MONTREAL — An investigational bispecific antibody, OLN324, demonstrated faster and numerically greater short-term improvements in visual acuity and retinal anatomy compared to faricimab (Vabysmo) in a randomized, proof-of-concept trial for neovascular age-related macular degeneration (nAMD). The findings, presented at the American Society of Retina Specialists meeting, suggest potential advantages of OLN324 in both speed and magnitude of therapeutic response in patients with this leading cause of vision loss in older adults.

David Eichenbaum, MD, of Retina Vitreous Associates of Florida in St. Petersburg, reported results from the nAMD cohort of the phase I JADE trial, which compared two doses of OLN324 against faricimab in previously untreated patients. Patients randomized to either dose of OLN324 showed a two-letter greater improvement in visual acuity than those receiving faricimab at the 20-week mark. Both OLN324 doses led to numerically greater gains in vision—+8.6 and +8.4 letters—compared to +6.4 letters with faricimab.

Improvement in visual acuity with OLN324 was evident within one week after the initial injection, signaling a rapid onset of action. In addition to visual gains, patients treated with OLN324 showed more rapid improvement in retinal fluid and faster, numerically greater reductions in pigment epithelial detachment (PED) thickness compared to those treated with faricimab. While PED thickness declined within the first week across all three treatment groups, the OLN324 groups maintained numerically greater reductions through the study period.

The JADE trial enrolled 80 patients with nAMD and 84 with diabetic macular edema (DME), though Eichenbaum reported findings only for the nAMD group. The trial’s primary objective was safety and tolerability at week 12, with continued follow-up through week 20. Exploratory efficacy endpoints included visual acuity and multiple anatomical measures of retinal health. The study met its primary safety objective: no patient assigned to OLN324 developed intraocular inflammation, retinal vasculitis, occlusive retinal vasculitis, or endophthalmitis.

All three treatment groups achieved rapid and sustained improvement in retinal fluid. At 20 weeks, the mean change from baseline in central subfield thickness (CST)—a key indicator of retinal swelling—was -128 µm and -142 µm with the two OLN324 doses, compared to -142 µm with faricimab. Durability of effect was also assessed: 82% of patients receiving the higher dose of OLN324 went 12 weeks without requiring retreatment, compared to 81% in the faricimab group, indicating similar treatment intervals despite OLN324’s enhanced early efficacy.

OLN324 is designed to inhibit both angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF), two key drivers of abnormal blood vessel growth and leakage in retinal diseases. It possesses 60 times greater potency for Ang2 inhibition than faricimab, a smaller molecular size that facilitates better tissue penetration, and a higher molar dose than faricimab 6 mg and aflibercept (Eylea) 2 mg and 8 mg. These pharmacological properties may underlie its more rapid and pronounced effects on retinal anatomy and vision.

Eichenbaum acknowledged challenges in measuring the full impact of Ang2 inhibition. "Prospectively, it's tough," he said. He noted that current imaging tools like optical coherence tomography (OCT) may not capture all biological effects of dual inhibition.

"I think the best Ang2 biomarker we have to show differentiation with that blockade is still fluorescein angiography and diabetes [to look for retinal leakage]," he added. He posed a series of unanswered questions: "Is there something to reduce leakage? Is there something in the blood-retinal barrier? Is there something that Ang2 or other biologies are doing that's beneficial that we just don't see with OCT?" He concluded, "We've got to figure that out," and suggested that "that is a narrative we can build on with other novel biologies, too."

Charles Wykoff, MD, PhD, of Retina Consultants of Texas in Houston, moderated the session and was a co-author on the study. The JADE trial represents an early but promising step in evaluating OLN324’s potential for nAMD, with plans for a phase III trial underway.

Neovascular age-related macular degeneration affects millions worldwide and requires frequent anti-VEGF injections to preserve vision. Current standard therapies, including faricimab (approved based on the TENAYA and LUCERNE trials published in The Lancet in 2022), aim to extend treatment intervals while maintaining efficacy. The JADE trial’s findings suggest OLN324 may offer not only comparable durability—12-week dosing in over 80% of patients—but also faster and greater visual and anatomical improvements, which could translate to better long-term outcomes or reduced treatment burden if confirmed in larger trials.

The dual inhibition of Ang2 and VEGF represents an evolving strategy in retinal therapeutics. Faricimab, also a bispecific antibody targeting both pathways, was first approved in 2022, as documented in Drugs and the Canadian Journal of Health Technologies. OLN324’s enhanced Ang2 potency and molecular properties may differentiate it within this class. If phase III trials confirm the early advantages seen in JADE, OLN324 could offer a meaningful advance for patients with nAMD, potentially improving vision recovery speed and magnitude while maintaining a manageable injection schedule.