ONL Therapeutics reports positive phase 1b data for xelafaslatide in GA

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 conducted across 9 sites in Australia and New Zealand, comparing xelafaslatide with a sham control. The study comprised 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). The second component utilized a natural history/treatment (NHS/T), allowing for an initial observation period of 24 weeks, after which patients were randomly assigned to receive 2 treatments of either a 50-μg or 200-μg dose of xelafaslatide or sham, 3 months apart.^1-3

The study's primary end points were the safety and tolerability of xelafaslatide in patients with GA secondary to AMD, assessed in the DE/OL and NHS/T components.^2,3

Criteria for enrollment in the DE/OL component included the following:

• 55 years or older
• Diagnosis of GA secondary to AMD in the study eye
• Best-corrected visual acuity (BCVA) ranging from 20/100 to counting fingers (Snellen equivalent) as measured by the ETDRS chart.^2,3

Investigators enrolled 28 patients in the trial: 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 μg, 100 μg, or 200 μg (nonrandomized; n = 2 per dose). All patients in the DE/OL component were included in the trial's safety population. Of the 22 patients in the NHS/T component (mean age, 77.6 ± 7.5), 17 were randomly assigned to 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%) in the 50-µg group, and 5 (83.3%) in the 200-µg group received both treatments. Three treatment-emergent adverse events 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 50-μg participants, and +6.50 ETDRS letters for xelafaslatide 200 μg. The differential BCVA between the sham and xelafaslatide 50-µg group was +8.25 letters, and +13.5 letters for the 200-µg group.

According to the study authors,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, –0.524 mm² [0.39]; P = 0.202) in the 200-μg xelafaslatide group than in the sham group in the treatment phase of the NHS/T component.

David N. Zacks, MD, PhD, chief scientific officer at 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 that the first patient had been randomized in its phase 2 GALAXY (NCT06659445) trial evaluating xelafaslatide in patients with GA associated with dry AMD. Xelafaslatide has also received an orphan drug designation from the 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. News release. ONL Therapeutics. 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. 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

3. ONL1204 ophthalmic solution in patients with geographic atrophy associated with age-related macular degeneration. ClinicalTrials.gov. Updated November 19, 2024. Accessed December 11, 2025. https://clinicaltrials.gov/study/NCT04744662?tab=table