ONL Therapeutics is a clinical-stage biopharmaceutical company committed to developing breakthrough therapeutics to protect the vision of patients across a number of retinal diseases. Rooted in academic research, ONL Therapeutics is pioneering an entirely new approach to preserve sight. By advancing a novel biotechnology designed to prevent the death of key retinal cells caused by the activation of the Fas pathway, ONL Therapeutics is the first and only company focused on preventing Fas-mediated death of retinal cells, which is a root cause of vision loss and a leading cause of blindness.

Origins and the Vision

ONL Therapeutics traces its origins back to the groundbreaking research of Dr. David Zacks, the company’s founder and Chief Scientific Officer. Dr. Zacks, a renowned retina specialist and clinician–scientist at the University of Michigan, identified the critical role of the Fas receptor in triggering cell death in the retina. This seminal work, conducted over a decade ago, set the stage for the inception of ONL Therapeutics in 2011 and helped set its mission: to develop innovative therapeutics to protect and improve the vision of patients with a range of retinal diseases and conditions. The vision driving ONL Therapeutics is clear: to help patients see the future.

Taking the reins as the Chief Executive Officer of ONL Therapeutics five years ago, David Esposito brought a wealth of experience, with a background spanning 30 years in the life sciences. Combining his knowledge of the biopharmaceutical industry and his expertise in building early-stage innovation, his leadership has guided ONL Therapeutics through a transition from an academic breakthrough to a robust, visionary company. Under his care, ONL Therapeutics has overseen funding of the company; the issuance of a patent for ONL1204, ONL Therapeutics’ lead compound, in the United States; and the company’s journey through clinical trials for multiple back-of-the-eye diseases and conditions.

Visionary Science

The core of ONL Therapeutics’ groundbreaking biotechnology lies in inhibiting the Fas receptor, one of the body’s cornerstone mechanisms for triggering death of retinal cells in various eye diseases. Fas (also known as CD95 or APO-1) is a cell surface receptor bound to the cell membrane. It contains an intracellular “death domain” and, when activated, can trigger apoptosis or programmed cell death. Various disease stressors lead to Fas activation, triggering cell death. The death of vital cells in the retina is a root cause of vision loss and has been specifically associated with a number of retinal diseases.

Additionally, Fas plays a far-reaching role in regulating immune signaling and accompanying inflammation. Activation of the Fas receptor initiates production of chemokines and cytokines, signaling molecules that contribute to the inflammatory microenvironment. This function of Fas is becoming more widely understood and appreciated. Fas-mediated immune signaling can induce additional cell death, increase damage to the surrounding tissues, and worsen the initial injury from the disease.

Together, Fas-mediated cell death and inflammation have been implicated in the development and progression of many diseases and conditions –– in the eye and beyond. ONL Therapeutics and others have demonstrated critical role of Fas receptor in a wide range of retinal diseases, including retinal detachment, age-related macular degeneration (AMD), diabetic retinopathy, and glaucoma.

ONL Therapeutics’ primary scientific focus is Fas-mediated signaling initiated by the activation of the Fas receptor at the cell surface and implicated in a variety of diseases. Inhibition of Fas signaling at the receptor represents the most direct and upstream approach to preventing its negative impact. ONL Therapeutics believes that the therapeutic benefits of blocking Fas activation and its subsequent signaling may have wide-ranging clinical value for patients suffering from retinal diseases.

ONL1204: Molecular Guardian of Vision

At the heart of ONL Therapeutics’ work is ONL1204, a small 12–amino acid peptide designed to inhibit the Fas receptor and block the Fas-mediated activation that triggers cell death, thereby protecting retinal cells from disease development. What sets ONL1204 apart is not only its role in protecting retinal cells from cell death but also its ability to block the inflammatory response that the body typically induces in response to eye disease. Moreover, by targeting Fas upstream of other inflammatory pathways, ONL1204 achieves a dual effect: cell protection and a reduced inflammatory response. This translates into clinical outcomes in terms of a better efficacy profile in slowing disease progression across different diseases. “We’re creating a whole new approach to solving vision problems affecting millions of people, whose options until now have been severely limited,” says Dr. Zacks.

Rhegmatogenous Retinal Detachment

Rhegmatogenous retinal detachment, or retinal detachment (RD) for short, is an acute and serious vision-threatening condition. In RD, a tear in the retina allows liquefied vitreous to enter the subretinal space. This results in detachment of the photoreceptor layer in the retina from the retinal pigment epithelium, the principal source of metabolic support for the photoreceptors. Once detached, photoreceptors undergo a cascade of inflammation and cell death leading to vision loss. There are nearly 100,000 retinal detachment repair procedures performed annually in the United States alone.

The company strategically chose retinal detachment as its initial clinical focus for a number of reasons. First, Dr. Zacks is an international expert on the subject. Second, treatment of retinal detachment requires a surgical intervention. This allows for the collection of the human vitreous for further study. Initial assessment of the target engagement of ONL1204 confirmed the findings from the preclinical rat models and validated the target engagement of ONL1204 in human tissue. Given the surgical nature of the disease, treatment with ONL1204 is envisioned to provide additional protection to retinal cells. An injection at the time of diagnosis can provide additional safeguard until the surgery can take place.

In 2019, ONL Therapeutics received an approval from the Australian regulatory body to proceed with a phase I study of ONL1204 in patients with RD. Over the next couple of years, ONL1204 successfully cleared the safety review at four different doses: 25 µg, 50 µg, 100 µg, and 200 µg.

Earlier this year, ONL Therapeutics completed enrollment for a phase II study of retinal detachment. With the primary objective to evaluate two doses (50 μg and 200 μg), the study seeks to determine the safety and efficacy of a single intravitreal injection of ONL1204 as an adjunct to standard-of-care surgical repair in patients with retinal detachment.

Other Back-of-the-Eye Diseases: Macular Degeneration and Open-Angle Glaucoma

Following the work on retinal detachment, it has become clear that the Fas-mediated cascade is a core common pathophysiological mechanism that underlies cell death in the retina across multiple disease states. The causative stressors vary across various retinal diseases and conditions, but, regardless of the stressor, the pathways controlling cell death overlap. This raised the possibility that the neuroprotection provided by ONL1204 could be extended to these other conditions. Currently, ONL Therapeutics is looking beyond retinal detachment into other back-of-the-eye diseases, such as dry AMD , open-angle glaucoma, and inherited retinal degeneration.

Dry AMD is a major cause of visual disability and legal blindness globally. It is affected by aging, smoking habits, obesity, diet, and a growing list of genetic factors. Dry AMD is becoming an increasingly prevalent public health concern, especially as the global population ages. Geographic atrophy (GA) is a progressive form of dry AMD, often associated with an advanced degeneration of the macula.

Currently, there are two approved drug treatments for dry AMD (e.g., Syfovre and Izervay). They target a different, but complementary, pathway, but the efficacy of these already approved therapies are modest at best. There is an unmet need that ONL Therapeutics is looking to fill: namely, to provide better efficacy and a reduced treatment burden. ONL1204 not only appears to offer better treatment efficacy but it also offers a less frequent dosing schedule.

A phase I clinical study is currently underway for the treatment of patients with geographic atrophy. Its primary objective is to evaluate the safety of two doses (50 μg and 200 μg) of intravitreal injections of ONL1204 ophthalmic solution, dosed three months apart, and to explore efficacy signals, in subjects with geographic atrophy associated with dry MD. The study is ongoing and is being conducted in Australia and New Zealand. Unlike with retinal detachment, wherein ONL-1204 is an adjunct therapy to surgery, this is being used as a monotherapy.

Open-angle glaucoma (OAG) is a leading cause of blindness in people aged 60 years and older and affects approximately 44.7 million people worldwide with an estimated prevalence in the United States of at least 2.5 million people. OAG is characterized by damage to the retinal ganglion cell axons resulting in progressive visual field defects. Elevated intraocular pressure (IOP) is the primary risk factor, and reducing IOP is the only clinical approach to date that has been shown to mitigate vision loss. Despite the availability of effective IOP-lowering drugs, many patients require multiple drugs, and together they often fail to achieve a target IOP.

ONL Therapeutic is developing an alternative approach to directly protect retinal ganglion cells. There are currently no approved pharmacological therapies for neuroprotection in glaucoma. The development of ONL1204 ophthalmic solution addresses a clear unmet medical need — the prevention of vision loss in patients suffering from progressing OAG. ONL Therapeutics is uniquely positioned to provide a new, IOP-independent therapeutic approach to help doctors get better visual field preservation on top of pressure control.

ONL1204 is currently undergoing a phase I study to assess the safety and tolerability of intravitreal ONL1204 ophthalmic solution. The primary objective of this study is to evaluate the safety of two doses (50 μg and 100 μg) of two intravitreal injections of ONL1204, dosed three months apart, and to explore efficacy signals, in subjects with progressing OAG.

ONL1204 Safety and Eye’s Immune Privilege

“All these studies are showing that ONL1204 is safe when delivered into the eye", says Dr. Zacks. However, the prevalence of Fas-mediated cell death and inflammation in the eye and the rest of the body raises the question of off-target effects of ONL1204, especially outside the eye.

Given the intravitreal route of administration, the off-target effects of ONL1204 have not been noticeable. All clinical models to date have showed no detectable exposure to the rest of the body. This may be possible for two reasons. One, ONL1204 is a small, 12–amino acid peptide and is broken down rapidly in the serum. Two, the eye is immune privileged and provides a protected pharmacodynamic space for ONL1204, minimizing the risk for the rest of the body.

Partnerships that Propel Progress

ONL Therapeutics’ journey thrives on strategic collaborations. The partnership with Novai, a UK-based company with innovative technology, exemplifies ONL Therapeutics’ commitment to magnify its impact. Nova’s Detection of Apoptosing Retinal Cells (DARC) technology introduces a novel dimension to the clinical assessment. DARC fluorescently labels stressed or sick retinal cells, providing a unique biomarker for evaluating treatment efficacy. The collaboration with Novai empowers ONL Therapeutics to leverage DARC in identifying stressed cells in eye diseases, offering a glimpse into the potential of early intervention.

Looking Ahead: A Future Envisioned

While ONL Therapeutics’ current focus revolves around the back-of-the-eye diseases, including acute and chronic conditions, the future is ripe with possibilities. The Fas receptor’s relevance extends beyond ocular boundaries, prompting considerations of venturing into diseases of the brain, with applications for Alzheimer’s disease, schizophrenia, and other conditions where the Fas receptor may play a critical role. ONL Therapeutics acknowledges the extensive work ahead and remains driven by the clarity of the Fas receptor's relevance in safeguarding cells beyond ocular domains.

Within the eye, the company envisions a broader pipeline. The versatility of ONL1204's mechanism prompts exploration into diverse therapeutic landscapes. Chronic diseases like diabetic macular edema and inherited retinal degeneration emerge as potential candidates for ONL Therapeutics' intervention. The company's gene therapy program designed to inhibit the Fas receptor opens avenues for tackling genetic defects leading to retinal degeneration. However, the journey to these uncharted territories requires careful navigation. Reformulations, route optimizations, and a nuanced understanding of each disease's pathophysiology become paramount considerations.

ONL Therapeutics Team

All this work is made possible by the small, dedicated team at ONL Therapeutics. Derived from a university-based laboratory project, the company’s journey from the bench back to the bedside was first envisioned by Zacks and carried through by Esposito’s leadership. The company’s success is a testament both to the importance of funding for scientific research and the brilliance of individual people who make a vision a reality.