluate changes in overall joint structure,165167 further validation studies and evaluation of their clinimetrics are required to gain acceptance by regulatory authorities as a suitable surrogate endpoint which is the focus of the FNIH OA Biomarkers Consortium.160

In addition, the emergence of approved surrogate outcomes would allow pharmaceutical companies to examine the efficacy of the DMOADs in a shorter duration of clinical trials and reduce drug development costs. In this way, there is a possibility of instituting accelerated approval based on surrogate imaging endpoints and post-marketing approval studies to prove the longitudinal benefit-to-harm profile and the durability of the potential new therapies.161

In the study design for post-marketing approval which uses observational outcomes such as time-to-event of joint replacement surgery, considerable barriers exist in terms of need for large sample sizes due to low annual incidence rates (1.611.9%),14 long study follow-ups (>5 years at least),46 and the impact of non-disease and other subjective factors on the outcome (ie, comorbidities and/or age of the patient, costs, insurance cover, etc.).168,169 There is a lack of universal consensus criteria for guiding patient recommendations regarding joint replacement surgery, leading to differences even among treatment centres within the same region. These issues need to be adequately addressed by study design.161 There is a need for developing a criteria set to define appropriateness for total knee replacement or a virtual total knee replacement.170

Instead of utilizing the systemic route of administration which may produce undesirable systemic toxicity and off-target effects, many of the agents in the development pipeline are focused on an intra-articular route for drug delivery. This can also potentially enhance the local bioavailability, thereby maximizing therapeutic effects locally in the joint with a higher safety profile compared to systemic exposure.171 On the other hand, the marked placebo effect generated by local intraarticular administration is well-documented in the literature,172 making the assessment of symptom efficacy more challenging.30

Another issue related with the intra-articular therapy is that drugs have a short residence time within the joint.171,173 To overcome this barrier, a variety of drug delivery systems were proposed to prolong drug residence time while providing a stable concentration within the therapeutic window, leading to a reduction of side effects and better patient compliance.174 It remains unclear how long particular drugs have to remain in the joint for a meaningful symptomatic relief and/or structure-modification after an intra-articular administration. An ideal drug delivery system should comply with adequate disease modification, biocompatibility, and biodegradability while responding to its physiological environment.175

In the randomized clinical trials for IA drugs, saline is commonly used as the placebo in the control group. A recent meta-analysis examining the effects of IA saline in 50 clinical trials (n=4076) revealed significant improvement of pain severity on 0100 VAS up to 6 months [13.4 (21.7/5.1)] and WOMAC function sub-score [10.1 (12.2,-8.0)]. The pooled responder rate after saline injections using the OMERACT-OARSI criteria is 48% at 3 months and 56% at 6 months,47 challenging the concept of saline being a mere placebo.176 However, there is no evidence supporting hypotheses advocating the disease-modifying role of saline injection. Future scientifically robust studies which examined the effects of sham injections compared with saline injections are required to shed new light on this issue.

The IA therapies show a considerably larger therapeutic effect after the adjustment for the effects of IA saline, suggesting an inappropriate underestimating of the true effect of the active medication.177 Further research is required to determine the underlying mechanisms and the factors influencing the placebo response and ways to overcome it. In addition, the mechanisms of pain genesis in OA are poorly understood and thought to involve a complex interaction among local pathological processes in the OA joint and neuronal mechanisms and alterations of pain processing (ie central sensitization, especially in advanced OA).178 Further studies should focus on the effects of these interactions on the outcomes in the placebo-controlled clinical trials. It is also necessary to strictly report in each clinical trial what placebo has been used as well as the presence or absence of any additional blinded clinical evaluator, even more, if considering clinical trials with intra-articular therapies.

As OA is a heterogeneous disease with a combination of different endotypes in varying degree at different stages of the disease process, a one size fits all approach using a single therapeutic agent targeting a single target within a single endotype may be unlikely to succeed in the management of OA.179 Therefore, as in the oncology therapeutic area, combinations of drugs targeting different hallmarks of OA pathogenic process should be considered. Further research examining the potential synergistic action of combining anabolic therapies with those that downregulate catabolic factors will be required.

OA is well known for marked variations of disease expression,180 involves a variety of tissue pathologies as a whole joint disease16 and presents with different pathobiological manifestations,181 suggesting the potential value of personalised and precision medicine from the treatment perspective. Personalized medicine is used for treatment focusing on the patient based on their individual clinical characterization, considering the diversity of symptoms, severity, and genetic traits.182 In precision medicine, the molecular information maximizes the accuracy with which the patients are categorized and treated, typically applying large amounts of data for identification of patient subtypes which possess sharing specific relevant characteristics to predict diagnosis, progression, or treatment response, and to utilize appropriate therapeutic targets.183 The use of precision medicine in OA remains limited.

The implementation of private/ public initiatives, such as the Osteoarthritis Initiative, the FNIH biomarkers consortium, the European APPROACH ((Applied Public-Private Research enabling OsteoArthritis Clinical Headway)) project have contributed greatly to moving the field forward. Clinical phenotypes, endotypes, and molecular and imaging biomarkers are being identified, but the exact interplay among them and underlying mechanisms of each remain to be elucidated.24 While these biomarkers may have potential benefits in detecting those patients with the greatest risk for structural progression, their use still needs to be translated into more efficient clinical trial design and widespread clinical application.184

There remains an immense unmet need for effective and safe targeted interventions to inhibit both pain and disease progression. The complex overlapping interplay among the pathobiological OA processes and heterogeneity of clinical presentations of patients with OA, call for a universally accepted classification of phenotypes and endotypes for developing targeted disease-modifying therapy and providing the appropriate treatment in clinical setting. Although challenges exist towards the eventual management of OA by applying the concepts of personalized and precision medicine, the lessons learned through failed clinical trials, the ongoing developments of more advanced imaging and sophisticated biomarkers tools and effective drug delivery systems are leading to substantial progress in our field.

WMO is supported by the Presidential Scholarship of Myanmar for his PhD course. DJH is supported by the NHMRC Investigator Grant. VD is supported by a University of Sydney Postgraduate Award scholarship.

DJH provides consulting advice on scientific advisory boards for Pfizer, Lilly, TLCBio, Novartis, Tissuegene, Biobone. CL has provided consulting advice for Merck Serono and Galapagos Pharmaceuticals, and receives research funding from numerous pharmaceutical companies (Fidia Farmaceutici, Inter-K Peptide Therapeutics Ltd, Taisho Pharmaceutical Co. Ltd, Concentric Analgesics Inc, Cynata Therapeutics, CEVA Animal Health, Regeneus) through specific services/testing contract research agreements between and managed by The University of Sydney or the NSLHD. The authors report no other conflicts of interest in this work.

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