Noveome Biotherapeutics is a clinical-stage company focused on developing therapies for the regenerative repair of tissues. Their product ST266, a first-of-its-kind, multi-targeted, non-cellular platform biologic comprised of a complex mixture of biomolecules, is currently being evaluated as a potential treatment for the severe inflammatory response observed in the lungs of some COVID-19 patients.Technology Networks recently spoke with William J. Golden, Noveome Biotherapeutics Founder, Chairman and CEO, who explains the underlying basis for investigating ST266s potential against COVID-19. Golden also elaborates on many of the other indications for which ST266 is being developed to treat.Laura Lansdowne (LL): Could you provide our readers with a brief overview of Noveome Biotherapeutics?William J. Golden (WJG): Noveome is a clinical-stage biotherapeutics company located in Pittsburgh, PA. The company was founded in 2000 by Bill Golden and Lancet Capital. The group was interested in exploring non-embryonic stem cells and identified a technology at the University of Pittsburgh that was using cells derived from human amnion, a membrane that closely covers the fetus during development. The company, named Kytaron Technologies, Inc. at the time, licensed that amnion cell technology but, ultimately, Noveome scientists were able to discover, develop and patent their own unique population of cells, called Amnion-derived Multipotential Progenitor (AMP) cells, using a proprietary culture method that follows current Good Manufacturing Practice (cGMP) regulations. These novel cells were used to produce our product, ST266.LL: What is ST266? Could you elaborate on its mechanism of action in relation to the healing process?WJG: Noveomes product, ST266, is the secretome produced by the AMP cells. It is a completely cell-free solution and is comprised of hundreds of biologically active molecules, including cytokines and growth factors. Interestingly, these cytokines and growth factors exist at very low physiological levels ranging from pg/mL ng/mL concentrations.1 The fact that such low concentrations of these molecules are biologically active is quite remarkable when you consider that traditional protein-based therapies are usually administered at concentrations that are orders of magnitude greater than the concentrations found in ST266.Because the composition of ST266 is so complex, its multiple mechanisms of action have only been partially elucidated. Clinical and preclinical studies have shown ST266 to be anti-inflammatory,2,3 promote wound healing,4,5 reduce apoptosis, reduce vascular permeability (manuscript in preparation), and restore cellular homeostasis.3 Preclinical studies have also shown ST266 to be neuroprotective. In a traumatic brain injury model, ST266 significantly protected against reactive gliosis, suggesting potent anti-inflammatory activity, and resulted in significant recovery of rotarod motor function.6,7 In another study, ST266 was tested in the experimental autoimmune encephalopathy (EAE) mouse model of multiple sclerosis (MS). In this model, the mice develop optic neuritis, which is among the presenting symptoms of MS in humans. ST266 was administered to the nares of mice 15 or 22 days after disease induction. ST266 is absorbed via capillary action along the olfactory nerves which bypasses the blood-brain barrier. This unique route of administration allows for the delivery of high molecular weight biologics to the optic nerve of the eye and the central nervous system. ST266 attenuated visual dysfunction, prevented retinal ganglion cell (RGC) loss, reduced inflammation, and decreased the rate of demyelination of the optic nerve in EAE mice.3Mechanistically, ST266 simultaneously acts on multiple cell receptor-activated and intracellular signaling pathways. For example, in the EAE MS model, neuroprotective effects involved oxidative stress reduction, SIRT1-mediated mitochondrial function promotion, and pAKT signaling.3 In a Phase 2 UV light burn study, ST266 reduced erythema and DNA damage and increased the expression of XPA DNA repair proteins.2Importantly, ST266 has a proven clinical safety profile. It has been administered to 243 patients by various routes of administration (topical skin, topical ocular, topical oral, targeted intranasal), and no drug-related serious adverse events have been reported. Preclinical studies of systemically administered ST266 have also yielded no drug-related safety concerns.LL: For what indications is ST266 currently being evaluated as a treatment?WJG: We refer to ST266 as a platform biologic. By this, we mean that ST266 is one product that has the potential to treat numerous and varied diseases. In the clinic, we have shown anti-inflammatory activity when ST266 is applied topically to UV light-burned the skin2 and topical application to the gums of patients with gingivitis and periodontitis showed a reduction in proinflammatory cytokines in the patients crevicular fluid (manuscript in preparation). We are currently conducting a Phase 2 open label trial of ST266 to treat persistent corneal epithelial defects (PEDs) when applied topically to the eye. Results from this trial will be published soon. We are currently planning a Phase 2b multi-center, randomized, double-masked trial to further evaluate the safety and efficacy of ST266 in this indication. Finally, we are conducting a Phase 1 study in patients at risk for developing glaucoma. This study is using the intranasal route of delivery described above in combination with a novel delivery device. The goal is to deliver ST266 directly to the optic nerve, where it can protect the RGCs that are damaged in glaucoma. We envision this route of delivery will be applicable to central nervous system and other back-of-the eye indications.We also have several ongoing preclinical programs that are evaluating systemically administered ST266 for more generalized inflammatory conditions. These data are not yet published but combined with the data we have compiled in preclinical and clinical studies of topical skin, topical oral and topical ocular administration, we believe ST266 has the potential to be an effective therapy for numerous systemic inflammatory conditions.LL: Could you elaborate on the underlying basis for your evaluation of ST266 as a potential treatment for COVID-19?WJG: As you know, a major complication of COVID-19 is the severe inflammatory response seen in the lungs of some patients. This response is called cytokine storm or cytokine release syndrome. As the pandemic continues and more data have become available, it is now known that the cytokine storm does not just affect the lungs. Multi-organ damage occurs in many of these patients. We believe that systemic delivery of ST266 and its anti-inflammatory activity has the potential to calm the storm. Our as-yet-unpublished preclinical studies with intravenous ST266 support this hypothesis and we are moving rapidly to initiate intravenous ST266 in a Phase 1 study. Once safety in humans is established by this route of administration, we will commence Phase 2 studies in COVID-19 patients.William J. Golden was speaking to Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.References

1. Steed, DL, C Trumpower, D Duffy, C Smith, V Marshall, R Rupp, and M Robson. (2008). Amnion-Derived Cellular Cytokine Solution: A Physiological Combination of Cytokines for Wound Healing. Eplasty 8: 15765.

2. Guan, Linna, Amanda Suggs, Emily Galan, Minh Lam, and Elma D. Baron. (2017). Topical Application of ST266 Reduces UV-Induced Skin Damage. Clinical, Cosmetic and Investigational Dermatology. DOI: https://doi.org/10.2147/CCID.S147112.

3. Khan, Reas S, Kimberly Dine, Bailey Bauman, Michael Lorentsen, Lisa Lin, Helayna Brown, Leah R Hanson, et al. (2017). Intranasal Delivery of A Novel Amnion Cell Secretome Prevents Neuronal Damage and Preserves Function In A Mouse Multiple Sclerosis Model. Scientific Reports. DOI: https://doi.org/10.1038/srep41768.

4. Bergmann, Juri, Florian Hackl, Taro Koyama, Pejman Aflaki, Charlotte a Smith, Martin C Robson, and Elof Eriksson. (2009). The Effect of Amnion-Derived Cellular Cytokine Solution on the Epithelialization of Partial-Thickness Donor Site Wounds in Normal and Streptozotocin-Induced Diabetic Swine. Eplasty 9: e49.

5. Franz, Michael G, Wyatt G Payne, Liyu Xing, D K Naidu, R E Salas, Vivienne S Marshall, C J Trumpower, Charlotte A Smith, David L Steed, and M C Robson. (2008). The Use of Amnion-Derived Cellular Cytokine Solution to Improve Healing in Acute and Chronic Wound Models. Eplasty 8: e21.

6. Deng-Bryant, Ying, Zhiyong Chen, Christopher van der Merwe, Zhilin Liao, Jitendra R Dave, Randall Rupp, Deborah a Shear, and Frank C Tortella. (2012). Long-Term Administration of Amnion-Derived Cellular Cytokine Suspension Promotes Functional Recovery in a Model of Penetrating Ballistic-like Brain Injury. The Journal of Trauma and Acute Care Surgery DOI: https://doi.org/10.1097/TA.0b013e3182625f5f.

7. Deng-Bryant, Ying, Ryan D. Readnower, Lai Yee Leung, Tracy L. Cunningham, Deborah A. Shear, and Frank C. Tortella. (2015). Treatment with Amnion-Derived Cellular Cytokine Solution (ACCS) Induces Persistent Motor Improvement and Ameliorates Neuroinflammation in a Rat Model of Penetrating Ballistic-like Brain Injury. Restorative Neurology and Neuroscience. DOI: https://doi.org/10.3233/RNN-140455.

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