ONL Therapeutics reports positive phase 1b data for xelafaslatide in geographic atrophy

ONL Therapeutics has released data from its phase 1b study of xelafaslatide (formerly known as ONL1204 ophthalmic solution) for the treatment of geographic atrophy (GA).

According to the company, xelafaslatide is a small-molecule Fas inhibitor designed to protect key retinal cells, including photoreceptors, from cell death that occurs across multiple retinal diseases and conditions, including GA associated with dry age-related macular degeneration (AMD)

The trial (NCT04744662) was a randomized, double-masked, multicenter study across 9 sites in Australia and New Zealand, comparing xelafaslatide to sham. The study itself was comprised of 2 components, the first of which evaluated xelafaslatide at 3 doses (50 μg, 100 μg, and 200 μg) using a single-injection dose-escalation/open-label design (DE/OL). While the second component of the trial utilized a natural history/treatment (NHS/T), allowing for an initial observation period of 24 weeks, after which patients were randomized to receive 2 treatments of either a 50 μg or 200 μg dose of xelafaslatide or sham, 3 months apart.^1-3

The primary endpoints of the study were safety and tolerability of xelafaslatide in patients with GA secondary to AMD, assessed in both the DE/OL and NHS/T components.^2,3

Criteria for enrollment in the DE/OL component required patients to be ≥55 years of age and have a diagnosis of GA secondary to AMD in the study eye, as well as a best-corrected visual acuity (BCVA) ranging from 20/100 to Counting Fingers (Snellen equivalent) as measured by the ETDRS chart.^2,3

In the trial, 28 patients were enrolled: 6 in the DE/OL component and 22 in the NHS/T component. For the 6 patients in the DE/OL component (mean age 78.3±6.4), each patient received a single injection of xelafaslatide at 50, 100, or 200 μg (nonrandomized; n=2 per dose). All patients in the DE/OL component were included in the safety population of the trial. Of the 22 patients in the NHS/T component (mean age 77.6±7.5), 17 were randomized into the treatment phase (5 patients withdrew from the trial prior to randomization). Treatment for this group included sham injection (n=6), xelafaslatide at 50 µg (n=5), and xelafaslatide at 200 µg (n=6).^1-3

Fifteen patients completed treatment, with 1 withdrawing from both sham and 50 µg. Five (83.3%) patients in the sham group, 4 (80.0%) patients in the 50 µg group, and 5 (83.3%) patients in the 200 µg group received both treatments. Three treatment-emergent adverse events (TEAE) were seen in 2 patients (increased IOP and vitreous floaters in 1 and open-angle glaucoma in the other) in the 200 µg group.²

BCVA at baseline for the study and fellow eyes in the DE/OL component was 23.0 and 66.8 ETDRS letters, respectively. Results showed that mean BCVA at week 24 was 30.3 and 68.5 ETDRS letters, showing an improvement of 7.3 and 1.6 letters for the study eyes and fellow eyes, respectively.

While in the NHS component, mean BCVA changes from baseline during the treatment phase compared with the NHS phase were –7.00 ETDRS letters for sham participants, +1.25 ETDRS letters for ONL1204 50μg participants, and +6.50 ETDRS letters for xelafaslatide 200μg. The differential BCVA between the sham and xelafaslatide 50µg group was +8.25 letters, and +13.5 letters for the 200 µg group.

According to authors of the study,² results suggest that the “novel mechanism of action of [xelafaslatide] as a small peptide acting to inhibit the interaction of the Fas receptor with Fas ligand may offer new opportunities to slow the progression of GA associated with AMD.” Additionally, numerically favorable slower lesion growth was seen compared with the fellow eye in the DE/OL component at 6 months and a numerically slower growth rate (mean difference of –0.524 mm² [0.39]; P = 0.202) in the 200 μg xelafaslatide group compared with the sham group in the treatment phase of the NHS/T component.

David N Zacks, MD, PhD, chief scientific officer of ONL Therapeutics, commented,¹ “Geographic atrophy remains one of the most devastating challenges in ophthalmology. With its unique mechanism of action targeting the Fas pathway and dosing every 3 or 6 months, xelafaslatide has the potential to protect vision while easing the treatment burden for patients. Our ultimate goal is to advance this neuroprotection therapy and redefine what is possible for patients living with this progressive disease.”

Recently, ONL Therapeutics announced the first patient was randomized in its phase 2 GALAXY (NCT06659445) trial evaluating xelafaslatide in patients with GA associated with dry AMD. Xelafaslatide has also received orphan drug designation by the United States Food and Drug Administration (FDA) for the treatment of macula-off retinal detachment.¹

References:

1. ONL Therapeutics Announces Publication of Data from Phase 1b Study of Xelafaslatide, an Investigational Therapy for Geographic Atrophy, in Ophthalmology Science. Published December 9, 2025. Accessed December 9, 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. ONL1204 for the Treatment of Geographic Atrophy: Phase Ib Study Evaluating Safety, Tolerability, and Efficacy. Kleinman, David M. et al. Ophthalmology Science, Volume 6, Issue 1, 100954

3. ONL1204 Ophthalmic Solution in Patients With Geographic Atrophy Associated With Age-related Macular Degeneration. NCT04744662. https://clinicaltrials.gov/study/NCT04744662?tab=table