ONL1204 for the Treatment of Geographic Atrophy: Phase Ib Study Evaluating Safety, Tolerability, and Efficacy.

Purpose: To evaluate the safety and tolerability of ONL1204, a novel, small peptide inhibitor of the fragment apoptosis stimulator receptor, for the treatment of patients with geographic atrophy (GA). Design: A phase Ib multicenter study involving a dose-escalation/open-label (DE/OL) component and a randomized, double-masked, sham-controlled natural history/treatment (NHS/T) component. Participants: Patients aged ≥55 years with GA secondary to age-related macular degeneration. Methods: Dose-escalation/OL patients received a single intravitreal injection of either 50 μg, 100 μg, or 200 μg of ONL1204 and were followed for 24 weeks. Participants in the NHS/T component were randomized (1:1:1) to either 50 μg or 200 μg of ONL1204 or sham injection, after a 24-week NHS phase. Two injections were administered 12 weeks apart, and patients were observed for an additional 12 weeks. Main Outcome Measures: The primary endpoint was safety, assessed by monitoring adverse events (AEs), ophthalmic examination, electrophysiology, fundus photography, fundus autofluorescence, and OCT. Additional endpoints included measurement of GA lesion area and best-corrected visual acuity. Results: Six patients were enrolled in the DE/OL component and 22 patients in the NHS/T component. All patients in the DE/OL component completed the study with no major safety findings or dose-limiting toxicities. Seventeen patients were randomized in the NHS/T component, with 15 patients completing the study. All ophthalmic AEs were mild or moderate in severity. ONL1204 demonstrated a favorable effect on GA lesion growth, with numerically favorable slower lesion growth compared with the fellow eye in the DE/OL component at 6 months and a numerically slower growth rate (mean difference [standard error of the mean] of -0.524 mm2 [0.39]; P = 0.202) in the 200 μg ONL1204 group compared with the sham group in the treatment phase of the NHS/T component. There were no changes in the treatment group with respect to visual acuity suggestive of any safety issues. Conclusions: ONL1204 was safe and well tolerated at all evaluated doses, with the potential to reduce GA lesion growth and improve vision. These results support further evaluation of ONL1204 in patients with GA. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.