Lejla Vajzovic, MD, FASRS and Durga S. Borkar, MD, MMCi
During the Retina Futura session at FLORetina on December 6, 2024, Lejla Vajzovic, MD, FASRS, Professor of Ophthalmology, Pediatrics, and Biomedical Engineering and Durga S. Borkar, MD, MMCi, Associate Professor of Ophthalmology], both from Duke University in Durham, North Carolina, presented results from two clinical studies evaluating the Fasinhibitor ONL1204 for treatment of Geographic Atrophy and Macula-OD Rhegmatogenous Retinal Detachment (RRD).
ONL1204 for Geographic Atrophy
Dr. Vajzovic detailed 2 components of the phase 1b study – component 1 was open-label and evaluated 3 doses of ONL1204: 50 μg, 100 μg, and 200 μg given as a single dose where eDects were observed over the course of 6 months and compared the study eye to the fellow eye and component 2 that evaluated 2 intravitreal injections of ONL1204 treatment compared to sham. Primary outcomes were safety while secondary outcomes were change in area of GA lesions. Exploratory outcomes included change in best-corrected visual acuity (BCVA) and low-luminance BCVA.
Overall, ONL1204 appears safe and well-tolerated; most adverse events across both components of the study were mild and related to the injection procedure. Dr. Vajzovic was pleased to report there were no reported cases of choroidal neovascularization in the study eye, dose limiting toxicities, or intraocular inflammation.
In the first component of the study, a single injection of ONL1204 demonstrated a 42% average reduction in lesion growth based on square root transformation and an average change of 5.7 letters in the study eye compared to the fellow eye at 24 weeks.
The second component of the study also demonstrated promising eDicacy at 24 weeks with 24% and 50% reduction in lesion growth rates from 50 μg and 200 μg doses, respectively.
“Overall, ONL1204 appears safe and well-tolerated while showing strong eDicacy signals with only 1 to 2 injections as early as 6 months after beginning treatment.” Dr. Vajzovic commented. “The results presented here strongly support the further evaluation of ONL1204 for geographic atrophy, and we are excited to be initiating a phase 2 study.”
“Developing safe and eDective treatments for geographic atrophy continues to be a priority among the retina community. Evaluating therapies based oD a variety of mechanisms of action while lowering the potential treatment burden will ensure patients receive the best possible care,” Dr. Vajzovic stated.
ONL1204 for Macula-O; Rhegmatogenous Retinal Detachment
Dr. Borkar further showcased the potential use of ONL1204 for retina complications such as macula-oD RRD. Macula-oD RRD is a severe complication that may result in vision loss, even after surgical repair.
“We know that patients with macula-oD RRD suDer from irreversible vision loss even after successful surgical repair. Many prior studies have shown that time is vision when it comes to the duration of macula-oD status, with worse visual outcomes after 8 days of detachment. There is an unmet need to try to improve visual acuity outcomes in these patients,” said Dr. Borkar.
The safety and eDicacy of ONL1204 was evaluated in a phase 2, randomized clinical trial. Patients presenting with macula-oD RRD for 24 hours to 14 days prior to presentation were randomized 1:1:1 to receive either 50 μg (n=40), 200 μg (n=38), or sham (n=43). ONL1204 was administered via a single intravitreal injection at least 12 hours before and up to 10 days prior to surgery. Patients received standard of care pars plana vitrectomy with or without scleral buckle. The primary endpoint was contrast sensitivity as measured with the AST Manifold Contrast vision meter at week 24 with a secondary endpoint of BCVA, also at week 24.
Although Dr. Borkar’s presentation reported that there was no statistically significant diDerence across treatment groups for the primary outcome measure, a prespecified subgroup analysis demonstrated trends toward neuroprotection in patients with greater than 8 days of macula-oD status, with those patients receiving ONL1204 200 μg showing approximately 2-line diDerence when compared to sham. Additionally, safety was welltolerated with no statistically significant redetachment rates.
“We are pleased to report a well-tolerated safety and promising eDicacy trends from ONL1204 treatment prior to macula-oD RRD surgical repair,” Dr. Borkar said. “We intend to conduct further research and analyses in those patients at highest risk of vision loss.”
About ONL1204
“ONL1204 is being developed as a first-in-class small peptide, Fas-inhibitor that is administered intravitreally. Targeting Fas has been shown to prevent activation of apoptotic pathways and inflammatory cascades that accelerate tissue damage and cell death.
ONL1204 targets Fas upstream of death signaling and inflammatory pathways, including the complement pathway, which has proven implications in the formation of dry AMD and geographic atrophy. ONL1204 has demonstrated the ability to preserve photoreceptors after retinal separation from the retinal pigment epithelium via Fas receptor inhibition in numerous preclinical models of retinal detachment.1
ONL1204 is currently being evaluated in phase 1b (NCT04744662) and phase 2 (GALAXY, NCT06659445) clinical trials for GA and a phase 2 trial (NCT05730218) for Macula-OD RRD.”
About geographic atrophy
Age-related macular degeneration (AMD) is a progressive retinal degenerative disease and the leading cause of irreversible vision loss in people 50 years of age or older, aDecting an estimated 196 million individuals worldwide.2
Geographic atrophy is an advanced form of the dry version of age-related macular degeneration, which is characterized by the formation and build-up of drusen in the retina. Deposits of drusen may eventually lead to atrophic lesion formation, which, if left untreated, may negatively impact visual acuity and eventually lead to blindness. Dysregulation in the complement pathway, an innate immune response, has been implicated in the accumulation of drusen. Up until recently, there were no treatments for geographic atrophy; however, 2 complement inhibitors are now approved for treatment in the US (pegcetacoplan, Apellis Pharmaceuticals, Waltham, Massachusetts and avacincaptad pegol, Astellas Pharma, Tokyo, Japan). Despite the availability of these treatments, safety outcomes and the necessity of frequent treatment via intravitreal injection remain a concern.
References
1. Zacks DN, Zheng QD, Han Y, Bakhru R, Miller JW; FAS-Mediated Apoptosis and Its Relation to Intrinsic Pathway Activation in an Experimental Model of Retinal Detachment. Invest. Ophthalmol. Vis. Sci. 2004;45(12):4563-4569
2. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106- e116. doi:10.1016/S2214-109X(13)70145-1