ONL Therapeutics Submits IPO Prospectus to Advance First-in-Class Fas Inhibitor ONL1204 for Retinal Diseases

"To help patients see the future," ONL Therapeutics states on its official website.

ONL Therapeutics is a clinical-stage biopharmaceutical company with the vision of helping patients suffering from a range of retinal diseases to protect and improve their vision. The company was founded in 2011 in Ann Arbor, Michigan, USA.

The World Health Organization (WHO) disclosed that ophthalmic diseases have become the third most hazardous and impactful disease affecting people's quality of life, following tumors and cardiovascular diseases. The first World Report on Vision released by WHO shows that among 2.2 billion people worldwide with vision impairment, at least 1 billion cases of vision impairment or blindness could have been prevented or have yet to receive effective treatment. These include untreated cataracts (65.2 million), glaucoma (6.9 million), corneal opacity (4.2 million), diabetic retinopathy (3 million), and others.

Leveraging its expertise in retinal neuroprotection, ONL Therapeutics is developing novel therapies for retinal diseases that severely threaten vision. Fas-mediated apoptosis of key retinal cells is the root cause of vision loss, the primary cause of blindness, and represents a significant unmet medical need. ONL Therapeutics is the world's first and only company focused on preventing Fas-mediated apoptosis of key retinal cells.

ONL Therapeutics' lead candidate drug, ONL1204, is a small peptide Fas inhibitor designed to protect retinal cells from apoptosis and inflammatory signaling pathways. The company owns an intellectual property system centered around the Fas pathway and its candidate drugs. By advancing a breakthrough technology aimed at preventing the apoptosis of key retinal cells caused by natural Fas pathway activation, ONL Therapeutics has pioneered a completely new approach to vision protection.

The focus of ONL Therapeutics' research and development efforts is on Fas-mediated signaling. This signaling, activated by the Fas receptor on the cell surface, is considered one of the cornerstone mechanisms by which the body initiates apoptosis. Apoptosis of critical cells is a fundamental cause of many diseases and is particularly relevant to numerous ophthalmic conditions. Fas-mediated immune signaling can induce additional apoptosis, increase damage to surrounding tissues, and exacerbate existing injuries.

Among them, the Fas receptor refers to the receptor of TNFSF6/FASLG, also known as the apoptosis-mediating surface antigen Fas and Apo-1 antigen. It is a cell surface protein that mediates apoptosis after binding with the Fas ligand. Fas-mediated programmed cell death is a naturally occurring cell death pathway that can be activated by various factors, such as oxidative stress, inflammation, ischemia, and trauma. When the Fas pathway is activated, it triggers a series of reactions, leading to cellular self-destruction.

Fas-mediated programmed cell death (including apoptosis) plays a critical role in photoreceptor loss, and photoreceptor cell death is the final cause of various retinal diseases and even permanent vision loss. ONL Therapeutics has demonstrated that Fas plays a significant role in inducing multiple retinal diseases, including retinal detachment, dry and wet age-related macular degeneration, uveitis, diabetic retinopathy, glaucoma, and optic neuropathy.

Inhibiting Fas signaling on the receptor is the most direct and upstream method to prevent its negative effects. ONL Therapeutics believes that blocking Fas activation and its subsequent signaling has broad clinical value in treating retinal diseases. Meanwhile, David Zacks, a pioneer and recognized thought leader in the fields of retinal neuroprotection and photoreceptor physiology, co-founder and chief scientist of ONL Therapeutics, demonstrated that the Fas pathway largely contributes to cell death and discovered a unique molecule capable of blocking the Fas receptor and protecting photoreceptors. Thus, ONL1204 was born.

ONL1204 is a novel small-molecule Fas inhibitor and the lead candidate of ONL Therapeutics, designed to protect key retinal cells, including photoreceptors, from a range of retinal diseases and the associated cell death occurring under these conditions.

ONL1204 is a small molecule peptide that works by inhibiting the Fas pathway to prevent the apoptosis of key retinal cells, such as photoreceptors. ONL1204 can bind to the Fas receptor, blocking its interaction with the Fas ligand, thereby preventing the activation of the Fas pathway and protecting retinal cells from apoptosis. Additionally, ONL1204 can inhibit inflammatory signaling pathways, further reducing retinal damage.

ONL1204 can protect various retinal cells, including photoreceptor cells, retinal pigment epithelial cells, and ganglion cells, thereby delaying or halting the progression of vision loss. It can also serve as an adjuvant therapy, combined with existing standard care procedures or medications, to enhance treatment efficacy and visual outcomes. It has a broad range of indications and can be used to treat multiple severe retinal diseases that may lead to blindness, including rhegmatogenous retinal detachment (RRD), central retinal artery occlusion (CRAO), glaucoma, and vascular eye diseases, among others. Currently, this compound has been granted orphan drug designation by the U.S. Food and Drug Administration (FDA).

On April 12, 2023, ONL Therapeutics announced that the first patient had been dosed in the Phase 2 clinical trial of ONL1204 ophthalmic solution for patients with macular hole-associated retinal detachment (RRD). The Phase 2 clinical trial is a randomized controlled study, enrolling 135 patients divided into three groups, including two treatment groups and one sham control group. The aim of the study is to evaluate the safety and efficacy of a single intravitreal (IVT) injection of ONL1204 as an adjunct to standard-of-care surgical repair for subjects with macula-off RRD across approximately 30 regions in the United States.

David Zacks, MD, PhD, Co-Founder and Chief Scientific Officer of ONL Therapeutics, stated that this is the first time the company has brought ONL1204 to patients and clinicians in the United States, marking an important milestone. "With its unique and differentiated mechanism of action targeting the Fas activation pathway, we look forward to advancing the clinical development of ONL1204 as a potential breakthrough neuroprotective therapy to address unmet medical needs across many ophthalmic conditions, including RRD."

Many clinicians recognize a significant unmet medical need in the field of ophthalmic diseases: a therapy that can protect patients' photoreceptor cells during the critical period after diagnosis and before surgery, and that should provide better visual outcomes after the retina reattaches. "ONL1204, a first-in-class neuroprotectant, can serve as an adjunctive treatment to standard-of-care surgery for patients with macular retinal detachment, which is exciting for professionals in the retina space," said Dr. Zacks.

ONL Therapeutics has a management and expert advisory team with decades of experience in drug development and retinal diseases. Its president and CEO, David Esposito, is the former CEO of Armune BioScience, where he led the development and commercialization of blood-based diagnostic technologies to improve early cancer detection, bringing extensive experience in healthcare. Co-founder and chief scientist David Zacks is an ophthalmology professor and clinician-scientist at the Kellogg Eye Center of the University of Michigan, with 15 years of experience in the molecular regulatory mechanisms controlling photoreceptor death or survival in retinal diseases.

Moreover, its Scientific Advisory Board includes many of the nation's top ophthalmology thought leaders, such as Dr. Joan W. Miller, Chair of the Department of Ophthalmology at Harvard Medical School and Chief of Ophthalmology at Massachusetts Eye and Ear and Massachusetts General Hospital, and Dr. Allen Ho, Director of the Clinical Retina Research Unit at Wills Eye Hospital, retinal surgeon, and Professor of Ophthalmology at Thomas Jefferson University. They provide authoritative and cutting-edge ophthalmic academic information and technical guidance to the company, helping ONL Therapeutics optimize its product development strategies and clinical trial designs.

On March 8, 2023, ONL Therapeutics announced the completion of a $15 million Series C financing round. This round was led by Visionary Venture Fund, Mayewell Capital, Bios Partners, and Alpine Visionary, with participation from PSQ Capital, MINTS, Kaitai Capital, and others. The funding supports the Phase 2 clinical trial of ONL1204 ophthalmic solution for patients with macular-off rhegmatogenous retinal detachment (RRD), as well as the company’s regulatory preparations for the GA and OAG second-phase projects.

Next, ONL Therapeutics will continue to focus on the clinical trials of ONL1204. The company is currently conducting a Phase 1b clinical trial (NCT04744662) in Australia and New Zealand for patients with geographic atrophy (GA) associated with age-related macular degeneration (AMD), as well as a Phase 1b clinical trial (NCT05160805) for patients with advanced open-angle glaucoma. Ongoing preclinical work will expand to other disease indications, including clinical trials for inherited retinal degeneration (IRD). In the future, ONL Therapeutics plans to further develop ONL1204, advance therapeutic innovations in the field of retinal diseases, and provide patients with more effective and safer treatment options.