Michael A. Singer, MD: Today for Retina Minute, I have the pleasure of speaking with Margaret A. Chang, MD, about the phase 2 JADE study evaluating OLN324 (Ollin Biosciences), a novel bispecific therapy for retinal vascular disease. Dr. Chang, you recently presented these data at Clinical Trials at the Summit. To begin, can you explain what OLN324 is and what makes it different from currently available bispecific therapies?
Margaret A. Chang, MD, MS: Absolutely. We all recognize the importance of targeting both VEGF-A and angiopoietin-2 (Ang-2) in retinal vascular disease. OLN324 is a novel bispecific fusion protein that targets both pathways, but it differs structurally from faricimab. Rather than being a full-length recombinant bispecific antibody, OLN324 links the coding sequences targeting Ang-2 and VEGF using a flexible linker sequence, creating a much smaller protein with a substantially lower molecular weight.
That smaller size has important theoretical advantages. It allows for higher molar dosing compared with larger antibody-based molecules, and in preclinical studies OLN324 demonstrated approximately 60-fold greater potency against Ang-2 than faricimab. The goal is to achieve robust inhibition of both VEGF and Ang-2 while potentially improving anatomic outcomes and durability.
Dr. Singer: Tell us about the JADE study and the patients who were enrolled.
Dr. Chang: JADE was a randomized proof-of-concept study that enrolled 164 patients across 2 disease cohorts. One cohort included treatment-naive patients with neovascular age-related macular degeneration (AMD), while the second enrolled patients with diabetic macular edema (DME), including both treatment-naive and previously treated eyes.
Patients were randomized head-to-head against faricimab, which makes this study particularly interesting because we rarely see direct comparative trials between investigational retinal therapies and an established bispecific agent. Patients received 3 loading injections and were followed through week 20, with the primary endpoint evaluated at week 12.
Dr. Singer: What were the key efficacy findings?
Dr. Chang: Overall, the results were encouraging in both disease states.
In neovascular AMD, all treatment groups demonstrated rapid and sustained improvements in retinal fluid through week 20 following the initial 3 injections. The OLN324-treated eyes showed numerically greater visual acuity gains than faricimab at both weeks 12 and 20. One of the most notable findings was the reduction in pigment epithelial detachment thickness, which occurred more rapidly after the loading phase in the OLN324 groups.
In DME, we also saw faster retinal drying with OLN324. Central subfield thickness declined more rapidly after the first 3 injections compared with faricimab, resulting in approximately 50% greater retinal drying at week 12. Those improvements were maintained through week 20. Nearly 90% of patients receiving OLN324 achieved complete resolution of diabetic macular edema after the loading phase, a finding that reached statistical significance in post hoc analyses compared with faricimab.
Dr. Singer: How did the visual acuity results compare?
Dr. Chang: Visual outcomes were strong across all treatment groups. In DME, mean best-corrected visual acuity improvements at week 20 were +7.4 letters in the lower-dose OLN324 arm, +8.1 letters in the 4-mg arm, and +7.7 letters with faricimab.
For neovascular AMD, mean gains at week 20 were +8.4 letters with 2 mg of OLN324, +8.6 letters with 4 mg, and +6.4 letters with faricimab.
These are relatively small phase 2 studies, so it's important not to overinterpret numerical differences in visual acuity. However, the data suggest that OLN324 performs at least comparably from a functional standpoint while demonstrating encouraging anatomic outcomes.
Dr. Singer: Looking specifically at the anatomy, did one disease appear to benefit more than the other?
Dr. Chang: From an anatomic perspective, the separation between OLN324 and faricimab appeared more pronounced in DME, particularly at the primary week-12 analysis. Although the drug performed well in both neovascular AMD and DME, the degree of retinal drying and reduction in central subfield thickness was especially notable in the diabetic cohort.
Dr. Singer: Why do you think that may be?
Dr. Chang: Although we can only speculate at this stage, there is a biologically plausible explanation. Ang-2 appears to play an especially important role in diabetic retinal disease. It sensitizes blood vessels to VEGF-A, contributes to vascular leakage and inflammation, and disrupts endothelial cell junctions. Because inflammation is a more prominent component of DME than neovascular AMD, enhanced inhibition of the Ang-2 pathway may translate into greater anatomic benefits in diabetic disease. That remains a hypothesis, but it is consistent with what we observed in the study.
Dr. Singer: Let’s talk about safety.
Dr. Chang: Safety was excellent through the 20-week follow-up period. There were no cases of intraocular inflammation, retinal vasculitis, occlusive retinal vasculitis, or endophthalmitis in patients receiving OLN324 in either the neovascular AMD or DME cohorts. There was 1 case of mild intraocular inflammation in the faricimab group. Overall, no new safety signals emerged, which is encouraging for a molecule entering late-stage development.
Dr. Singer: Were there any practical considerations regarding administration?
Dr. Chang: OLN324 is administered using a standard 30-gauge intravitreal injection needle. During the JADE study, the 2-mg dose was delivered in a 0.05-mL injection, while the 4-mg dose required a 0.1-mL injection.
The company is reformulating the drug so that the higher 4-mg dose can also be administered in the standard 0.05-mL injection volume, which would simplify clinical use if the therapy ultimately reaches the market.
Dr. Singer: What comes next for the program?
Dr. Chang: The next step is phase 3 development. Pivotal studies are planned in both neovascular AMD and DME later this year. The final study designs have not yet been publicly disclosed, but the phase 2 results provide encouraging support for advancing the program.
Dr. Singer: Any final thoughts?
Dr. Chang: It’s exciting to see continued innovation beyond VEGF inhibition alone. As our understanding of retinal vascular disease evolves, we're developing therapies that target additional biologic pathways with the goal of improving both efficacy and durability. Ultimately, that means fewer treatment visits and better long-term outcomes for our patients.
Dr. Singer: Margaret, thank you for sharing these important data. It's encouraging to see continued development of therapies that address multiple disease pathways, particularly for conditions like diabetic macular edema where inflammation plays such an important role. We'll certainly be watching the phase 3 program with great interest. RP
