Prevention of photoreceptor cell death with intravitreal Fas-receptor antagonist

DESCRIPTION (provided by applicant): Death of photoreceptor cells is a consequence of many acute as well as chronic retinal diseases which lead to severe vision loss in patients. If photoreceptors could be helped to survive the period of disease, the visual outcomes for patients would be significantly better. Retinal degenerative disease and injury are among the leading causes of irreversible vision loss and blindness in the United States and the developed world, affecting hundreds of thousands of people every year and resulting in billions of dollars in added healthcare costs and lost productivity. A problem limiting the efficacy of current treatments is that currently there are no interventions that can specifically prevent photoreceptor cell death; therefore, a safe, potent, photoreceptor protectant would provide a significant visual benefit to hundreds of thousands of people every year. ONL Therapeutics is developing a product candidate, a novel small peptide inhibitor of the Fas receptor (ONL-101), forperi-operative adjunctive use in patients with acute retinal detachment (an orphan indication), with the goal of preventing photoreceptor cell death until definitive surgical repair can occur. This acute indication provides a rapid development pathway that will lay the groundwork for future expansion of ONL-101 development for chronic indications such as AMD (Age Related Macular Degeneration). The product for acute retinal detachment will be a prescription drug for single dose intravitreal injection (an established route of administration in ophthalmology). Upon completion of this SBIR Phase I study, ONL Therapeutics will have tested and validated the hypothesis that it is feasible to deliver therapeutic levels of ONL-101 to the retina by intravitrel injection. We will demonstrate that: 1) Intravitreal injection of ONL-101 results in measurable levels of drug in the retina, 2) Intravitreal injection of ONL-101 results in dose-dependent photoreceptor preservation in a well-established rodent model of retinaldetachment, and 3) the therapeutic target retinal concentration, as determined in the rodent studies, can be achieved after intravitreal injection in the rabbit, a large animal model that that more closely resembles te human eye in size and function than the rodent model. The results obtained from this Phase I study will lay the foundation for the Phase II SBIR application, which will focus on formulation, toxicity studies and finalization of the IND package required to begin clinical trials for the use f ONL-101 as an adjunctive treatment in patients with macula-off retinal detachments. The commercialization strategy for ONL Therapeutics is to partner with a large ocular pharmaceutical company for Phase I-III clinical trials to establish safety and efficacyin humans. PUBLIC HEALTH RELEVANCE: Diseases of the retina are a leading cause of irreversible blindness in the United States and result in tremendous social and economic impact on patients and society. ONL Therapeutics, LLC is dedicated to the development of a novel therapeutic agent that will prevent photoreceptor cell death during retinal disease. Successful development of our lead product, ONL-101, a small peptide antagonist of the Fas-receptor, would result in the first photoreceptor neuroprotective agent available to physicians to improve visual outcomes and reduce blindness in patients.