ONL Therapeutics randomizes first European patient in phase 2 GA trial of Xelafaslatide

European investigators have begun enrolling patients in the phase 2 GALAXY trial evaluating xelafaslatide (formerly ONL1204), an investigational Fas pathway inhibitor, for the treatment of geographic atrophy (GA) secondary to dry age-related macular degeneration (AMD). The first European participant was recently randomized at a clinical site in Switzerland, marking the start of the trial’s European recruitment phase in what is planned as a global, multicenter study.

The trial, sponsored by ONL Therapeutics, aims to enroll approximately 324 patients across sites in Europe, the United States, and Canada. Investigators will evaluate the safety and efficacy of intravitreal xelafaslatide for slowing GA lesion progression, a key clinical endpoint in therapeutic development for this advanced stage of AMD. If successful, the program could add a neuroprotective strategy to a treatment landscape that has only recently seen the first regulatory approvals targeting disease progression.

Phase 2 GALAXY Trial Design

GALAXY (NCT06659445) is a randomized, double-masked, sham-controlled phase 2 study evaluating 2 dose levels of xelafaslatide administered via intravitreal injection at either 12-week or 24-week intervals. The study’s primary endpoint is the rate of GA lesion growth compared with sham treatment, measured by fundus autofluorescence at 48 weeks. Follow-up assessments are planned through 72 weeks to evaluate the durability of treatment effects.¹

According to the study protocol, approximately 324 participants with GA associated with dry AMD will be enrolled. An active reference arm will be included at US sites only, while the broader trial remains placebo-controlled.¹ Investigators aim to determine whether modulation of Fas signalling—a pathway implicated in retinal cell apoptosis—can slow degeneration of photoreceptors and other retinal cells implicated in GA progression.²

The phase 2 trial builds on earlier clinical studies of the compound. A phase 1b trial including 28 participants with GA evaluated dose escalation and randomized treatment components. The therapy was reported to be generally safe and well tolerated over a 24-week follow-up period, with exploratory analyses suggesting slower lesion growth in treated eyes compared with controls.³ These findings were considered hypothesis-generating and informed the design of the current randomized trial.

Clinical Context: Geographic Atrophy and Unmet Needs

Geographic atrophy is an advanced form of AMD characterized by progressive degeneration of the retinal pigment epithelium, photoreceptors, and choriocapillaris in the macula. The disease leads to irreversible central vision loss, often impairing activities such as reading and driving.²

Until recently, no pharmacologic therapies were available to slow disease progression. In 2023, the US Food and Drug Administration approved pegcetacoplan, a complement C3 inhibitor, as the first treatment for GA secondary to AMD. Phase 3 trials (OAKS and DERBY) showed that intravitreal pegcetacoplan reduced the rate of GA lesion enlargement by approximately 17% to 22% at 24 months compared with sham treatment.⁴⁻⁶ Later that year, avacincaptad pegol, a complement C5 inhibitor, also received approval, further expanding treatment options targeting the complement cascade.

Despite these advances, currently approved therapies require frequent intravitreal injections and primarily slow lesion growth rather than restoring vision. As a result, additional approaches targeting alternative mechanisms—including retinal neuroprotection—are under investigation.

Mechanism and Development Background

Xelafaslatide is a small-molecule inhibitor of the Fas receptor signalling pathway, which plays a role in apoptosis and inflammatory signalling in retinal degeneration. By inhibiting Fas activation, the drug is designed to prevent or reduce retinal cell death, potentially preserving photoreceptors and other critical retinal structures.²

The compound’s development program extends beyond GA. Xelafaslatide has also been evaluated in retinal detachment and glaucoma studies, and it has received orphan drug designation from the US FDA for the treatment of macula-off retinal detachment.²

In early clinical testing, intravitreal doses ranging from 50 µg to 200 µg were evaluated, with follow-up analyses focusing on safety, lesion growth rate, and visual acuity outcomes. While early signals suggested potential disease-modifying activity, the small sample size and exploratory nature of the analyses limit definitive interpretation of efficacy.

Interpretation and Remaining Questions

The initiation of European enrollment reflects the ongoing expansion of global clinical research in GA, where several therapeutic strategies—including complement inhibition, gene therapy, and neuroprotective agents—are being explored.

However, whether Fas pathway inhibition can translate into clinically meaningful slowing of GA progression remains uncertain. Previous experience with GA therapeutics has shown that reductions in lesion growth do not always correlate with improvements in visual function outcomes.⁴

The GALAXY trial will therefore provide important mid-stage evidence regarding both biological activity and dosing strategy for xelafaslatide. If the study demonstrates a meaningful effect on lesion growth with an acceptable safety profile—particularly with extended dosing intervals—it could justify progression to phase 3 development.

For now, investigators and clinicians will be watching closely as the trial advances enrollment across its international sites.

References

1. ClinicalTrials.gov. A Study to Evaluate the Efficacy and Safety of ONL1204 in Patients With Geographic Atrophy Associated With AMD (GALAXY). Updated 2025. https://clinicaltrials.gov/study/NCT06659445

2. ONL Therapeutics. ONL Therapeutics Announces Randomization of First Patient in Global Phase 2 GALAXY Trial of Xelafaslatide (ONL1204). October 28, 2025. https://onltherapeutics.com/2025/10/28/onl-therapeutics-announces-randomization-of-first-patient-in-global-phase-2-galaxy-trial-of-xelafaslatide-onl1204-in-patients-with-geographic-atrophy-ga-associated-with-dry-amd/

3. ONL Therapeutics. Phase 1b Study Results of Xelafaslatide in Geographic Atrophy. 2025. https://onltherapeutics.com/wp-content/uploads/2025/12/ONL-PR-2025.1209-GAPh1-Pub.pdf

4. Heier JS, Lad EM, Holz FG, et al. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet. 2023;402(10411):1434-1448. https://doi.org/10.1016/S0140-6736(23)01520-9

5. FDA Center for Drug Evaluation and Research. NDA 217171: Pegcetacoplan (SYFOVRE) Clinical Review. 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/217171Orig1s000SumR.pdf

6. Sadda SR, et al. Complement inhibition for geographic atrophy: emerging therapies and clinical implications. BMJ Open Ophthalmology. 2024. https://bmjophth.bmj.com/content/9/1/e001854