SAN CARLOS, Calif., May 05, 2020 (GLOBE NEWSWIRE) -- BioCardia, Inc.[Nasdaq: BCDA], a leader in the development of comprehensive solutions for cardiovascular regenerative therapies, today announced data from a recent animal study performed by the Company that demonstrate meaningful improvements in heart function for subjects treated with its allogenic (from another donor, or off the shelf) neurokinin 1 receptor positive mesenchymal stem cell (NK1R+ MSC) program for heart failure, known as CardiALLO. In addition, the Company is planning further exploration and discussion with the U.S. Food and Drug Administration (FDA) on the use of its allogenic cells for COVID-19 related Acute Respiratory Distress Syndrome (ARDS).

In the 26 animals treated with both low dose and high dose NK1R+ MSC, echocardiographic measures of cardiac ejection fraction, fractional shortening and cardiac outflow were meaningfully improved, with all three measures being statistically significant for both dosage levels over control animals.

The CardiALLO cell therapy is being developed initially to treat heart failure patients whose cells do not qualify for its lead autologous cell therapy, CardiAMP (BCDA-01).

BioCardia Chief Scientific Officer Ian McNiece, PhD, said, In light of these positive data on our allogenic NK1R+ MSC therapy, we expect to meet our internal timeline to complete our submission to the FDA for our first indication for CardiALLO, and potentially receive IND acceptance by the end of the second quarter. The MSCs that were studied are subtypes of MSC that we have delivered previously in our co-sponsored trials, which we believe have enhanced potency over MSC generated from unselected bone marrow cells. We look forward to seeing additional data from this animal study that are currently being analyzed, including histology and pathology of the heart and lungs.

COVID-19 Induced Acute Respiratory Distress Syndrome (ARDS) Exploration

The Company also intends to submit an IND for the use of its NK1R+ MSC delivered via intravenous (IV) infusion for Acute Respiratory Distress Syndrome (ARDS) caused by COVID-19.

Based on preliminary clinical reports on COVID-19, respiratory failure complicated by ARDs is the leading cause of death for COVID-19 patients.1 ARDS is a type of respiratory failure characterized by the rapid onset of widespread inflammation in the lungs.

The anti-inflammatory effects of MSC have been well-documented and MSC have been shown to reduce inflammation and injury in models of lung disease.2 The specific MSCs used in BioCardias allogenic cell therapy are expanded from cells selected for the presence of the NK1 receptor, which is known to bind to substance P, an important neuropeptide associated with inflammation throughout the body and a primary mediator of inflammation in the airways.3,4

Our NK1R+ allogenic MSC may have more potential than other MSC approaches being advanced today due to their interaction with Substance P, said BioCardia CEO Peter Altman, PhD. This COVID-19 related work will be the Companys first clinical investigation outside of the cardiac space and our first exploring therapy for the lung. A recent patent publication (US 2020/0101113 A1) shows that BioCardia has long intended for these remarkable reparative cells to be targeted for respiratory disorders, in addition to cardiovascular disease. Addressing inflammation in the lungs is an important contribution we may be able to make using our NK1R+ allogenic MSC therapy.

The Companys allogenic cells are expected to be manufactured at BioCardias clinical stage cell manufacturing facility in San Carlos, California.

About BioCardiaBioCardia, Inc., headquartered in San Carlos, California, is developing regenerative biologic therapies to treat cardiovascular disease. CardiAMP and CardiALLO cell therapies are the Companys biotherapeutic product candidates in clinical development. The Company's approved products include the Helix transendocardial delivery system and its steerable guide and sheath catheter portfolio. BioCardia also partners with other biotherapeutic companies to provide its Helix System and clinical support to their programs studying therapies for the treatment of heart failure, chronic myocardial ischemia and acute myocardial infarction.

Forward Looking Statements This press release contains forward-looking statements that are subject to many risks and uncertainties. Forward-looking statements include, among other things, references to the development of NK1R+ cells for the treatment of heart failure and ARDS secondary to COVID-19, potential FDA IND acceptances, and potential FDA filings, statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations. Such risks and uncertainties include, among others, the inherent uncertainties associated with developing new products or technologies. These forward-looking statements are made as of the date of this press release, and BioCardia assumes no obligation to update the forward-looking statements.

We may use terms such as believes, estimates, anticipates, expects, plans, intends, may, could, might, will, should, approximately or other words that convey the uncertainty of future events or outcomes to identify these forward-looking statements. Although we believe that we have a reasonable basis for each forward-looking statement contained herein, we caution you that forward-looking statements are not guarantees of future performance and that our actual results may differ materially from the forward-looking statements contained in this press release. As a result of these factors, we cannot assure you that the forward-looking statements in this press release will prove to be accurate. Additional factors that could materially affect actual results can be found in BioCardias Form 10-K filed with the Securities and Exchange Commission on April 9, 2020, under the caption titled Risk Factors. BioCardia expressly disclaims any intent or obligation to update these forward-looking statements, except as required by law.

Media Contact: Michelle McAdam, Chronic Communications, Inc.michelle@chronic-comm.com(310) 902-1274

Investor Contact: David McClung, Chief Financial Officerinvestors@BioCardia.com(650) 226-0120

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BioCardia Announces Positive Preclinical Results Supporting Investigational New Drug Application for Anti-Inflammatory Cell Therapy in Heart Failure -...

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Abstract:Vaccine therapies for treatment andprevention of cancer have seen modest degrees of efficacy with wide variationrelated to the tumor type, vaccine type, adjuvants and clinical setting fortheir study. Over the course of the last two decades, various peptide vaccinesfor breast cancer have been studied. The current leading peptide vaccine forhuman application is a HER2-based vaccine known as Nelipepimut-S, which hasdemonstrated immune activity and promising clinical activity in some settings.This review covers the development of this newer peptide vaccine for both HER2amplified and non-amplified breast cancer.

Keywords:vaccine, breast cancer, HER2, peptide,human

INTRODUCTION

The human epidermal growth factor receptor 2 (HER2) proteinhas been one of the most extensively studied and targeted markers in oncologyin the last 30 years. The identification of the HER2 receptor and thedevelopment of antibodies to target it such as trastuzumab, pertuzumab andothers, are among the most successful advances in the treatment of breastcancer in the past 50 years. The research community learned that HER2signalling through its membrane-bound tyrosine kinase domain results indownstream activation of a cascade of events leading to angiogenesis, cellularinvasiveness, proliferation and survival proficiency. It is well known thatabout 20 percent of breast cancers will have marked overexpression of the HER2receptor and will benefit from HER2 targeting agents. It is generally acceptedthat most of the other 80% of breast cancers will express HER2, but at lowerlevels. There remains debate about the potential role of the HER2 protein andHER2 targeting in lower expressing breast cancers. Nevertheless, as a targetfor either passive or active immunotherapy, HER2 has been immunogenic due toantigens such as HER2369-377(also known as the E75 peptide)that are easily recognized by T cells and dendritic cells.

The currently available agents approved for HER2-overexpressing breast cancer include: trastuzumab, ado-trastuzumab, pertuzumab, lapatinib, neratinib, most recently trastuzumab deruxtecan, and five trastuzumab biosimilars (as of 1/2020). Additionally, the novel HER2 targeted monoclonal antibody, margetuximab, and a small molecule inhibitor, tucatinib, are currently being reviewed by the US FDA for possible approvals. While some of those drugs have been tested in HER2-low settings and non-breast settings, none have been approved to date for an indication outside of HER2-high or HER2 over-expressed cancer. Likewise, vaccine strategies have tested peptides, whole cell vaccines, dendritic cell vaccines, DNA vaccines and multipeptide vaccine in both HER2-high and HER2-low settings. The present review will examine the activity, development, efficacy and safety of the E75 peptide (also known as Nelipepimut-S when combined with GMCSF) as a peptide vaccine for breast cancer. Nelipepimut-S is currently in Phase III clinical development (NCT01479244) and has strong evidence of immunologic activity, though there is mixed evidence to date of clinical activity against early stage HER2-overexpressed breast cancer and there is little clinical activity reported against advanced metastatic disease. There is emerging data on Nelipepimut-S for HER2-low and triple negative breast cancer that will be reviewed.1

METHODS: LITERATURE SEARCH, INCLUSION AND EXCLUSION CRITERIA

We performed a systematic search of peer-reviewed literaturedatabases from 11/1/2019 to 12/9/2019. This review was limited to manuscripts,abstracts and chapters available in the English language and catalogued inPubmed, Web of Science, Scopus and proceedings of national meetings including:ASCO, SITC, SABCS, ESMO (American Society of Clinical Oncology, Society forImmunoTherapy of Cancer, San Antonio Breast Cancer Symposium, and EuropeanSociety of Medical Oncology). We searched for keywords including: HER2peptide E75 peptide, Nelipepimut-S, Neu-vax, breast cancer. Weexcluded trials examining cancers other than breast cancer and other related peptidesoutside the studied amino acid sequence from HER2369-377.Multipeptide vaccine studies were included for completeness.

BACKGROUND OF NELIPEPIMUT-S

The aim of a cancer vaccine is to stimulate a cancerpatients immune system to recognize tumor associated antigens via activeimmunotherapy. Successful active immunotherapy results in T cell recognitionand killing of cells expressing the antigen of interest. Ideally, successful Tcell mediated tumor killing should lead to epitope spreading to increase therepertoire of T cells for cytolysis, and lead to long term T cell memory.Several peptide vaccines have been investigated for these purposes, and apeptide sequence that is successful to date is the E75 HER2 peptide vaccine,otherwise known as Nelipepimut-S.2This vaccine has severalpublished clinical and preclinical reports and has been studied in aregistrational phase III study.3Nelipepimut-S, or the E75vaccine, is a 9 amino acid sequence from the extracellular domain of the HER2receptor (residues 369377 of HER2neu: KIFGSLAFL4). This 9 aminoacid sequence has long been known to be the immunologically dominant epitope ofthe protein and is presented both by HLA-A2 and HLA-A3 (HLA restricted).2,5,6Thesetwo alleles represent a majority of patients with breast cancer. HER2 is ofcourse a self-antigen, but overexpression is largely limited to breast cancers(and occasionally lung, gastric and colon cancers). Surprisingly, there doesnot appear to be negative thymic selection of HER2369-377specificT cells as shown by several groups.710Thus the E75 antigenfrom HER2 is a reasonable target for a variety of immunotherapies.

During in vitro preclinical development, the E75 peptide wasrecognized by CD8+ T lymphocytes. Subsequently, it was demonstrated thatE75-stimulated cytotoxic T lymphocytes were capable of lysis of HER2-expressingcancer cell lines.4,10,11The specificity of pulsed T cells forHER2 expressing cells was replicated in mouse models of cancer.8,12Additionally,it was found by multiple groups that lymphocytes in circulation occasionallyharbor pre-existing responses against the E75, 9 amino acid sequence HER2neu369-377usedin the subsequent development of Nelipepimut-S.6,11-13Likewise,dendritic cells from normal donor blood sources have been shown to be able topresent the E75 peptide and to generate E75-specific T cells.14

CLINICALS TRIALS WITH THE E75 PEPTIDE

The earliest Phase I pilot study of the E75 peptide inhumans also incorporated a MUC1 peptide (M1.2) in an autologous dendritic cellvaccine in breast and ovarian cancer.14Among 10 patients, CD8responses to E75 and M1.2 were observed (via intracellular interferon assay andchromium release assays) in 5 patients. The authors also reported evidence ofepitope spreading in two patients after repeat vaccination.

A study by Zaks and Rosenberg (Table 1) examined theactivity of the single E75 peptide formulated with incomplete Freunds adjuvantin various solid tumors, including breast cancer. CD8 responses were againobserved in human leukocyte antigen (HLA) -A2 and HLA-A3 patients, but anergyrather than memory was the long term outcome,15possibly due tooverstimulation related to incomplete Freunds adjuvant.

Subsequently, the E75 peptide was combined with GM-CSF toattempt to overcome the anergy suspected to be due to the incomplete Freundsadjuvant in the prior study. When combined with GM-CSF, the vaccine is termedNelipepimut-S (also previously called Neu-vax). Two phase I studies of 6 and 14patients respectively with advanced disease were completed using Nelipepimut-Sby intradermal injection, and safety was observed for up to 1000 micrograms(mcg) of Nelipepimut-S along with 250mcg of GM-CSF. Immune response wasobserved by means of ELIspot and delayed type hypersensitivity analysis.16,17Patientsreceived monthly vaccinations for up to 10 months and no dose limiting toxicitywas observed.

Given the challenge of developing an immunotherapy inheavily pre-treated metastatic patients, the Nelipepimut-S was subsequentlytested in early stage, surgically resected breast cancer patients. Testing inearly stage disease was expected to be safe given the excellent safety profileobserved in the metastatic setting. Thus, a paired set of trials (NCT00841399,NCT00584789) were performed for stage II or stage III, HER2-expressing breastcancer as defined as any immunohistochemical (IHC) staining from 1+ to 3+. Thesister clinical trials (phase II) were performed in the United States and havesince been published.7,18,19In the studies, all patients wereclinically disease-free and were permitted to use concomitant endocrinetherapies as well as prior Trastuzumab therapy. The dose and schedule wereoptimized in these early adjuvant trials. Ultimately, 195 patients wereenrolled and followed for 60 months.18,19There were 100patients vaccinated and 95 control patients. In the primary analysis, with amedian 20 months follow-up after vaccination, the recurrence rates were 5.6% vs14.2% in vaccinated vs unvaccinated participants (p=0.04).20Thusthe studies met their primary endpoint. However, for secondary analysis it wasfound that the short-term recurrence difference observed at 20 months did notpersist at any of the later analyses. For example, there was no difference inrecurrence at the 26month analysis (p=0.15) nor at 60 months (p=0.08). Therewas no difference in overall survival (OS) with p value=0.1. The authorssuggested that waning immunity due to lack of boosting contributed to the lackof long term benefit of the vaccine strategy.20Interestingly,there was a higher rate of visceral metastases in the vaccine-treated patientswhen they recurred. The toxicities of this vaccine strategy included flu-likesymptoms, fatigue, and bone pain. Less than 2% of patients experienced any highgrade toxicity (highest grade=3). The study concluded that an optimal dosewould be 1000mcg and that a potential phase III trial should be performed.

In the sister Phase II trials, boosting was explored and asuggestion of benefit was observed with boosting once every 6 months.Exploratory analysis also showed that the low-grade breast cancers seemed toderive greater benefit from Nelipepimut-S vaccination than higher grade breastcancers. In a late followup report, there was only one recurrence observed inthe 21 participants with optimal dosing of booster vaccines.18

Following completion of the phase II studies, a phase IIIstudy of Nelipepimut-S as a single agent, was designed and given the acronym,PRESENT. The PRESENT study (NCT01479244) fully accrued across 197 researchsites by Galena Biopharma Inc. PRESENT was a registrational study of 758patients with early stage, node positive breast cancer with low to intermediateHER2 expression with a primary endpoint of 3 year disease free survival (DFS).Patients received either Nelipepimut-S with GM-CSF or GM-CSF alone over thecourse of six intradermal injections followed by boosting every 6 months for 3years.3The interim analysis was published in 2019 anddemonstrated no overall difference in disease free survival (DFS) between armsat 16 months follow-up. There was a numerically higher number ofimaging-detected recurrences in the Nelipepimut-S vaccinated patients (54.1%)compared to placebo (29.2%).3The phase III PRESENT study wasdiscontinued due to futility in 2016, based on that interim analysis and thedata monitoring committee recommendation. No new safety signals were reported,and no cardiac signals were seen. The protocol design required empiriccross-sectional body imaging yearly in all patients. This imaging requirementwas a deviation from the existing standard of care (which would be for no crosssectional imaging unless symptoms arise). The required cross sectional imagingmay have impacted on the early termination of the study. The control arm had arecurrence rate comparable to rates seen in contemporary trials in early stagepatients. There is some speculation about whether pseudoprogression findingsmight have been observed in the radiographic recurrences, but biopsyconfirmation was not undertaken, so no conclusion can be drawn. Given anegative phase III result in PRESENT, there is unclear future for thedevelopment of Nelipepimut-S in the node positive, HER2-low, adjuvant breastcancer population.

COMBINATION CLINICAL TRIALS WITH NELIPEPIMUT-S

Given the challenge and phase III disappointment ofdeveloping Nelipepimut-S as a stand-alone therapy, it is now also beingexamined in combinatorial studies. Preclinical data had suggested thattrastuzumab could increase cross presentation of the E75 epitope and moreefficient expansion of specific CD8+T cells. The first phaseIIb combination trial of E75 and trastuzumab (NCT01570036) enrolled 275patients with HER2 low (IHC 1+ or 2+) breast cancer in the United States andcombined Nelipepimut-S with trastuzumab.1The patients receivedeither Nelipepimut-S with trastuzumab or trastuzumab/GM-CSF. The study designwas based on the observation, during the early phase Nelipepimut-S studies,that 12 patients were concurrently exposed to trastuzumab as a standard of careand none of those 12 patients experienced recurrent breast cancer.21Inthis newer phase IIb combinatorial study of Nelipepimut-S with trastuzumab,overall, there was no statistically significant difference in DFS (p=0.18),although there was a benefit seen in the subgroup of patients deemed to betriple negative. In this subset of 97 patients, the DFS for Nelipepimut-S plustrastuzumab was 92.6% compared with 71.9% for the trastuzumab/GM-CSF group (HR=0.26, p=0.01).1This encouraging subset finding has reportedlyled to the design of an upcoming clinical trial in the triple-negative earlystage setting.

NELIPEPIMUT-S WITH TRASTUZUMAB IN HER2 IHC3+ BREAST CANCER

In a recently completed randomized phase II trial (NCT02297698), 100 patients with traditionally-defined HER2 overexpression (IHC 3+) and otherwise high risk, non-metastatic breast cancer were enrolled to 1 to 1 randomized study of trastuzumab Nelipepimut-S and followed for DFS. This study completed accrual in 2017, and interim results demonstrated that Nelipepimut-S was well tolerated, and no significant difference in side effect profile nor cardiac ejection fraction was observed between the two arms of the study.22Clinical results have not been released to date.

TRIAL OF NELIPEPIMUT-S IN DCIS OF THE BREAST

A phase II study (NCT02636582) termed the VADIS study isassessing Nelipepimut-S against GM-CSF for ductal carcinoma in situ (DCIS) inthe neo-adjuvant window of opportunity design.23The premisefor this is supported by work published by Lowenfeld et al.24Inthis ongoing VADIS study, Nelipepimut-S or GM-CSF is given as two injectionsprior to definitive breast surgery. The primary endpoint is circulating immuneresponse at 6 months after vaccination. Secondary endpoints are toxicity andsafety. The study completed accrual in July 2019, and findings are stillpending.

OTHER E75 STUDIES IN BREAST CANCER

The potential promise of Nelipepimut-S vaccines, butnegative results in the large phase III trial, raise questions of whetheralternate vaccine formulations may induce stronger and more effective immuneresponses. A recently published study created and tested a liposomalformulation of the vaccine by attaching the E75 peptide to the surface ofdistearoyl phosphocholine and distearoyl phophoglycerol of nano-liposomes forvaccination.25ELISpot analysis and flow cytometry demonstratedsignificantly enhanced antitumor responses as well as tumor inhibition andprolonged survival time in the mouse TUBO model, which is a cell line thatoverexpresses the rHER/neu protein. Thus, this approach offers promise fortranslation to human clinical trials. There is also an ongoing autologous dendriticcell vaccine of the E75 peptide in combination with vinorelbine and trastuzumabin human cancer patients at the University of North Carolina (NCT00266110).26Finally,a series of four clinical trials performed at the University of Virginiaincorporated the E75 peptide into multipeptide vaccines for breast and ovariancancer, and using either polyICLC or incomplete Freunds adjuvant, rather thanGM-CSF (NCT00892567, NCT00304096, NCT01532960, NCT00091273). Immune responseswere detected, but clinical activity was not observed.27,28

DISCUSSION

The Nelipepimut-S vaccine alone demonstrates immune activityin patients expressing HLA-A2 or HLA-A3. As detailed above, the use of theNelipepimut-S vaccine in adjuvant breast cancer settings has not led toclinically meaningful improvements in overall survival or disease free survivalin a large randomized trial to date. Nevertheless, there are hints that thisparticular vaccine may hold potential clinical value in selected settings. Forexample, a meta-analysis of the 5 human clinical trials that involvedrandomization was performed in an effort to combine data from the smallertrials. In a published meta-analysis, the delayed hypersensitivity (DTH)responses and DFS combined data across trials suggested significant benefits tovaccination over control (p<0.05 and p=0.001 respectively). The combineddata for OS and recurrence were suggested to also have relevance (p=0.863 andp=0.388).29The conclusions of the meta-analysis do notablydiffer from some of the individual trials and obviously the patient populationshad major differences, thus rendering the impact of a meta-analysis unclear.Despite the criticisms of aggregation of data in the meta-analysis, it doessuggest that in appropriate settings that the Nelipepimut-S may have clinicalbenefits for some patients without untoward toxicity. Raw data from the large750 patient randomized phase III PRESENT trial, which was stopped for futility,was not available for analysis in that meta-analysis.

Thus, vaccine researchers in breast cancer are leftwondering which direction to focus limited resources on. Clearly there isimmunogenicity when vaccinating with the E75 peptide, and it tends todemonstrate synergy with passive antibody-based immunotherapy (ie, trastuzumabcombinations). It is also intriguing that the triple negative early stagebreast cancer population may have the greatest relative benefit afterNelipepimut-S vaccination. To date, there has been little traction indeveloping combinatorial strategies with checkpoint inhibitors or with myeloidsuppressing immunotherapy strategies. With checkpoint inhibitors approved inthe metastatic triple negative setting and expected in the triple negativeadjuvant setting, it is unclear what role peptide vaccination strategies may beable to play in the future triple negative treatment landscape.

Some remaining concerns for the E75 HER2 peptide developmentinclude the criticism that the peptide is HLA restricted and thus not availableuniversally to all patients. Also there is an unresolved question about how toaddress waning immunity and the need for long-term boosting strategies. Finally,the question about how best to select patients, especially in light of majorimmune system modulation that occurs during and immediately following adjuvantchemotherapy. It remains unknown whether the rebounding immune system in the 6months following cytotoxic chemotherapy presents a stimulatory or suppressiveenvironment for peptide vaccine generally and specifically for thisNelipepimut-S vaccine. Likewise, since HER2 targeting antibodies also impact onthe immune recognition of antigens from HER2, it is further unclear whetherearly adjuvant vaccination at the time of adjuvant HER2 antibodies or followingthe course of HER2 maintenance antibodies will be optimal.

CONCLUSION

Nelipepimut-S demonstrated immune activity against HER2positive breast cancer and suggestion of activity against triple negativebreast cancer. Its development in the adjuvant HER2 low to intermediatepopulation might be unlikely to continue based on the negative phase IIIPRESENT trial. Nevertheless, several important studies are yet to be performedfor the Nelipepimut-S and related E75 vaccines, such as combinatorial studies,novel adjuvant studies, boosting strategies, and biomarker driven studies.Recently there is rising interest in vaccine therapy for breast cancer, so thisor related vaccine strategies are likely to continue to be explored. Optimalpatient selection and monitoring may aid in future development of this cancertherapy.

Acknowledgments

Drs. Dillon, Brenin and Slingluff are supported by NCIsupport grant: 2P30CA044579-26 for the University of Virginia Cancer Center.

Disclosure

Drs. Dillon and Slingluff have published studies on peptidesreferenced in this manuscript. The University of Virginia was a subsite for aclinical trial referenced in this manuscript. Dr Dillon participated in aclinical trial for Galena Pharmaceuticals. Dr. Slingluff is an inventor onlicensed patents held by the University of Virginia Licensing and Venturesgroup for peptides used in melanoma vaccines. Dr Slingluff reports grants,non-financial support from Celldex for providing antibodies for clinical trialsand for preclinical studies. He also reports grants and/or non-financialsupport from Merck, Immatics, Polynoma, and GlaxoSmithKline; non-financialsupport from Theraclion, outside the submitted work. Dr Slingluff also in theprocess of joining the scientific advisory board with CureVac. In addition, DrSlingluff has patents on peptides used in cancer vaccines with royalties paid,a pending patent on biomarkers, a patent for a surgical device issued. Theauthors report no other conflicts of interest in this work.

Patrick M. Dillon,1Christiana M. Brenin,1Craig L. Slingluff Jr2

1University of Virginia, Division of Hematology/Oncology, Charlottesville, VA 22908, USA;2University of Virginia, Department of Surgery, Charlottesville, VA 22908, USA

Correspondence: Patrick M DillonDivision of Hematology/Oncology, University of Virginia, Box 800716, Charlottesville, VA 22908, USATel +1-434-982-1495Fax +1-434-244-7534Email Pmd5b@hscmail.mcc.virginia.edu

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22.Peace KM, Litton JK, Murthy RK, et al. Pre-specified interim analysis in a prospective, randomized phase II trial of trastuzumab vs trastuzumab + NeuVax to prevent breast cancer recurrence in HER2+ breast cancer patients.Paper presented at: American Association of Cancer Researchers, Annual Meeting; 2017;Washington, DC.

23.Mittendorf Elizabeth A, Plitas G, Garber J, et al. Abstract OT3-01-04: VADIS trial: phase II trial of the nelipepimut-S peptide vaccine in women with DCIS of the breast.Paper presented at: San Antonio Breast Cancer Symposium; 2016;San Antonio, TX.

24.Lowenfeld L, Mick R, Datta J, et al. Dendritic cell vaccination enhances immune responses and induces regression of HER2(pos) DCIS independent of route: results of randomized selection design trial.Clin Cancer Res. 2017;23(12):29612971. doi:10.1158/1078-0432.CCR-16-1924

25.Arab A, Behravan J, Razazan A, et al. A nano-liposome vaccine carrying E75, a HER-2/neu-derived peptide, exhibits significant antitumour activity in mice.J Drug Target. 2018;26(4):365372. doi:10.1080/1061186X.2017.1387788

26.Serody J; 2020. Vaccine Therapy, Trastuzumab, and Vinorelbine in Treating Patients With Locally Recurrent or Metastatic Breast Cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT00266110.AccessedMarch11, 2020.

27.Chianese-Bullock KA, Irvin WPJr., Petroni GR, et al. A multipeptide vaccine is safe and elicits T-cell responses in participants with advanced stage ovarian cancer.J Immunother. 2008;31(4):420430. doi:10.1097/CJI.0b013e31816dad10

28.Dillon PM, Petroni GR, Smolkin ME, et al. A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer.J Immunother Cancer. 2017;5(1):92. doi:10.1186/s40425-017-0295-5

29.Chamani R, Ranji P, Hadji M, Nahvijou A, Esmati E, Alizadeh AM. Application of E75 peptide vaccine in breast cancer patients: a systematic review and meta-analysis.Eur J Pharmacol. 2018;831:8793. doi:10.1016/j.ejphar.2018.05.010

Source: Breast Cancer: Targets and Therapy.Originally published April 3, 2020.

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Evaluating Nelipepimut-S in the Treatment of Breast Cancer: A Short Report on the Emerging Data - Oncology Nurse Advisor

Cardiac Stem Cells Comments Off on Evaluating Nelipepimut-S in the Treatment of Breast Cancer: A Short Report on the Emerging Data – Oncology Nurse Advisor | May 4th, 2020

TEL AVIV, Israel & PARSIPPANY, N.J. & INCHEON, South Korea--(BUSINESS WIRE)-- Teva Pharmaceuticals USA, Inc., a U.S. affiliate of Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA), and Celltrion Healthcare, Co., Ltd. (KRX KOSDAQ:091990), today announced that TRUXIMA (rituximab-abbs) injection is now available in the United States for the treatment of:

TRUXIMA is the only biosimilar to the reference product Rituxan1 (rituximab) available to treat rheumatoid arthritis in the United States. See important safety information below including Boxed Warning regarding fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation and progressive multifocal leukoencephalopathy.

We are proud to make TRUXIMA available to patients and providers as a treatment option for these indications, especially as this is the only rituximab biosimilar indicated for rheumatoid arthritis, said Brendan OGrady, Executive Vice President, North America Commercial, Teva. Following the launch of our other biosimilar earlier this year, we remain focused on our commitment to lower healthcare costs and increase price competition through the availability of biosimilars.

Celltrion Healthcare and Teva Pharmaceutical Industries Ltd. entered into an exclusive partnership in October 2016 for Teva to commercialize TRUXIMA in the U.S. and Canada. In May 2019, TRUXIMA was approved by the U.S. Food and Drug Administration (FDA) to match all of the reference products oncology indications described below.

We are pleased that patients in the United States can now have access to TRUXIMA for these new indications, said Mr. Hyoung-Ki Kim, Vice Chairman at Celltrion Healthcare. We believe that the continued use of biosimilars in the U.S. market will contribute to addressing unmet needs for patients and providers.

Earlier this year, the Centers for Medicare and Medicaid Services (CMS) granted pass-through status for TRUXIMA in the hospital outpatient setting. The Wholesale Acquisition Cost (WAC or list price) for TRUXIMA will be 10 percent lower than the reference product. TRUXIMA is expected to be available through primary wholesalers at a WAC of $845.55 per 100mg vial and $4,227.75 per 500mg vial. Actual costs to individual patients and providers for TRUXIMA are anticipated to be lower than WAC because WAC does not account for additional rebates and discounts that may apply. Savings on out-of-pocket costs may vary depending on the patients insurance payer and eligibility for participation in the assistance program.

Teva also offers dedicated patient support services through the CORE program. CORE is available to help eligible patients, caregivers and healthcare professionals navigate the reimbursement process. CORE offers a range of services, including benefits verification and coverage determination, support for precertification and prior authorization, assistance with coverage guidelines and claims investigation, and support through the claims and appeals process. A savings program is also available for eligible commercially insured patients. To learn more, please visit TevaCORE.com.

Please see the Important Safety Information below including the Boxed Warning regarding fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation and progressive multifocal leukoencephalopathy. For more information, please see the full prescribing information.

Indications TRUXIMA (rituximab-abbs) is indicated for the treatment of adult patients with:

Non-Hodgkins Lymphoma (NHL)

Chronic Lymphocytic Leukemia (CLL)

Rheumatoid Arthritis (RA)

Granulomatosis with Polyangiitis (GPA) (Wegeners Granulomatosis) and Microscopic Polyangiitis (MPA)

Important Safety Information

WARNING: FATAL INFUSION-RELATED REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Infusion-Related Reactions: Administration of rituximab products, including TRUXIMA, can result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of rituximab infusion have occurred. Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion. Monitor patients closely. Discontinue TRUXIMA infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion-related reactions

Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab products

Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with rituximab products, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with TRUXIMA. Discontinue TRUXIMA and concomitant medications in the event of HBV reactivation

Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab products

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions - Rituximab products can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30-120 minutes. Rituximab product-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death

Premedicate patients with an antihistamine and acetaminophen prior to dosing. For RA, GPA, and MPA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue TRUXIMA. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (25,000/mm3)

Severe Mucocutaneous Reactions - Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab products. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. Discontinue TRUXIMA in patients who experience a severe mucocutaneous reaction. The safety of re-administration of rituximab products to patients with severe mucocutaneous reactions has not been determined

Hepatitis B Virus Reactivation - Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab products. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [anti-HBs] positive)

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with TRUXIMA. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during TRUXIMA treatment

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following TRUXIMA therapy. HBV reactivation has been reported up to 24 months following completion of rituximab therapy

In patients who develop reactivation of HBV while on TRUXIMA, immediately discontinue TRUXIMA and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming TRUXIMA treatment in patients who develop HBV reactivation. Resumption of TRUXIMA treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV

Progressive Multifocal Leukoencephalopathy (PML) - JC virus infection resulting in PML and death can occur in rituximab product-treated patients with hematologic malignancies. The majority of patients with hematologic malignancies diagnosed with PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of PML were diagnosed within 12 months of their last infusion of rituximab

Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture

Discontinue TRUXIMA and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML

Tumor Lysis Syndrome (TLS) - Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of rituximab products in patients with NHL. A high number of circulating malignant cells ( 25,000/mm3) or high tumor burden, confers a greater risk of TLS

Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated

Infections - Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure). New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue TRUXIMA for serious infections and institute appropriate anti-infective therapy. TRUXIMA is not recommended for use in patients with severe, active infections

Cardiovascular Adverse Reactions - Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving rituximab products. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of TRUXIMA for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina

Renal Toxicity - Severe, including fatal, renal toxicity can occur after rituximab product administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and TRUXIMA is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue TRUXIMA in patients with a rising serum creatinine or oliguria

Bowel Obstruction and Perforation - Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving rituximab in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1-77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur

Immunization - The safety of immunization with live viral vaccines following rituximab product therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment

Prior to initiating TRUXIMA physicians should ensure patients vaccinations and immunizations are up-to-date with guidelines. Administration of any non-live vaccines should occur at least 4 weeks prior to a course of TRUXIMA

Embryo-Fetal Toxicity - Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the risk to a fetus. Females of childbearing potential should use effective contraception while receiving TRUXIMA and for 12 months following the last dose of TRUXIMA

Concomitant Use With Other Biologic Agents and DMARDS Other Than Methotrexate

Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly as limited safety data is available.

Use of concomitant immunosuppressants other than corticosteroids has not been studied in GPA or MPA patients exhibiting peripheral B-cell depletion following treatment with rituximab products

Use in RA Patients Who Have Not Had Prior Inadequate Response to TNF Antagonists

TRUXIMA should only be used in patients who have had a prior inadequate response to one or more TNF antagonist

Most common adverse reactions in clinical trials of NHL (25%) were: infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia

Most common adverse reactions in clinical trials of CLL (25%) were: infusion-related reactions and neutropenia

Most common adverse reactions in clinical trials of RA (10%) were: upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis (other important adverse reactions include infusion-related reactions, serious infections, and cardiovascular events)

Most common adverse reactions in clinical trials of GPA and MPA (15%) were: infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, and infusion-related reactions

Nursing Mothers - There are no data on the presence of rituximab in human milk, the effect on the breastfed child, or the effect on milk production. Since many drugs including antibodies are present in human milk, advise a lactating woman not to breastfeed during treatment and for at least 6 months after the last dose of TRUXIMA due to the potential for serious adverse reactions in breastfed infants

About TRUXIMA TRUXIMA (rituximab-abbs) is a U.S. Food and Drug Administration (FDA)-approved biosimilar to RITUXAN (rituximab) for the treatment of: adult patients with CD20-positive, B-cell NHL to be used as a single agent or in combination with chemotherapy or CLL in combination with fludarabine and cyclophosphamide (FC); for rheumatoid arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies; and granulomatosis with polyangiitis (GPA) (Wegeners Granulomatosis) and microscopic polyangiitis (MPA) in adult patients in combination with glucocorticoids

TRUXIMA has the same mechanism of action as Rituxan and has demonstrated biosimilarity to Rituxan through a totality of evidence.

About Celltrion Healthcare, Co. Ltd. Celltrion Healthcare conducts the worldwide marketing, sales and distribution of biological medicines developed by Celltrion, Inc. through an extensive global network that spans more than 120 different countries. Celltrion Healthcares products are manufactured at state-of-the-art mammalian cell culture facilities, designed and built to comply with the US Food and Drug Administration (FDA) cGMP guidelines and the EU GMP guidelines.

About Teva Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) has been developing and producing medicines to improve peoples lives for more than a century. We are a global leader in generic and specialty medicines with a portfolio consisting of over 3,500 products in nearly every therapeutic area. Around 200 million people around the world take a Teva medicine every day, and are served by one of the largest and most complex supply chains in the pharmaceutical industry. Along with our established presence in generics, we have significant innovative research and operations supporting our growing portfolio of specialty and biopharmaceutical products. Learn more at http://www.tevapharm.com.

Teva's Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 regarding the launch of TRUXIMA Injection for Rheumatoid Arthritis in the United States, which are based on managements current beliefs and expectations and are subject to substantial risks and uncertainties, both known and unknown, that could cause our future results, performance or achievements to differ significantly from that expressed or implied by such forward-looking statements. Important factors that could cause or contribute to such differences include risks relating to:

and other factors discussed in our Annual Report on Form 10-K for the year ended December 31, 2019, including in the sections captioned "Risk Factors and Forward Looking Statements. Forward-looking statements speak only as of the date on which they are made, and we assume no obligation to update or revise any forward-looking statements or other information contained herein, whether as a result of new information, future events or otherwise. You are cautioned not to put undue reliance on these forward-looking statements.

1 RITUXAN is a registered trademark of Genentech and Biogen.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200504005064/en/

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Teva and Celltrion Healthcare Announce the Launch of TRUXIMA (rituximab-abbs) Injection for Rheumatoid Arthritis, the Only Biosimilar to Rituxan...

Cardiac Stem Cells Comments Off on Teva and Celltrion Healthcare Announce the Launch of TRUXIMA (rituximab-abbs) Injection for Rheumatoid Arthritis, the Only Biosimilar to Rituxan… | May 4th, 2020

Asfiled with the Securities and Exchange Commission on May 1,2020

RegistrationNo. 333-

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM S-3

REGISTRATION STATEMENT

UNDER

THE SECURITIES ACT OF 1933

VISTAGEN THERAPEUTICS, INC.

(Exactname of registrant as specified in its charter)

Nevada

2834

20-5093315

(Stateor Other Jurisdiction of

Incorporationor Organization)

(PrimaryStandard Industrial

ClassificationCode Number)

(I.R.S.Employer

IdentificationNumber)

343 Allerton Ave.

South San Francisco, California 94090

(650) 577-3600

(Address,including zip code, and telephone number,

includingarea code, of registrants principal executiveoffices)

Shawn K. Singh

Chief Executive Officer

VistaGen Therapeutics, Inc.

343 Allerton Avenue

South San Francisco, California 94080

(650) 577-3600

(Name,address, including zip code, and telephone number,

includingarea code, of agent for service)

Copies to

Daniel W. Rumsey, Esq.

Jessica R. Sudweeks, Esq.

Disclosure Law Group, a Professional Corporation

655 West Broadway, Suite 870

San Diego, CA 92101

Telephone: (619) 272-7050

Facsimile: (619) 330-2101

Approximate date of commencement of proposed sale to thepublic: As soon as practicable after this registrationstatement becomes effective.

If the only securities being registered on this form are beingoffered pursuant to dividend or interest reinvestment plans, pleasecheck the following box.

If any of the securities being registered on this form are to beoffered on a delayed or continuous basis pursuant to Rule 415 underthe Securities Act of 1933, other than securities offered only inconnection with dividend or interest reinvestment plans, check thefollowing box.

If this form is filed to register additional securities for anoffering pursuant to Rule 462(b) under the Securities Act of 1933,please check the following box and list the Securities Actregistration statement number of the earlier effective registrationstatement for the same offering.

If this form is a post-effective amendment filed pursuant to Rule462(c) under the Securities Act, check the following box and listthe Securities Act registration statement number of the earliereffective registration statement for the sameoffering.

If this form is a registration statement pursuant to GeneralInstruction I.D. or a post-effective amendment thereto that shallbecome effective upon filing with the Commission pursuant to Rule462(e) under the Securities Act, check the followingbox.

If this form is a post-effective amendment to a registrationstatement filed pursuant to General Instruction I.D. filed toregister additional securities or additional classes of securitiespursuant to Rule 413(b) under the Securities Act, check thefollowing box.

Indicateby check mark whether the registrant is a large accelerated filer,an accelerated filer, a non-accelerated filer, smaller reportingcompany, or an emerging growth company. See the definitions oflarge accelerated filer, acceleratedfiler, smaller reporting company, andemerging growth company in Rule 12b-2 of the ExchangeAct.

Largeacceleratedfiler

[]

Acceleratedfiler

[]

Non-acceleratedfiler

[ ]

Smallerreportingcompany

[X]

Emerginggrowth company

[ ]

If anemerging growth company, indicate by check mark if the registranthas elected not to use the extended transition period for complyingwith any new or revised financial accounting standards providedpursuant to Section 13(a) of the Exchange Act.

CALCULATION OF REGISTRATION FEE

Titleof each class of securities to be registered

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be

registered(1)(2)

Proposed

maximum

offeringprice per

share(3)

Proposed

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VistaGen Therapeutics, Inc. S-3 May. 1, 2020 4:59 PM - Seeking Alpha

Cardiac Stem Cells Comments Off on VistaGen Therapeutics, Inc. S-3 May. 1, 2020 4:59 PM – Seeking Alpha | May 3rd, 2020

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Progenitor Cell Product Market 2020 Recent Industry Developments and Growth Strategies Adopted by Top Key Players Worldwide and Assessment to 2025 ...

Cardiac Stem Cells Comments Off on Progenitor Cell Product Market 2020 Recent Industry Developments and Growth Strategies Adopted by Top Key Players Worldwide and Assessment to 2025 … | May 1st, 2020

India with its huge population can become an ideal place for medical research in stem cell, but due to lack of awareness and investment, its progress is slowing down. Vipul Jain, CEO, Advancells talks about the companys vision for stem cell research and progress in India, to Usha Sharma

Give us a brief about your companys inception?

I have been a part of healthcare marketing for over 12 years now and somewhere in 2009-10, a few patients started talking about stem cell therapies if I could help them find a centre, where they could opt for these therapies. Unfortunately, none such centre operated in India and there were very few across the world. Once I studied the subject in-depth it occurred to me that this would be the future of medicine and it was the right time to enter this field. The hope of changing medicine as we know it today inspired me to get into this practice and I established Advancells in 2013.

In the past seven years of our operations, we have grown strength to strength and are today one of the largest providers of stem cell therapies in India.

When we started Advancells, we aimed at becoming a pioneer in the research and development of regenerative medicine. We wanted to have India at the forefront of protocols and technologies in the industry and so we decided to venture into a wide array of services. In order to become a centre of medical advancement, we had to ensure we offered services to all sorts of patients, irrespective of their condition. We believe in treating our patients in a progressive manner.

Tell us about the challenges you faced while setting up your business?

Lack of investment is the biggest challenge. Most new investments in healthcare sector still come from Trusts and charities who enter the segment for charity and with a no-profit no-loss mindset. This restrains their capacity to invest in research and new technologies and hence it is not easy to get cutting edge technologies in the country. India with its huge population base can be a perfect place for strong medical research but the lack of awareness and investment are the major reasons for India to lag behind in research. It is not easy for healthcare researchers to attract private money as private investors are worried about the long gestation period for their investment.

The other major challenge is the acceptance of doctors of a new branch of medicine. It is very difficult to convince doctors of a new way to treat patients and understandably they want long term follow-up data. This data will take time to come and hence growth can not be as fast as you expect it to be. Government regulations are another challenge as agencies are always a little slow to react to innovation.

The expense of research and clinical preliminaries is high in the case of regenerative medicine, in this way confining the research objectives. Aside from cost/enormous speculations, other challenges are administrative difficulties with changing rules across nations, on account of contrasts in the suppositions and social perspectives. Setting up a solitary/regular arrangement or rule worldwide to administer stem cell research could be helpful. Human embryos for research, somatic cell, nuclear move, IPSCs have raised concerns due to their long hatching periods.

So how does your model work?

Advancells works in four different verticals. Firstly, we produce basic human stem cells that are used by partner hospitals and doctors in providing regenerative therapies to the patients. Advancells also writes protocols for therapies and provide training to doctors on various facets of regenerative medicine. In the second vertical, we produce organ, species and disease-specific primary cells, which are used by research institutes, academic institutes and pharma companies around the world to further their research in the field of biology and drugs.

In the third vertical, we produce our patented range of bioscaffolds which once seeded with our cells, are used in the regeneration of bones, organs and healing of wounds. Fourthly, we print 3D human organs and finally seed our scaffolds with our primary cells and paste them on the 3D printed organ models and try to create working modal of a human organ that can be used by pharma companies for drug discovery models. Our moonshot is to be able to produce a transplantable human artificial organ that can one day put an end to mortality rate due to non-availability of transplantable human organs.

We are essentially a B2B business where doctors and hospitals, research institutes, pharma companies etc., are our clients, but we regularly get approached by a number of patients both from India and abroad who want our protocols for treatment. We do provide B2C services to such patients also.

We are currently operating out of our centralised lab in Noida, Delhi/NCR and are able to ship cells to various hospitals not just across India but also in various countries around the world.

Does India have well-defined stem cell treatment regulations?

Surprisingly very well. India has been always been a follower especially when it comes to medical research. There has hardly been any major medical innovation that has come out of India but things seem to be changing this time. It looks like there will be a good case study where India might just take the lead in stem cell technology and be a world leader in it. We have all the required resources and brainpower to make it happen, all we need is a supportive legislature, progressive regulators, understanding investors and gritty innovators and you will see things rolling.

The Government of India has started promoting Stem Cell Research with the help of its agencies. The focus is on identifying diseases and conditions that can be cured. Programmes to support embryonic and adult stem cell research are in place. Some of the developments include setting up human embryonic stem cell lines, using limbal stem cells to repair corneal surface disorder; classification of haematopoietic, mesenchymal and liver stem cells; as well as segregation of stem cells into neural, cardiac and cell lineages, etc.

For the rest of the world, there are many researchers who are creating pathbreaking records. Scientists from the University of California, for instance, have created an approach via stem cells to deal with cancerous tissue while anticipating some dangerous reactions of chemotherapy by treating the disease in a progressive manner.

So whats the scope for stem cell research/ therapy?

Stem cells present a unique opportunity to treat the disease that currently is termed as untreatable. They also help us in treating the diseases from the core and not just managing the symptoms. These properties give regenerative medicine a unique status.

You conduct 15-20 treatment in a month despite the unclear regulations in India? Do you see this as a challenge and deal with it?

We deal only with hospitals and doctors who have taken permission from the government and hence the reach is very low.

How do you differentiate your therapies from other existing players? What all guideline you follow and what is the success ratio?

There is no real credible competition for us. The big players in the market are primarily into cord blood banking and for the therapy is a side product on which they dont concentrate. There are few doctors who practice regenerative medicine on their own but could never match up with the product catalogue or research backing that we have.

There is an exhaustive consent form and clear inclusion and exclusion criterion and the patients are council-led at multiple points before the procedure.

Which are the therapeutic areas Advancells provides stem cell solutions and how safe are they? What is your future plan?

Advancells provide stem cell solutions for orthopaedics, neurology, diabetes etc. It is completely safe. We are targeting to venture into Cosmetics, Ophthalmology.

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Lack of investment is the biggest challenge in stem cell research - Express Healthcare

Cardiac Stem Cells Comments Off on Lack of investment is the biggest challenge in stem cell research – Express Healthcare | April 30th, 2020

When the ISS reaches its retirement date, the Axiom complex will detach and operate as a free-flying commercial space station.

This is the second contract SpaceX grabbed as it reached an agreement with Space Adventures on February 18 to launch private citizens on Crew Dragon spacecraft into an Earth orbit higher than ISS between late-2021 to mid-2022.

SpaceX will attempt to land the rocket booster back at Cape Canaveral, meaning residents in the area could hear a sonic boom. "This will be just the first of many missions to ISS to be completely crewed and managed by Axiom Space - a first for a commercial entity". In 2014, SpaceX and Boeing snagged a coveted launch contract collectively worth $6.8 billion to each build a spacecraft capable of transporting astronauts to the space station and back.

B1059 returned to Port Canaveral on December 7th, 2019 and will launch CRS-20 - its second Dragon mission - nearly exactly three months later. The flight's crew will live onboard the existing station for at least eight days.

When Dragon does return home, it will mark the end of SpaceX's original Commercial Resupply Services (CRS) contract with NASA. While this is not an issue for astronauts on board, as food from Earth is supplied regularly, for long-duration spaceflight-like those to the moon and Mars, which NASA is now planning-the issue of nutrition could become a problem.

Among the payloads on the Dragon is Bartolomeo, an external experiment platform developed by Airbus that will be installed on the station's Columbus module. The Earth views are supposed to be spectacular. Potential applications include Earth observation, robotics, material science and astrophysics. Studying these "tissue chips" may provide a better understanding on how they may cause disease on Earth.

Generation of Cardiomyocytes From Human Induced Pluripotent Stem Cell-derived Cardiac Progenitors Expanded in Microgravity (MVP Cell-03) examines whether microgravity increases the production of heart cells from human-induced pluripotent stem cells (hiPSCs).

"Since 2012, SpaceX has been delivering cargo to the International Space Station in partnership with NASA and later this year, we will fly NASA astronauts for the first time", said SpaceX President and Chief Operating Officer Gwynne Shotwell.

These are just a few of the hundreds of investigations providing opportunities for US government agencies, private industry, and academic and research institutions to conduct microgravity research that leads to new technologies, medical treatments and products that improve life on Earth.

Axiom Space is inviting individuals seeking out a trip of a lifetime.

A lot of the packaged food loses its nutritional value over time in Space, so it has been one of NASA's prime focuses to find products that can be grown on the ISS so as to provide astronauts with proper nutrition, as well as keeping their morale high.

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SpaceX, Axiom to send three tourists to ISS in 2021 - ClickLancashire

Cardiac Stem Cells Comments Off on SpaceX, Axiom to send three tourists to ISS in 2021 – ClickLancashire | April 30th, 2020

MOSCOW, 28 APR RIA Novosti. A new approach to the regeneration of organs that are unrivalled in price and efficiency, has been developed by scientists at the National research University MIET. They created the material, as explained by the authors, will allow to restore the cardiac tissue after a heart attack in just 2-4 months. Data published in the journal Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy.

the Experts of national research UNIVERSITY MIET for the first time in the world, according to them, managed to find a way of chemical bonding of carbon nanotubes with molecules of the most common blood protein albumin. Outdoor their physical mechanism has allowed us to develop a new method of laser 3D printing of nanocomposites.

Under the action of the laser between the albumin and carbon nanotubes there is a strong covalent bond that allows you to print the design specified shape. Living cells, e.g., connective tissue or myocardium easy root on some of the frames (scaffold), making possible the efficient recovery of damaged tissues of the body, said the head of the laboratory of biomedical nanotechnology, Institute of biomedical systems, national research UNIVERSITY MIET Alexander Gerasimenko.

As explained by scientists, they created cardiac implants is 3-4 times cheaper than Russian and 6-8 times cheaper than their foreign counterparts, outperforming both those, and others on a number of parameters. Except scaffolds used in tissue engineering, the technology is also suitable for the production of biosensors, microfluidic systems, and even advanced drugs against cancer.

We are able to print the material close to the characteristics of cardiac tissue: it can be reduced along with the myocardium and has electrical conductivity, the flowing currents of the heart. Our method also allows you to adjust the porosity of the structures, providing penetration as living cells and sprouting of capillaries and nerve endings, explained Alexander Gerasimenko.

Before implantation scaffold populated printed living cells and some time to ripen. As noted by experts of national research UNIVERSITY MIET, a number of successful experiments have shown that it can be used, including stem cells that can turn into cells of that tissue into which they are transplanted.

Scientists believe that their method will effectively deal with such pathologies as congenital heart disease and myocardial infarction, aneurysm, atherosclerosis and infarction. According to them, nano-composite patch on myocardial infarction after 2-4 months completely restores the affected area, and the frame is thus resolved.

the Scientists noted that the technology is implemented in close cooperation with leading Russian scientific centers. In the future, the team intends to proceed to introduce the method into clinical practice, and to adapt the technology for creating coatings for various implantable systems.

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In Russia figured out how to cure myocardial infarction in a matter of months - The KXAN 36 News

Cardiac Stem Cells Comments Off on In Russia figured out how to cure myocardial infarction in a matter of months – The KXAN 36 News | April 28th, 2020

By Guy Adams and John Naish Apr 25, 2020

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London - Modern science has scarcely presented a more crucial goal, offering untold riches and perhaps even a Nobel prize to the victor, as well as the chance to return the world to normal.

Yet the search for a cure for coronavirus is also uniquely perilous thanks to the dangers inherent in rushing new medical products to market.

Across the globe, thousands of researchers employed by governments, laboratories and drug firms are working flat-out to crack this all-important riddle.

As are endless armchair experts, whose numbers now evidently include Donald Trump.

Yesterday, the worlds most powerful man used a press conference to propose various highly unorthodox new treatments for coronavirus, including injecting disinfectant into the body and blasting patients with ultraviolet light.

Back in the real world, researchers are working tirelessly to combat the virus.

But while bullish claims have been made for a host of possible treatments, the truth is that scientists have little idea which ones might end up being of use.

Four months into the pandemic, we have had millions of people infected but no data yet to show that any particular treatment is especially effective, says Professor Babak Javid, the Principal Investigator at Tsinghua University school of medicine in Beijing, and a consultant in infectious diseases at Cambridge University Hospitals.

Nonetheless, here are some of the most likely candidates.

In mid-March, the American President used Twitter to amplify reports that Covid-19 patients could be successfully treated via a combination of the malaria drug hydroxychloroquine and a common antibiotic, Azithromycin.

In a later press conference, the President insisted that common sense qualified him to make such a claim, urging Americans to take it and asking them: What have you got to lose?

Well, quite a lot, as it turned out. The drugs have a catalogue of nasty side-effects, including an increased risk of cardiac arrest, skin blistering, hearing loss and an inability to move the eyes.

A study this week of 368 male coronavirus patients found that 28 per cent of those treated via hydroxychloroquine alone and 22 per cent who received both drugs (the malaria treatment and azithromycin) in U.S. hospitals died. This compares to a death rate of just 11 per cent for patients who received standard care without either drug.

Hope and hype about the drug Remdesivir have set Californian biotech firm Gileads share price soaring in recent weeks.

The medicine, which is administered via a drip, was originally developed to fight the ebola virus and works by interfering with its genetic makeup.

Although other drugs were soon found to be more effective at treating ebola, subsequent tests suggested Remdesivir had some effect on respiratory viruses such as Sars and Mers. It also appears to be relatively safe.

Gilead has so far given Remdesivir to 1,700 coronavirus patients, with dramatic effects reported in some cases. Two major studies, in the U.S. and Europe, are currently underway.

Sadly, a full-scale clinical trial in China, which has been running for longer, found no evidence it improved the fate of hospital patients, according to documents accidentally leaked this week by the World Health Organisation.

Gilead responded that these leaks contained inappropriate characterisations and insisted their findings were inconclusive.

One reason that the Chinese trials outcome was so disappointing could be that Remdesivir is likely to work best if administered early.

With Covid-19, the virus mostly replicates soon after infection, says Professor Javid. If you give the anti-viral later in the course of an illness, when a patient is hospitalised, there is not much virus left for the drug to attack.

The golden goose for pharmaceutical firms is to discover a new antibody treatment that can attach to individual particles of coronavirus and stop them wreaking havoc.

Two US drug companies, Amgen and Adaptive, recently announced a partnership to study recovered Covid-19 patients in an effort to identify and manufacture crucial virus-killing antibodies.

Another firm, Regeneron, has been conducting a study using the viruss genetic material in mice. Dozens of other companies are pursuing similar projects.

Although an antibody strategy was used against ebola, most new drugs take more than five years to develop, thanks among other things to rigorous testing designed to ensure they do not have dangerous side-effects.

This fashionable, if highly experimental, field involves harvesting blood from people who have recently recovered from coronavirus and donating it to patients who are still suffering from the disease.

Because blood plasma contains antibodies that have learned how to detect and destroy the virus, the theory is that a transfusion will kick-start the recipients ability to fight it.

Its quite easy to harvest plasma from surviving patients, says Professor Javid. It was done even during the Spanish Flu epidemic of 1918-19.

About 600 patients in America have already received this treatment. The NHS is also said to be preparing to carry out an extensive trial in the UK.

However, some experts have pointed out that many Covid-19 victims die because of an overactive immune response to the virus, causing inflammation of lungs and other vital organs. These experts worry that boosting a patients immunity via plasma therapy could actually worsen their condition.

Another problem with plasma therapy is the old-fashioned issue of supply and demand. A limited number of recovered patients are prepared to give blood, and only a finite amount can be taken from them.

However, technology now exists to manufacture synthetic antibodies using the blood of Covid-19 survivors.

Such monoclonal antibodies have become the standard treatment for ebola. Several laboratories have identified monoclonal antibodies that can apparently inhibit coronavirus in test-tubes.

Professor Javid warns, however: No one has yet worked out which of the promising monoclonal antibodies work best for Covid-19, or what might be the best way to use them in combination. This is why they are not in production yet for Covid-19.

Contracting HIV was once a virtual death sentence, but after decades of research, its now mostly a highly manageable condition thanks to a raft of well-tolerated drugs.

Indeed, many HIV drugs are now being touted as possible treatments for coronavirus, including Lopinavir and Ritonavir.

These are being trialled on coronavirus patients in studies at the Universities of Oxford and Nebraska.

But so far there is little evidence of them working outside of a laboratory setting.

The so-called master cells that develop into blood, brain, bones and organs have been touted as the basis for cures for cancer, heart disease and arthritis for years.

Little wonder, then, that the pioneering field of stem cell therapy is now being targeted at coronavirus. Among firms exploring this modish area are Mesoblast, whose boffins are testing bone-marrow cells to establish whether they can help patients develop immunity to the virus. In Wuhan, meanwhile, doctor Dongcheng Wu last month claimed hed treated nine patients by injecting umbilical stem cells. He said they all made a complete recovery within days. The success has not yet been convincingly replicated, however. Stem cell treatments are often risky, too when trialled on Parkinsons, they caused brain tumours.

Around half the patients who die with coronavirus suffer a so-called cytokine storm, in which their immune system goes into overdrive, causing, among other things, acute lung inflammation that stops them from taking on enough oxygen. With this in mind, many products designed to combat inflammation are now being trialled on Covid patients.

They include Tocilizumab, used to treat rheumatoid arthritis, and Dexamethasone, a steroid used against asthma.

The World Health Organisations Solidarity trial is meanwhile testing interferon-beta, which is used to treat multiple sclerosis.

Professor Javid believes immune drugs should be accompanied by effective antiviral treatment: We know from treating flu patients suffering cytokine storms that if you dampen their immune response without also giving them an antiviral drug, it can reduce the patients virus-fighting defences and allow the virus to run wild.

These are the cholesterol-lowering drugs prescribed to millions at risk of heart disease. Now scientists wonder if statins should be given to patients with severe Covid-19 symptoms, for two reasons.

Harvard University investigators recommend their use because they have anti-inflammatory powers.

Scientists added last month in the journal Drug Development and Research that statins have also shown an ability to moderate the immune system and thus protect patients lungs from cytokine storm damage.

Professor Jon Cohen, emeritus professor of infectious diseases at Brighton and Sussex Medical School, argues that while statins have shown potential in test-tube trials, in living patients they have only really shown benefits for the cardiovascular system.

In normal circumstances viruses develop a key that enables them to pick a cells locks and break in, hijacking the cells machinery to make more copies of the virus. Peptide inhibitors stick to this key, rendering it unable to do its job.

We already know that Covid-19 invades human cells through a protein receptor, ACE2.

The big question, therefore, is: what might block the coronavirus attaching to the ACE2 receptor?

Chemists at Illinois University used high-powered computers to identify the amino-acid chemicals in the ACE2 receptor that the virus targets. They then constructed a drug with amino-acids that should stick to the viruss key, rendering it useless.

But as the scientists acknowledge in journal ACS Nano this month, they have tested their chemical in computer simulations not in the lab and certainly not on humans. A lot of hurdles lie ahead.

Ultimately, most scientists agree that coronavirus prevention a vaccine is better than any treatment or cure.

Thats why governments are throwing the proverbial kitchen sink at efforts to create one, with more than 140 projects currently running in parallel all over the world.

Everyone expects a vaccine to appear in the end. But much hinges on how quickly that happens.

Thats why there was so much excitement this week when it emerged that scientists at Oxford University have already begun to conduct their first human vaccine tests.

Other clinical trials in humans are already underway in China.

Nevertheless, Professor Chris Whitty, Englands Chief Medical Officer, says the chance of a vaccine becoming available in the next calendar year are incredibly small.

Why? Because we can move only as quickly as extreme caution will allow, says inoculation expert Dr Kai Hu of Imperial College. He reports Imperials lab has already created a harmless pseudo-virus that carries a coronavirus protein. But, he stresses: Safety is our number one priority. We dont yet know how toxic the vaccine would be to humans.

Given Covid-19s devastating infectiousness, the world will have to keep its fingers crossed that the dash for an effective jab proves a success rather than inadvertently plunging humanity into further peril.

Three members of the same family are taking part in a groundbreaking coronavirus vaccine trial. Mum Katie, dad Tony and daughter Rhiannon Vinney are among more than 1,000 participants taking part in the Oxford University trials.

Teaching assistant Katie, 46, saw the plea for healthy volunteers and urged her husband, 53, who runs two pubs, and their 18-year-old student daughter to sign up with her.

The mum-of-four, from Oxford, said she was not worried about health risks from taking part, because she believes the team have done everything they could to make it safe.

She added: I just want to help so life can return to normal. You have to live in a cave not to know somebody who is affected by this. I really do hope this is the cure.

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Will the race for a Covid-19 cure end in triumph or tragedy? - IOL

Cardiac Stem Cells Comments Off on Will the race for a Covid-19 cure end in triumph or tragedy? – IOL | April 28th, 2020

Latest Market Research Report onAutologous Stem Cell Based Therapies Market size | Industry Segment by Applications (Neurodegenerative Disorders, Autoimmune Diseases? and Cardiovascular Diseases), by Type (Embryonic Stem Cell, Resident Cardiac Stem Cells and Umbilical Cord Blood Stem Cells), Regional Outlook, Market Demand, Latest Trends, Autologous Stem Cell Based Therapies Industry Share & Revenue by Manufacturers, Company Profiles, Growth Forecasts 2025.Analyzes current market size and upcoming 5 years growth of this industry.

TheAutologous Stem Cell Based TherapiesMarketAnalysis report attempts to offer foremost and deep understandings into the current market scenario and the advanced development dynamics. The report onAutologous Stem Cell Based Therapies Marketaims to provides the extensive view of the market landscape. The comprehensive research will enable the well-established as well as the emerging players to expand their business approaches and achieve their targeted goals.

This report on Autologous Stem Cell Based Therapies Market covers the manufacturers data including shipment, revenue, gross profit, business distribution etc., these data help the consumer know about the competitors better. This report also covers topmost regions and countries of the world, which shows a regional development status, including Autologous Stem Cell Based Therapies market size, volume and value as well as price data.

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List of Major Key playersoperating in the Autologous Stem Cell Based Therapies Market are:

The objectives of this report are:

Autologous Stem Cell Based Therapies Market Segmentation by Product Type:

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Most significant topics covered in Autologous Stem Cell Based Therapies market report are:

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Autologous Stem Cell Based Therapies Market Demand, Recent Trends and Developments Analysis 2025 - Express Journal

Cardiac Stem Cells Comments Off on Autologous Stem Cell Based Therapies Market Demand, Recent Trends and Developments Analysis 2025 – Express Journal | April 27th, 2020

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

Know the Growth Opportunities in Emerging Markets

Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

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Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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Stem Cell Therapy Market to Discern Steadfast Expansion During 2025 - Cole of Duty

Cardiac Stem Cells Comments Off on Stem Cell Therapy Market to Discern Steadfast Expansion During 2025 – Cole of Duty | April 27th, 2020

Ischemic heart disease (characterized by decreased blood supply to the heart muscle) is one of the leading causes of death worldwide.It manifests as a coronary artery occlusion, which in turn leads to myocardial infarction, accompanied by death of myocardial cells.This overloads the surviving heart muscle and eventually leads to heart failure.In addition, other causes can also cause heart failure, including chronic hypertension, which is also characterized by the gradual loss of cardiomyocytes, and experimental inhibition of programmed cell death can improve heart function.Clinically, the effective treatment to solve the fundamental problem of heart loss is heart transplantation.The new discovery that stem cells and progenitor cells have regenerative potential to treat and prevent heart failure has changed experimental research and caused explosive growth in clinical research.

Heart RegenerationAlthough heart cells have a slight ability to regenerate.However, it is generally believed that the regenerative capacity of the human heart muscle is seriously insufficient, and it is not enough to make up for the severe loss of myocardium caused by catastrophic myocardial infarction or other heart disease.Studies have found that the heart of some vertebrates (such as zebrafish and salamanders) does undergo a regenerative reaction after injury;under normal conditions, mouse and human cardiomyocytes rarely divide.But after a serious injury, the remaining cardiomyocytes will start DNA synthesis and re-enter the cell cycle.Therefore, the division of existing cardiomyocytes seems to be the most important factor for heart regeneration in mice and humans.The dedifferentiation of cardiomyocytes near the damaged area occurs before their proliferation and is characterized by the loss of expression of myocardial contractile proteins (such as -myosin heavy chain and troponin T). Studies find zebrafish heart regeneration may be mainly caused by undifferentiated stem cells or progenitor cells from the outer layer of the heart (epithelium).Further research on salamanders and zebrafish will more clearly define whether cardiac regeneration in these organisms requires dedifferentiation, proliferation and subsequent cardiomyocyte differentiation, or whether regeneration is driven by the recruitment of stem cells to the injured site.In contrast, in mammalian hearts, cardiomyocytes rarely divide after a myocardial infarction, although transgene overexpression of specific genes in mice increases the division of cardiomyocytes.

There is strong evidence that endothelial cells are renewed by bone marrow-derived progenitor cells, but the idea that cardiomyocytes are renewed by such cells has been heatedly debated. Less controversial is that adult mammalian heart muscle has a resident cardiac stem cell (CSC) population, which has the potential to differentiate into cardiomyocytes and other cell types (such as endothelial and vascular smooth muscle cells). The study found that CSCs can support the basic turnover of cardiomyocytes, but this turnover occurs at a very low rate without damage. CSCs have high proliferation and differentiation potential in vitro, and it may be a promising therapeutic direction to expand autologous CSCs in vitro or stimulate the regeneration of these cells in vivo.

The recognition that there is indeed a regeneration mechanism in the mammalian myocardium has aroused intense attention. Researchers have discovered that it may hinder the existence of aplastic disorders, including ischemia, inflammation and fibrosis at various stages of myocardial infarction. This unfavorable microenvironment may prevent the activation of resident CSCs, thereby reducing the success rate of exogenous cell therapy. Certain components of the inflammatory response may be essential to promote angiogenesis and progenitor cell recruitment, but excessive inflammation may also prevent the recruitment and survival of progenitor cells. Similarly, after myocardial infarction, a certain degree of fibrosis is required to prevent myocardial rupture, but dense fibrosis presents a strong physical barrier to regenerative cells.

Which Stem Cells Are Used In Heart Therapy?Perhaps the most confusing aspect of current cardiac regeneration is the different cell types, which are considered to be candidates for cardiac therapy.Multiple cell candidates reflect that human research on cell regeneration is not deep enough, so further research and exploration are needed.

Figure 1. Many cell types and mechanisms have been proposed for cardiac therapy.

Skeletal MyoblastOne of the earliest cell-based cardiac regeneration strategies was to inject autologous skeletal muscle myoblasts into ischemic myocardium.Myoblasts are resistant to ischemia, and can be differentiated into myotubes (but not into cardiomyocytes) in the laboratory animal experiments and improve ventricular function.The myocardial tube will not integrate with the surviving cardiomyocytes, so it will not beat synchronously with the surrounding myocardium.However, related clinical trials were terminated due to lack of efficacy, so it is unlikely that skeletal myoblasts will actually regenerate the heart muscle.Interestingly, studies found that mouse skeletal muscle contains a large number of non-satellite cells, which can differentiate into spontaneous pulsatile cells with cardiomyocyte characteristics, but no one has found similar cells in human skeletal muscle.

Bone Marrow-Derived Cells

In stem cell cardiac therapy, it was first reported that adult stem cells or progenitor cells transplanted into the infarcted heart of mice that can differentiate into cardiac myocytes are a subset of hematopoietic cells derived from bone marrow. The first evidence that adult bone marrow-derived progenitor cells are involved in the formation of cardiomyocytes in the adult human heart is based on reports of Y chromosome-positive cardiomyocytes in male recipients of transplanted female donor hearts. Animal studies using labeled hematopoietic stem cells for bone marrow transplantation and subsequent myocardial infarction have shown that cardiomyocytes are derived from transplanted cells, but the proportion is extremely low. Moreover, other studies in animals have not demonstrated that hematopoietic progenitor cells can differentiate into cardiomyocytes or improve heart function. Therefore, there is currently no consensus on whether bone marrow-derived progenitor cells differentiate into cardiomyocytes in vivo.

Embryonic stem cell

Embryonic stem (ES) cells are prototype stem cells.They clearly meet all the requirements of stem cells: cloning, self-renewal and multi-potency.ES cells can differentiate into any type of cells present in an adult organism, so it has the potential to completely regenerate the heart muscle.The two obstacles facing the clinical application of ES therapy are immune rejection and the tendency of injecting ES cells to form teratomas.With the increase in knowledge of ES cell differentiation and cardiac embryonic development pathways, ES cell differentiation may become more controllable.Methods to limit teratoma formation include genetic selection of differentiated ES cells, or differentiation of ES cells into cardiomyocytes or endothelial cells in vitro before injection.For example, tumor necrosis factor promotes the differentiation of ES cells into cardiomyocytes.If the differentiated ES cells are delivered to the myocardium in a rich survival mixture, they can survive and improve myocardial function.The inherent difficulty in controlling the growth and differentiation of ES cells and other pluripotent stem cells is that the timing of activating specific signaling pathways may be crucial.For example, recent studies on mouse and zebrafish embryos have shown that the role of the Wnt--catenin pathway in heart development depends on the stage of development.

Endogenous cardiac stem cells

Because allogeneic cells face immunological challenges that may require immune rejection, the isolation of endogenous adult mammalian CSCs based on cell surface markers has attracted great interest. However, no clear CSC mark has been determined so far. Mammalian heart muscle includes a small percentage of stem cells expressing cell surface markers Kitor Scal. In addition, some side population cells also express Kit and / or Sca1, and like Kit +CSC and Sca1 +CSC, side population cells can produce cardiomyocytes in vitro and in vivo. In addition to Kit +CSC, Sca1+CSC and side population cells, the fourth type of CSC also expresses the transcription factor Isl1. The tracer experiments showed that during embryonic heart development, cells expressing Isl1can differentiate into endothelial cells, endocardial cells, smooth muscle cells, conduction system cells, right ventricular myogenic cells and atrial myogenic cells. There are also cells that express Isl1 in the heart of adult mammals, but they are limited to the right atrium, are found in fewer numbers than the embryonic heart, and have unknown physiological effects. Recently, epicardial-derived progenitor cells with angiogenic potential have been described.

Stem cell therapy for heart disease faces some challenges.The most important question to be answered in preclinical research is which stem or progenitor cells are the best choice for treatment.So far, under certain circumstances (acute myocardial infarction), bone marrow-derived progenitor cell therapy has proven to be safe and beneficial, but the regeneration potential of this cell is still controversial.CSC may have the potential to target patients, but isolation and cultivation procedures are still in the early stages of development.ES cells have the greatest differentiation potential, but face moral barriers and the greatest risk of teratoma formation.Whether ES cell derivatives will be rejected by the hosts immune response is still under debate.However, in principle, rejection can be avoided by using cells from a pool of only 150 donors with different HLA types.If new technologies for reprogramming human and mouse fibroblasts into ES-like cells can be used, the use of patient-reprogrammed cells can reduce or even eliminate immune rejection.When designing a more rational cell-based treatment for heart disease, a key issue is to understand the mechanism by which each stem or progenitor cell type can affect myocardial function.Similarly, different cardiology, such as acute myocardial infarction and chronic ischemic cardiomyopathy, may require different types of stem or progenitor cells.

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The lungs are ground zero, but COVID-19 also tears through organ systems from brain to blood vessels.

Science's COVID-19 coverage is supported by the Pulitzer Center.

The coronavirus wreaked extensive damage (yellow) on the lungs of a 59-year-old man who died at George Washington University Hospital, as seen in a 3D model based on computed tomography scans.

On rounds in a 20-bed intensive care unit one recent day, physician Joshua Denson assessed two patients with seizures, many with respiratory failure, and others whose kidneys were on a dangerous downhill slide. Days earlier, his rounds had been interrupted as his team tried, and failed, to resuscitate a young woman whose heart had stopped. All of the patients shared one thing, says Denson, a pulmonary and critical care physician at the Tulane University School of Medicine. They are all COVID positive.

As the number of confirmed cases of COVID-19 approaches 2.5 million globally and deaths surpass 166,000, clinicians and pathologists are struggling to understand the damage wrought by the coronavirus as it tears through the body. They are realizing that although the lungs are ground zero, the virus' reach can extend to many organs including the heart and blood vessels, kidneys, gut, and brain.

[The disease] can attack almost anything in the body with devastating consequences, says cardiologist Harlan Krumholz of Yale University and Yale-New Haven Hospital, who is leading multiple efforts to gather clinical data on COVID-19. Its ferocity is breathtaking and humbling.

Understanding the rampage could help doctors on the front lines treat the roughly 5% of infected people who become desperately and sometimes mysteriously ill. Does a dangerous, newly observed tendency to blood clotting transform some mild cases into life-threatening emergencies? Is an overzealous immune response behind the worst cases, suggesting treatment with immune-suppressing drugs could help? And what explains the startlingly low blood oxygen that some physicians are reporting in patients who nonetheless are not gasping for breath? Taking a systems approach may be beneficial as we start thinking about therapies, says Nilam Mangalmurti, a pulmonary intensivist at the Hospital of the University of Pennsylvania (HUP).

What follows is a snapshot of the fast-evolving understanding of how the virus attacks cells around the body. Despite the more than 1500 papers now spilling into journals and onto preprint servers every week, a clear picture is elusive, as the virus acts like no pathogen humanity has ever seen. Without larger, controlled studies that are only now being launched, scientists must pull information from small studies and case reports, often published at warp speed and not yet peer reviewed. We need to keep a very open mind as this phenomenon goes forward, says Nancy Reau, a liver transplant physician who has been treating COVID-19 patients at Rush University Medical Center. We are still learning.

WHEN AN INFECTED PERSON expels virus-laden droplets and someone else inhales them, the novel coronavirus, called SARS-CoV-2, enters the nose and throat. It finds a welcome home in the lining of the nose, according to a recent arXiv preprint, because cells there are rich in a cell-surface receptor called angiotensin-converting enzyme 2 (ACE2). Throughout the body, the presence of ACE2, which normally helps regulate blood pressure, marks tissues potentially vulnerable to infection, because the virus requires that receptor to enter a cell. Once inside, the virus hijacks the cell's machinery, making myriad copies of itself and invading new cells.

As the virus multiplies, an infected person may shed copious amounts of it, especially during the first week or so. Symptoms may be absent at this point. Or the virus' new victim may develop a fever, dry cough, sore throat, loss of smell and taste, or head and body aches.

If the immune system doesn't beat back SARS-CoV-2 during this initial phase, the virus then marches down the windpipe to attack the lungs, where it can turn deadly. The thinner, distant branches of the lung's respiratory tree end in tiny air sacs called alveoli, each lined by a single layer of cells that are also rich in ACE2 receptors.

Normally, oxygen crosses the alveoli into the capillaries, tiny blood vessels that lie beside the air sacs; the oxygen is then carried to the rest of the body. But as the immune system wars with the invader, the battle itself disrupts healthy oxygen transfer. Frontline white blood cells release inflammatory molecules called chemokines, which in turn summon more immune cells that target and kill virus-infected cells, leaving a stew of fluid and dead cellspusbehind (see graphic, below). This is the underlying pathology of pneumonia, with its corresponding symptoms: coughing; fever; and rapid, shallow respiration. Some COVID-19 patients recover, sometimes with no more support than oxygen breathed in through nasal prongs.

But others deteriorate, often suddenly, developing a condition called acute respiratory distress syndrome. Oxygen levels in their blood plummet, and they struggle ever harder to breathe. On x-rays and computed tomography scans, their lungs are riddled with white opacities where black spaceairshould be. Commonly, these patients end up on ventilators. Many die, and survivors may face long-term complications (see sidebar, p. 359). Autopsies show their alveoli became stuffed with fluid, white blood cells, mucus, and the detritus of destroyed lung cells.

Some clinicians suspect the driving force in many gravely ill patients' downhill trajectories is a disastrous overreaction of the immune system known as a cytokine storm, which other viral infections are known to trigger. Cytokines are chemical signaling molecules that guide a healthy immune response; but in a cytokine storm, levels of certain cytokines soar far beyond what's needed, and immune cells start to attack healthy tissues. Blood vessels leak, blood pressure drops, clots form, and catastrophic organ failure can ensue.

Some studies have shown elevated levels of these inflammation-inducing cytokines in the blood of hospitalized COVID-19 patients. The real morbidity and mortality of this disease is probably driven by this out of proportion inflammatory response to the virus, says Jamie Garfield, a pulmonologist who cares for COVID-19 patients at Temple University Hospital.

But others aren't convinced. There seems to have been a quick move to associate COVID-19 with these hyperinflammatory states. I haven't really seen convincing data that that is the case, says Joseph Levitt, a pulmonary critical care physician at the Stanford University School of Medicine.

He's also worried that efforts to dampen a cytokine response could backfire. Several drugs targeting specific cytokines are in clinical trials in COVID-19 patients. But Levitt fears those drugs may suppress the immune response that the body needs to fight off the virus. There's a real risk that we allow more viral replication, Levitt says.

Meanwhile, other scientists are zeroing in on an entirely different organ system that they say is driving some patients' rapid deterioration: the heart and blood vessels.

IN BRESCIA, ITALY, a 53-year-old woman walked into the emergency room of her local hospital with all the classic symptoms of a heart attack, including telltale signs in her electrocardiogram and high levels of a blood marker suggesting damaged cardiac muscles. Further tests showed cardiac swelling and scarring, and a left ventriclenormally the powerhouse chamber of the heartso weak that it could only pump one-third its normal amount of blood. But when doctors injected dye in her coronary arteries, looking for the blockage that signifies a heart attack, they found none. Another test revealed the real cause: COVID-19.

How the virus attacks the heart and blood vessels is a mystery, but dozens of preprints and papers attest that such damage is common. A 25 March paper in JAMA Cardiology found heart damage in nearly 20% of patients out of 416 hospitalized for COVID-19 in Wuhan, China. In another Wuhan study, 44% of 36 patients admitted to the intensive care unit (ICU) had arrhythmias.

The disruption seems to extend to the blood itself. Among 184 COVID-19 patients in a Dutch ICU, 38% had blood that clotted abnormally, and almost one-third already had clots, according to a 10 April paper in Thrombosis Research. Blood clots can break apart and land in the lungs, blocking vital arteriesa condition known as pulmonary embolism, which has reportedly killed COVID-19 patients. Clots from arteries can also lodge in the brain, causing stroke. Many patients have dramatically high levels of D-dimer, a byproduct of blood clots, says Behnood Bikdeli, a cardiovascular medicine fellow at Columbia University Medical Center.

The more we look, the more likely it becomes that blood clots are a major player in the disease severity and mortality from COVID-19, Bikdeli says.

Infection may also lead to blood vessel constriction. Reports are emerging of ischemia in the fingers and toesa reduction in blood flow that can lead to swollen, painful digits and tissue death.

In the lungs, blood vessel constriction might help explain anecdotal reports of a perplexing phenomenon seen in pneumonia caused by COVID-19: Some patients have extremely low blood-oxygen levels and yet are not gasping for breath. In this scenario, oxygen uptake is impeded by constricted blood vessels rather than by clogged alveoli. One theory is that the virus affects the vascular biology and that's why we see these really low oxygen levels, Levitt says.

If COVID-19 targets blood vessels, that could also help explain why patients with pre-existing damage to those vessels, for example from diabetes and high blood pressure, face higher risk of serious disease. Recent Centers for Disease Control and Prevention (CDC) data on hospitalized patients in 14 U.S. states found that about one-third had chronic lung diseasebut nearly as many had diabetes, and fully half had pre-existing high blood pressure.

Mangalmurti says she has been shocked by the fact that we don't have a huge number of asthmatics or patients with other respiratory diseases in her hospital's ICU. It's very striking to us that risk factors seem to be vascular: diabetes, obesity, age, hypertension.

Scientists are struggling to understand exactly what causes the cardiovascular damage. The virus may directly attack the lining of the heart and blood vessels, which, like the nose and alveoli, are rich in ACE2 receptors. By altering the delicate balance of hormones that help regulate blood pressure, the virus might constrict blood vessels going to the lungs. Another possibility is that lack of oxygen, due to the chaos in the lungs, damages blood vessels. Or a cytokine storm could ravage the heart as it does other organs.

We're still at the beginning, Krumholz says. We really don't understand who is vulnerable, why some people are affected so severely, why it comes on so rapidly and why it is so hard [for some] to recover.

THE WORLDWIDE FEARS of ventilator shortages for failing lungs have received plenty of attention. Not so a scramble for another type of equipment: kidney dialysis machines. If these folks are not dying of lung failure, they're dying of renal failure, says neurologist Jennifer Frontera of New York University's Langone Medical Center, which has treated thousands of COVID-19 patients. Her hospital is developing a dialysis protocol with a different kind of machine to support more patients. What she and her colleagues are seeing suggests the virus may target the kidneys, which are abundantly endowed with ACE2 receptors.

According to one preprint, 27% of 85 hospitalized patients in Wuhan had kidney failure. Another preprint reported that 59% of nearly 200 hospitalized COVID-19 patients in China's Hubei and Sichuan provinces had protein in their urine, and 44% had blood; both suggest kidney damage. Those with acute kidney injury were more than five times as likely to die as COVID-19 patients without it, that preprint reported.

The lung is the primary battle zone. But a fraction of the virus possibly attacks the kidney. And as on the real battlefield, if two places are being attacked at the same time, each place gets worse, says co-author Hongbo Jia, a neuroscientist at the Chinese Academy of Sciences's Suzhou Institute of Biomedical Engineering and Technology.

One study identified viral particles in electron micrographs of kidneys from autopsies, suggesting a direct viral attack. But kidney injury may also be collateral damage. Ventilators boost the risk of kidney damage, as do antiviral compounds including remdesivir, which is being deployed experimentally in COVID-19 patients. Cytokine storms can also dramatically reduce blood flow to the kidney, causing often-fatal damage. And pre-existing diseases like diabetes can increase the chances of kidney injury. There is a whole bucket of people who already have some chronic kidney disease who are at higher risk for acute kidney injury, says Suzanne Watnick, chief medical officer at Northwest Kidney Centers.

ANOTHER STRIKING SET of symptoms in COVID-19 patients centers on the brain and nervous system. Frontera says 5% to 10% of coronavirus patients at her hospital have neurological symptoms. But she says that is probably a gross underestimate of the number whose brains are struggling, especially because many are sedated and on ventilators.

Frontera has seen patients with the brain inflammation encephalitis, seizures, and a sympathetic storm, a hyperreaction of the sympathetic nervous system that causes seizurelike symptoms and is most common after a traumatic brain injury. Some people with COVID-19 briefly lose consciousness. Others have strokes. Many report losing their sense of smell and taste. And Frontera and others wonder whether, in some cases, infection depresses the brain stem reflex that senses oxygen starvationanother explanation for anecdotal observations that some patients aren't gasping for air, despite dangerously low blood oxygen levels.

ACE2 receptors are present in the neural cortex and brain stem, says Robert Stevens, an intensive care physician at Johns Hopkins Medicine. And the coronavirus behind the 2003 severe acute respiratory syndrome (SARS) epidemica close cousin of today's culpritwas able to infiltrate neurons and sometimes caused encephalitis. On 3 April, a case study in the International Journal of Infectious Diseases, from a team in Japan, reported traces of new coronavirus in the cerebrospinal fluid of a COVID-19 patient who developed meningitis and encephalitis, suggesting it, too, can penetrate the central nervous system.

But other factors could be damaging the brain. For example, a cytokine storm could cause brain swelling. The blood's exaggerated tendency to clot could trigger strokes. The challenge now is to shift from conjecture to confidence, at a time when staff are focused on saving lives, and even neurologic assessments like inducing the gag reflex or transporting patients for brain scans risk spreading the virus.

Last month, Sherry Chou, a neurologist at the University of Pittsburgh Medical Center, began to organize a worldwide consortium that now includes 50 centers to draw neurological data from care patients already receive. Early goals are simple: Identify the prevalence of neurologic complications in hospitalized patients and document how they fare. Longer term, Chou and her colleagues hope to gather scans and data from lab tests to better understand the virus' impact on the nervous system, including the brain.

No one knows when or how the virus might penetrate the brain. But Chou speculates about a possible invasion route: through the nose, then upward and through the olfactory bulbexplaining reports of a loss of smellwhich connects to the brain. It's a nice sounding theory, she says. We really have to go and prove that.

A 58-year-old woman with COVID-19 developed encephalitis, with tissue damage in the brain (arrows).

Most neurological symptoms are reported from colleague to colleague by word of mouth, Chou adds. I don't think anybody, and certainly not me, can say we're experts.

IN EARLY MARCH, a 71-year-old Michigan woman returned from a Nile River cruise with bloody diarrhea, vomiting, and abdominal pain. Initially doctors suspected she had a common stomach bug, such as Salmonella. But after she developed a cough, doctors took a nasal swab and found her positive for the novel coronavirus. A stool sample positive for viral RNA, as well as signs of colon injury seen in an endoscopy, pointed to a gastrointestinal (GI) infection with the coronavirus, according to a paper posted online in The American Journal of Gastroenterology (AJG).

Her case adds to a growing body of evidence suggesting the new coronavirus, like its cousin SARS, can infect the lining of the lower digestive tract, where ACE2 receptors are abundant. Viral RNA has been found in as many as 53% of sampled patients' stool samples. And in a paper in press at Gastroenterology, a Chinese team reported finding the virus' protein shell in gastric, duodenal, and rectal cells in biopsies from a COVID-19 patient. I think it probably does replicate in the gastrointestinal tract, says Mary Estes, a virologist at Baylor College of Medicine.

Recent reports suggest up to half of patients, averaging about 20% across studies, experience diarrhea, says Brennan Spiegel of Cedars-Sinai Medical Center in Los Angeles, coeditor-in-chief of AJG. GI symptoms aren't on CDC's list of COVID-19 symptoms, which could cause some COVID-19 cases to go undetected, Spiegel and others say. If you mainly have fever and diarrhea, you won't be tested for COVID, says Douglas Corley of Kaiser Permanente, Northern California, co-editor of Gastroenterology.

The presence of virus in the GI tract raises the unsettling possibility that it could be passed on through feces. But it's not yet clear whether stool contains intact, infectious virus, or only RNA and proteins. To date, We have no evidence that fecal transmission is important, says coronavirus expert Stanley Perlman of the University of Iowa. CDC says that, based on experiences with SARS and with the coronavirus that causes Middle East respiratory syndrome, the risk from fecal transmission is probably low.

The intestines are not the end of the disease's march through the body. For example, up to one-third of hospitalized patients develop conjunctivitispink, watery eyesalthough it's not clear that the virus directly invades the eye.

Other reports suggest liver damage: More than half of COVID-19 patients hospitalized in two Chinese centers had elevated levels of enzymes indicating injury to the liver or bile ducts. But several experts told Science that direct viral invasion isn't likely the culprit. They say other events in a failing body, like drugs or an immune system in overdrive, are more likely causes of the liver damage.

This map of the devastation that COVID-19 can inflict on the body is still just a sketch. It will take years of painstaking research to sharpen the picture of its reach, and the cascade of effects in the body's complex and interconnected systems that it might set in motion. As science races ahead, from probing tissues under microscopes to testing drugs on patients, the hope is for treatments more wily than the virus that has stopped the world in its tracks.

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A rampage through the body - Science Magazine

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Detailed market survey on the Global Autologous Stem Cell Based Therapies Market Research Report 2020-2026. It analyses the vital factors of the Autologous Stem Cell Based Therapies market supported present business Strategy, Autologous Stem Cell Based Therapies market demands, business methods utilised by Autologous Stem Cell Based Therapies market players and therefore the future prospects from numerous angles well. Business associatealysis could be a market assessment tool utilized by business and analysts to grasp the quality of an business. Autologous Stem Cell Based Therapies Market report It helps them get a sense of what is happening in an industry, i.e., demand-supply statistics, Autologous Stem Cell Based Therapies Market degree of competition within the industry, Autologous Stem Cell Based Therapies Market competition of the business with different rising industries, future prospects of the business.

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The Global Autologous Stem Cell Based Therapies market worth about xx billion USD in 2020 and it is expected to reach xx billion USD in 2026 with an average growth rate of x%. United States is the largest production of Autologous Stem Cell Based Therapies Market and consumption region in the world, Europe also play important roles in global Autologous Stem Cell Based Therapies market while China is fastest growing region.

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Geographically, Autologous Stem Cell Based Therapies market report is segmented into several key Regions, with production, consumption, revenue. The major regions involved in Autologous Stem Cell Based Therapies Market are (United States, EU, China, and Japan).

Leading companies reviewed in the Autologous Stem Cell Based Therapies report are:

RegeneusMesoblastPluristem Therapeutics IncU.S. STEM CELL, INC.Brainstorm Cell TherapeuticsTigenixMed cell Europe

Autologous Stem Cell Based Therapies Market Product Type Segmentation As Provided Below:The Autologous Stem Cell Based Therapies Market report is segmented into following categories:

The product segment of the report offers product market information such as demand, supply and market value of the product.

The application of product in terms of USD value is represented in numerical and graphical format for all the major regional markets.The Autologous Stem Cell Based Therapies market report is segmented into Type by following categories;Embryonic Stem CellResident Cardiac Stem CellsUmbilical Cord Blood Stem Cells

The Autologous Stem Cell Based Therapies market report is segmented into Application by following categories;Neurodegenerative DisordersAutoimmune DiseasesCardiovascular Diseases

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Study on Autologous Stem Cell Based Therapies Market (impact of COVID-19) 2020-2026 Brainstorm Cell Therapeutics, Tigenix, Med cell Europe - Bandera...

Cardiac Stem Cells Comments Off on Study on Autologous Stem Cell Based Therapies Market (impact of COVID-19) 2020-2026 Brainstorm Cell Therapeutics, Tigenix, Med cell Europe – Bandera… | April 21st, 2020

Many in the medical community view an experimental antiviral drug called remdesivir, manufactured by Gilead Sciences, as the best chance for a treatment. In tests in academic labs, in work sponsored by the federal government, it has been shown to block viral replication. A clutch of clinical trials are underway worldwide to test it in patients, and Gilead is distributing it to thousands of people on a "compassionate use" basis. Remdesivir is considered a broad-spectrum antiviral, meaning it is believed to work against multiple types of virus. But it failed in a test against Ebola last year. Also, it has a big drawback: It is a liquid that must be given intravenously, which means people must go to a hospital or clinic on 10 consecutive days to be treated. Gilead, the National Institutes of Health and the World Health Organization are among those sponsoring multiple clinical trials, and preliminary results are expected within weeks.

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Here are the drugs that could treat coronavirus. But don't expect a silver bullet. - The Philadelphia Inquirer

Cardiac Stem Cells Comments Off on Here are the drugs that could treat coronavirus. But don’t expect a silver bullet. – The Philadelphia Inquirer | April 18th, 2020

Advance Market Analyticsreleased the research report ofGlobal Liver CirrhosisMarket, offers a detailed overview of the factors influencing the global business scope.Global Liver Cirrhosis Market research report shows the latest market insights with upcoming trends and breakdown of the products and services.The report provides key statistics on the market status, size, share, growth factors of the Global Liver Cirrhosis.This Report covers the emerging players data, including: competitive situation, sales, revenue and global market share of top manufacturers are F. Hoffmann-La Roche AG (Switzerland), Merck & Co., Inc (United States), Abbott Laboratories (United States), Novartis International AG (Switzerland), Bristol Myers Squibb Company (United States), Gilead Sciences, Inc (United States), Conatus Pharmaceuticals (United States), GlaxoSmithKline plc (United Kingdom), Grifols, S.A. (Spain), GWOXI Stem Cell Applied Technology Co., Ltd (China), Hepion Pharmaceuticals (United States), Intercept Pharmaceuticals, Inc. (United States) and Lepu Medical Technology (Beijing) Co., Ltd. (China).

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The liver cirrhosis means the condition that causes scar tissue of the liver to replace healthy liver tissue cells, it happens over the period due to the chronic infection or alcohol addiction. It is diagnosed by various radiology tests such as computed tomography (CT), ultrasound, magnetic resonance imaging (MRI), needle biopsy of the liver. A new imaging technique called elastography, which can be performed with ultrasound or MRI, can also diagnosis cirrhosis.

Market Trend

Market Drivers

Opportunities

Restraints

Challenges

The Global Liver Cirrhosisis segmented by following Product Types:

Type (Alcoholic Cirrhosis, Atrophic Cirrhosis, Biliary Cirrhosis, Cardiac Cirrhosis, Cryptogenic Cirrhosis), Application (Hospitals, Specialty Clinics, Others), Treatment (Self-care, Medications {Diuretic, Ammonia Reducer, Beta Blocker, Antibiotics, Antiviral Drug}, Medical procedure {Rubber Band Ligation, Therapeutic Endoscopy, and Transjugular Intrahepatic Portosystemic Shunt}, Surgery {Liver transplantation}), Stages (Stage 1, Stage 2, Stage 3, Stage 4), Tests (Computed Tomography (CT), Ultrasound, Magnetic Resonance Imaging (MRI), Needle Biopsy)

Region Included are: North America, Europe, Asia Pacific, Oceania, South America, Middle East & Africa

Country Level Break-Up: United States, Canada, Mexico, Brazil, Argentina, Colombia, Chile, South Africa, Nigeria, Tunisia, Morocco, Germany, United Kingdom (UK), the Netherlands, Spain, Italy, Belgium, Austria, Turkey, Russia, France, Poland, Israel, United Arab Emirates, Qatar, Saudi Arabia, China, Japan, Taiwan, South Korea, Singapore, India, Australia and New Zealand etc.Enquire for customization in Report @:https://www.advancemarketanalytics.com/enquiry-before-buy/63193-global-liver-cirrhosis-market

Strategic Points Covered in Table of Content of Global Liver Cirrhosis Market:

Chapter 1: Introduction, market driving force product Objective of Study and Research Scope the Global Liver Cirrhosis market

Chapter 2: Exclusive Summary the basic information of the Global Liver Cirrhosis Market.

Chapter 3: Displayingthe Market Dynamics- Drivers, Trends and Challenges of the Global Liver Cirrhosis

Chapter 4: Presenting the Global Liver Cirrhosis Market Factor Analysis Porters Five Forces, Supply/Value Chain, PESTEL analysis, Market Entropy, Patent/Trademark Analysis.

Chapter 5: Displaying the by Type, End User and Region 2013-2018

Chapter 6: Evaluating the leading manufacturers of the Global Liver Cirrhosis market which consists of its Competitive Landscape, Peer Group Analysis, BCG Matrix & Company Profile

Chapter 7: To evaluate the market by segments, by countries and by manufacturers with revenue share and sales by key countries in these various regions.

Chapter 8 & 9: Displaying the Appendix, Methodology and Data Source

Finally, Global Liver Cirrhosis Market is a valuable source of guidance for individuals and companies.

Data Sources & Methodology

The primary sources involves the industry experts from the Global Liver Cirrhosis Market including the management organizations, processing organizations, analytics service providers of the industrys value chain. All primary sources were interviewed to gather and authenticate qualitative & quantitative information and determine the future prospects.

In the extensive primary research process undertaken for this study, the primary sources Postal Surveys, telephone, Online & Face-to-Face Survey were considered to obtain and verify both qualitative and quantitative aspects of this research study. When it comes to secondary sources Companys Annual reports, press Releases, Websites, Investor Presentation, Conference Call transcripts, Webinar, Journals, Regulators, National Customs and Industry Associations were given primary weight-age.

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Liver Cirrhosis Market Projected to Gain Significant Value by 2024 - Science In Me

Cardiac Stem Cells Comments Off on Liver Cirrhosis Market Projected to Gain Significant Value by 2024 – Science In Me | April 15th, 2020

Global Stem Cell Therapy Market: Overview

Also called regenerative medicine, stem cell therapy encourages the reparative response of damaged, diseased, or dysfunctional tissue via the use of stem cells and their derivatives. Replacing the practice of organ transplantations, stem cell therapies have eliminated the dependence on availability of donors. Bone marrow transplant is perhaps the most commonly employed stem cell therapy.

Osteoarthritis, cerebral palsy, heart failure, multiple sclerosis and even hearing loss could be treated using stem cell therapies. Doctors have successfully performed stem cell transplants that significantly aid patients fight cancers such as leukemia and other blood-related diseases.

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Global Stem Cell Therapy Market: Key Trends

The key factors influencing the growth of the global stem cell therapy market are increasing funds in the development of new stem lines, the advent of advanced genomic procedures used in stem cell analysis, and greater emphasis on human embryonic stem cells. As the traditional organ transplantations are associated with limitations such as infection, rejection, and immunosuppression along with high reliance on organ donors, the demand for stem cell therapy is likely to soar. The growing deployment of stem cells in the treatment of wounds and damaged skin, scarring, and grafts is another prominent catalyst of the market.

On the contrary, inadequate infrastructural facilities coupled with ethical issues related to embryonic stem cells might impede the growth of the market. However, the ongoing research for the manipulation of stem cells from cord blood cells, bone marrow, and skin for the treatment of ailments including cardiovascular and diabetes will open up new doors for the advancement of the market.

Global Stem Cell Therapy Market: Market Potential

A number of new studies, research projects, and development of novel therapies have come forth in the global market for stem cell therapy. Several of these treatments are in the pipeline, while many others have received approvals by regulatory bodies.

In March 2017, Belgian biotech company TiGenix announced that its cardiac stem cell therapy, AlloCSC-01 has successfully reached its phase I/II with positive results. Subsequently, it has been approved by the U.S. FDA. If this therapy is well- received by the market, nearly 1.9 million AMI patients could be treated through this stem cell therapy.

Another significant development is the granting of a patent to Israel-based Kadimastem Ltd. for its novel stem-cell based technology to be used in the treatment of multiple sclerosis (MS) and other similar conditions of the nervous system. The companys technology used for producing supporting cells in the central nervous system, taken from human stem cells such as myelin-producing cells is also covered in the patent.

The regional analysis covers:

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Global Stem Cell Therapy Market: Regional Outlook

The global market for stem cell therapy can be segmented into Asia Pacific, North America, Latin America, Europe, and the Middle East and Africa. North America emerged as the leading regional market, triggered by the rising incidence of chronic health conditions and government support. Europe also displays significant growth potential, as the benefits of this therapy are increasingly acknowledged.

Asia Pacific is slated for maximum growth, thanks to the massive patient pool, bulk of investments in stem cell therapy projects, and the increasing recognition of growth opportunities in countries such as China, Japan, and India by the leading market players.

Global Stem Cell Therapy Market: Competitive Analysis

Several firms are adopting strategies such as mergers and acquisitions, collaborations, and partnerships, apart from product development with a view to attain a strong foothold in the global market for stem cell therapy.

Some of the major companies operating in the global market for stem cell therapy are RTI Surgical, Inc., MEDIPOST Co., Ltd., Osiris Therapeutics, Inc., NuVasive, Inc., Pharmicell Co., Ltd., Anterogen Co., Ltd., JCR Pharmaceuticals Co., Ltd., and Holostem Terapie Avanzate S.r.l.

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Stem Cell Therapy Market Set to Witness an Uptick during 2017 to 2025 - Science In Me

Cardiac Stem Cells Comments Off on Stem Cell Therapy Market Set to Witness an Uptick during 2017 to 2025 – Science In Me | April 13th, 2020

it would be a good thing!

There are oodles of old rules in Cardiology. The provocateur in me loves it when dogma falls.

Niftier even, is when one can invoke the biology of newts to explain how yet another certainty was proven wrong.

As it turns out, those funny-looking mud-lovers possess a property that may revolutionize the treatment of heart disease. Unlike humans, newts can regrow damaged organs, including the heart! The newts organs contain cells that arent fully committed (biologists say terminally differentiated) to function.

Thats different than humans. Our organs, the heart among them, once damaged, do not recover. In humans, scar tissue replaces dead cells and the organ is diminished. This is how heart attacks result in heart failure: non-contracting scar tissue replaces the blood-starved (infarcted) muscle. This leads to a weaker pump (congestive heart failure) and susceptibility to rhythm problems (sudden death). Sadly, this process takes only an hour or so to occur. Hence the rush in stenting open a blocked artery.

Millions of heart patients suffer from weak hearts due to heart muscle damage. Until recently, most doctors held to the old belief that self-renewal of heart muscle is impossible. All doctors can do is micro-manage medicines and maybe implant risky defibrillators. The heart remains weak, the patient limited. The wordirreversibility.

Until recently that is.

New and emerging data reveals that our hearts may indeed have progenitor (stem) cells capable of growing into mature squeezing muscle cells. Call them, newt-like if you will.

Here goes the thinking: Unlike the newt, we humans cant signal heart stem cells to grow new muscle. But imagine if we could? Scar could be replaced with beating muscle, thereby restoring pump function. Heart attacks and heart muscle problems (cardiomyopathy), once thought permanently disabling, could be reversed like skin infections. Its like a fantasy.

Stem cells? Yes. I think its possible that cardiac stems cells may be the key that opens the treasure chest of the next generation of cardiac care. And how neat is it that my hometown, Louisville KY, happens to be at the epicenter of stem cell research?

Dr Roberto Bolli, a hard-working, self-made research scientist from Italy, who now chairs the Department of Cardiology at the University of Louisville has broken exciting new ground. His teams work, published in the journal, Lancet, has brought new momentum to the dreamy possibility of using cardiac stem cells to regrow damaged heart muscle.

Dr Bollis study (called SCIPIO) was the first in-man study of heart-derived stem cells. Previous stem cell studies used animal models, or those done in humans used bone marrow cells rather than heart cells.

Heres my brief synopsis of the Lancet study:

The U of L researchers enrolled patients with prior heart attacks and weakened hearts that were referred for bypass surgery. During surgery, a sample of the heart was cut out, sent to Boston where the cardiac stem cells were isolated. (This process involves serious biochemistry, above my pay grade; I like to think of the sample as being juiced down to the stem cells.). At four months, time enough for improvement from bypass to have occurred, one group (16 patients) underwent heart cath where a balloon angioplasty catheter was used to infuse a syringe full of the patients own (1 million) stem cells. The control group (7 patients) had standard bypass but no stem cell infusions.

The results were striking:

Compared to the control subjects who showed no improvement in heart function during the follow-up period (1 year), those who received stem cells sustained significant improvements in heart function, physical capacity and scored better on quality of life questionnaires. Most remarkably, ultrasound and MRI imaging revealed the areas where stem cells were infused showed the most improvement, and the enhanced squeezing function continued over the year. There were no safety issues with stem cell infusions.

These findings led the authors to conclude that cardiac stem cells induced regeneration of heart muscle.

Wow.

I have to admit that my knee-jerk reaction tended towards naysaying. No way could this work, I thought. The study involved only 16 patients followed for only a year. Lots of limitations. Very preliminary.

But after spending a couple of hours reading about the biology of stem cells, Im pretty excited about the Louisville research. For instance, I learned that injected stem cells might not have to en-graft themselves into the scar, rather they may signal the native heart to repair itself. Biologists call this a paracrine function.

Dr Bolli told our local paper that he has been besieged with letters from desperate patients with weakened hearts. Promising press reports on very early research tend to amplify hope. Rightly, Dr Bolli emphasizes the preliminary nature of this work. He adds that the SCIPIO study is ongoing and more data is forthcoming.

Its surely way too early to speculate on whether this novel approach evolves into Cardiologys Facebook or iPhone.

We will see. But let it be known that I am marking this post with a new category, Cardiac stem cells. Im keeping my eye on this exciting topic.

Put me down as optimistic and hopefulthe heart-healthy outlook.

JMM

Disclosure: I dont own Baxter stock.

h/t to Larry Husten (@cardiobrief)

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Cardiac Stem CellsHope for Congestive Heart Failure

Cardiac Stem Cells Comments Off on Cardiac Stem CellsHope for Congestive Heart Failure | April 12th, 2020

Supplemental Biologics License Application (sBLA) Accepted for KEYTRUDA Monotherapy in Patients Whose Tumors Are Tumor Mutational Burden-High (TMB-H) Who Have Progressed Following Prior Treatment

Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has accepted and granted priority review for a new supplemental Biologics License Application (sBLA) for KEYTRUDA, Merck's anti-PD-1 therapy. The application seeks accelerated approval of KEYTRUDA monotherapy for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors with tissue tumor mutational burden-high (TMB-H) 10 mutations/megabase, as determined by an FDA-approved test, who have progressed following prior treatment and who have no satisfactory alternative treatment options. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 16, 2020.

"From the start, biomarker research has been a critical aspect of our clinical program evaluating KEYTRUDA monotherapy," said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. "TMB has been an area of scientific interest to help identify patients most likely to benefit from KEYTRUDA. We look forward to working with the FDA throughout the review process to help bring KEYTRUDA monotherapy to patients with cancer in the second-line or higher treatment setting, where options remain limited."

The application was based in part on results from the Phase 2 KEYNOTE-158 trial, which also supported Merck's 2017 FDA approval for KEYTRUDA as the first cancer treatment based on a biomarker, regardless of cancer type, in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. MSI-H is on the highest end of the TMB spectrum. Data from KEYNOTE-158 on the TMB-H patient population were presented at the European Society for Medical Oncology (ESMO) 2019 Congress.

About KEYNOTE-158

KEYNOTE-158 (NCT02628067) is a multicenter, multi-cohort, non-randomized, open-label trial evaluating KEYTRUDA (200 mg every three weeks) in patients with solid tumors. Tissue TMB status was determined using the Foundation Medicine, Inc. FoundationOneCDx assay. Tumor response was assessed every nine weeks per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by independent, central, blinded radiographic review. The major efficacy outcome measures were objective response rate (ORR) and duration of response (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.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body's 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 industry's largest immuno-oncology clinical research program. There are currently more than 1,200 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

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.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of 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 confirmatory trials.

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 head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of 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.

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. 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 confirmatory trials. 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 [combined positive score (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 metastatic urothelial carcinoma (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 (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 (MSI-H) 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)

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.

Gastric Cancer

KEYTRUDA 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 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 recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

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 (RCC).

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes 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.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

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 a PD-1 or PD-L1 blocking antibody 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%).

In KEYNOTE-002, KEYTRUDA was permanently discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). The most common adverse reactions were fatigue (43%), pruritus (28%), rash (24%), constipation (22%), nausea (22%), diarrhea (20%), and decreased appetite (20%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those 1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those 2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those 2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those 2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with hepatocellular carcinoma (HCC) were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

More:
Merck Receives Priority Review from FDA for Second Application for KEYTRUDA (pembrolizumab) Based on Biomarker, Regardless of Tumor Type - Benzinga

Cardiac Stem Cells Comments Off on Merck Receives Priority Review from FDA for Second Application for KEYTRUDA (pembrolizumab) Based on Biomarker, Regardless of Tumor Type – Benzinga | April 12th, 2020

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Autologous Stem Cell and Non-Stem Cell Based Therapies Market: Incredible Possibilities, Growth With Industry Study, Detailed Analysis And Forecast To...

Cardiac Stem Cells Comments Off on Autologous Stem Cell and Non-Stem Cell Based Therapies Market: Incredible Possibilities, Growth With Industry Study, Detailed Analysis And Forecast To… | April 12th, 2020