ONL Therapeutics Advances Xelafaslatide Phase 2 Trial for Geographic Atrophy Treatment

This analysis is based on the ONL Therapeutics announcement [1] published on October 28, 2025, regarding the randomization of the first patient in the global Phase 2 GALAXY trial evaluating xelafaslatide for geographic atrophy treatment.

ONL Therapeutics has achieved a significant clinical development milestone with the randomization of the first patient in its Phase 2 GALAXY trial for xelafaslatide (ONL1204) in patients with geographic atrophy (GA) associated with dry age-related macular degeneration [1]. This progression follows recent regulatory approvals from the World Health Organization and the United States Adopted Names Council establishing “xelafaslatide” as the official nonproprietary name for ONL1204 Ophthalmic Solution [1].

The therapeutic represents a first-in-class approach through its Fas receptor inhibition mechanism, fundamentally differentiating it from current FDA-approved GA treatments that target complement proteins [1]. Xelafaslatide functions as a small peptide designed to protect retinal cells from apoptosis by blocking Fas activation at the receptor level, thereby preventing downstream death pathways and inflammatory cascades [3]. This neuroprotective strategy contrasts with the inflammation-focused approach of existing complement inhibitors [2].

The Phase 2 GALAXY trial is evaluating two dosing frequencies (every 12 weeks and every 24 weeks) at dose levels of 100 µg and 200 µg over a 72-week treatment period [2]. This extended dosing schedule could substantially reduce treatment burden compared to current approved therapies requiring administration every 25-60 days [4]. Previous Phase 1b results demonstrated that xelafaslatide was generally safe and well-tolerated, with efficacy signals showing slowed GA lesion growth compared to untreated eyes after 6 months [2].

: Xelafaslatide’s Fas inhibition approach represents a paradigm shift from complement inhibition to neuroprotection in GA treatment. By targeting cell death prevention rather than inflammation reduction, the therapy addresses the underlying pathology at a different biological level [3]. This mechanism may offer broader application potential across multiple retinal diseases, with ongoing studies also evaluating the therapy in progressive open-angle glaucoma and rhegmatogenous retinal detachment [2].

: The GA treatment market is experiencing rapid growth, projected to expand from $1.86 billion in 2024 to $3.50 billion by 2029 at a 13.5% CAGR [5]. With only two FDA-approved complement inhibitors currently dominating the market, xelafaslatide’s entry could capture significant market share, particularly if it demonstrates superior efficacy or safety profiles. Current market leaders IZERVAY and SYFOVRE are projected to reach approximately $2.26 billion and $1.98 billion in revenues respectively by 2034 [5].

: ONL Therapeutics has implemented a comprehensive development approach with multiple indication expansion potential. The therapy’s established safety profile across completed clinical studies provides a strong foundation for advancement [2]. The 72-week treatment duration in the Phase 2 trial exceeds many current therapy evaluation periods, potentially providing more robust efficacy data for regulatory submission.

: The therapy must demonstrate meaningful slowing of GA progression to compete with established complement inhibitors [4]. Long-term safety data will be crucial given the chronic nature of GA treatment, and regulatory approval remains contingent on successful Phase 2 and subsequent Phase 3 trial results. The novel mechanism may face additional scrutiny from regulatory agencies requiring comprehensive safety validation.

: Physician acceptance of a new mechanism of action may be gradual, as retina specialists become familiar with Fas inhibition’s clinical implications [4]. Treatment frequency advantages must be balanced against efficacy and safety considerations, and new therapies typically face initial reimbursement hurdles that could impact market access.

: Established market players may respond with improved formulations or expanded indications for their complement inhibitors [4]. Other companies are developing alternative GA treatments with different mechanisms, potentially creating additional competitive pressure. Market dynamics could also introduce pricing challenges for new entrants in this high-value therapeutic area.

: Scale-up challenges for commercial manufacturing of the biologic peptide product may present technical hurdles [2]. Ensuring reliable supply chain management and addressing cold chain requirements for product stability could impact market access and commercial success.

Xelafaslatide represents a potentially significant advancement in GA treatment through its innovative Fas inhibition mechanism and extended dosing intervals. The therapy targets approximately 5 million individuals globally affected by GA, including 1.5 million in the United States [4]. GA accounts for roughly 25% of legal blindness cases in the United Kingdom and 20% of cases in North America, highlighting the substantial unmet medical need [4].

The Phase 2 GALAXY trial marks a critical development milestone that could position ONL Therapeutics as a meaningful competitor in the rapidly growing GA market. The product’s differentiated approach offers potential advantages including less frequent dosing (every 3-6 months versus monthly or bimonthly for current therapies) and a novel neuroprotective mechanism [1]. However, commercial success will depend on demonstrating robust clinical efficacy and maintaining a favorable safety profile through the remainder of clinical development.

With the GA market projected to reach $3.5 billion by 2029 [5], xelafaslatide has significant commercial potential if it can successfully navigate the regulatory pathway and establish competitive differentiation in an increasingly crowded therapeutic landscape. The therapy’s success would also validate the Fas inhibition platform for broader retinal disease applications, potentially creating additional value opportunities for ONL Therapeutics’ pipeline development.