The Retina TL;DR with Dr. Weng: Targeting the Fas signaling pathway with David Zacks, MD, PhD

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In this episode of The Retina TL;DR with Dr. Weng, powered by Modern Retina, host Christina Y. Weng, MD, MBA, FASRS, welcomes David Zacks, MD, PhD, the Edna H. Perkiss Research Professor of Ophthalmology and Visual Sciences at the University of Michigan, Kellogg Eye Center, in Ann Arbor, and co-founder and chief scientific officer of ONL Therapeutics. Their discussion centers on ONL1204, a first-in-class investigational therapy targeting the Fas signaling pathway to provide neuroprotection across multiple retinal diseases. Weng is professor and the Alice R. McPherson Retina Research Foundation Chair in Ophthalmology, and fellowship program director, vitreoretinal diseases and surgery, with Baylor College of Medicine in Houston, Texas. (Editor’s note: ONL1204 has been renamed xelafaslatide. For consistency, the article refers to the therapy as ONL1204 throughout.)

A platform for neuroprotection

When asked to summarize the company’s “TL;DR” (“too long; didn’t read”), Zacks said, “ONL Therapeutics is building a platform for neuroprotection.” He explained that ONL1204 has been studied in retinal detachment, geographic atrophy (GA) secondary to age-related macular degeneration (AMD), and open-angle glaucoma. Across these indications, the molecule has shown “strong efficacy signals for the potential to prevent retinal cell death and to improve vision for these patients.”

Why target the Fas signaling pathway?

Zacks described Fas as “an upstream activator of cell death and inflammation” that becomes activated in the retina under stressors such as retinal detachment, elevated intraocular pressure, and oxidative stress in AMD. Activation of this pathway leads to both direct cell death and an inflammatory cascade. ONL1204 is designed to inhibit Fas at the initiation point, addressing both processes. As Zacks noted, inflammation “serves to amplify and accelerate the degenerative processes,” and dual inhibition may help preserve retinal cell health and viability.

Inside ONL1204

ONL1204 is a 12–amino acid peptide designed for intravitreal injection. Phase 1 trials have been completed in open-angle glaucoma and GA, and the program has advanced through a phase 2 study in macula-off rhegmatogenous retinal detachment. Although these conditions may seem disparate, Zacks explained that stressed retinal cells respond through common mechanisms. “They’re responding to the stress through the end and dying through the Fas pathway,” providing the rationale for evaluating ONL1204 across multiple indications.

Lessons from the retinal detachment program

Zacks highlighted the unmet need in retinal detachment, where successful surgery does not always prevent permanent vision loss due to photoreceptor damage. In the phase 2 macula-off retinal detachment trial, patients received a single ONL1204 injection at diagnosis, followed by standard vitrectomy surgery with or without scleral buckle. Although the study did not meet its primary end point of contrast sensitivity, prespecified analyses showed a significantly higher percentage of treated patients achieved 20/50 vision or better. Post hoc analyses suggested that patients with macula-off duration of 8 days or longer—particularly pseudophakic patients—achieved “1 to 2 lines better visual acuity” compared with surgery alone.

Geographic atrophy: The next focus

The discussion concluded with ONL Therapeutics’ phase 2 GA trial (Editor's note: The GALAXY trial started enrolling in October 2025).^1,2

In a prior phase 1 study, intravitreal ONL1204 was shown to be safe and well tolerated without subsequent surgery. Zacks reported efficacy signals, including slowing of GA lesion growth by up to 50% after 2 injections given 3 months apart, with some patients experiencing improved vision. “By stopping cell death, blocking the Fas pathway… we slow lesion growth,” he said. The international phase 2 study will enroll approximately 325 patients, with GA lesion growth as the primary end point.

Additional resources

For more information about ONL1204 and ONL Therapeutics’ broader development programs, Zacks encourages ophthalmologists to visit the company’s pipeline page or follow recent news releases for clinical updates and announcements.

Christina Y. Weng, MD, MBA, FASRS, is professor and the Alice R. McPherson Retina Research Foundation Chair in Ophthalmology, and fellowship program director, vitreoretinal diseases and surgery with Baylor College of Medicine in Houston, Texas. Weng is a consultant for Astellas Pharma, Apellis Pharmaceuticals, and Annexon Biosciences.

David Zacks, MD, PhD, is the Edna H. Perkiss Research Professor of Ophthalmology and Visual Sciences at the University of Michigan, Kellogg Eye Center, in Ann Arbor, and co-founder and chief scientific officer of ONL Therapeutics.

REFERENCES

1. ONL Therapeutics announces publication of data from Phase 1b study of xelafaslatide, an investigational therapy for geographic atrophy, in Ophthalmology Science. News release. December 9, 2025. Accessed December 18, 2025. https://onltherapeutics.com/2025/12/09/onl-therapeutics-announces-publication-of-data-from-phase-1b-study-of-xelafaslatide-an-investigational-therapy-for-geographic-atrophy-in-ophthalmology-science/

2. Kleinman DM, Wykoff CC, Borkar DS, et al. ONL1204 for the treatment of geographic atrophy: Phase Ib study evaluating safety, tolerability, and efficacy. Ophthalmol Sci. 2025;6(1):100954. doi:10.1016/j.xops.2025.100954