Sozinibercept for Wet AMD Misses Primary Endpoint in Phase 3 COAST Trial

Sozinibercept 2 mg combined with 2 mg aflibercept (Eylea) for neovascular (wet) age-related macular degeneration (nAMD) failed to meet the 52-week primary endpoint of the Phase 3 COAST trial for mean change in best-corrected visual acuity (BCVA).1

Announced by Opthea on March 24, 2025, sozinibercept combination therapy with dosing every 4 or 8 weeks resulted in a mean BCVA improvement of 13.5 and 12.8 letters at 52 weeks, respectively, compared with 13.7 letters for aflibercept monotherapy.

“At this stage, no decision has yet been taken with respect to either trial, including whether to discontinue activities for the COAST trial or accelerate and unmask the ShORe trial,” Opthea wrote in the release.1 “Discussions continue with the Development Funding Agreement (DFA) Investors to determine the most appropriate course of action.”

A first-in-class vascular endothelial growth factor (VEGF) C/D ‘trap’ fusion protein, sozinibercept, in combination with anti-VEGF-A monotherapy, was targeted as the first therapy in nearly 20 years to provide superior visual outcomes in wet AMD.1 The US Food and Drug Administration granted Fast Track Designation to sozinibercept in July 2021, acknowledging the significant unmet medical need that sozinibercept could address.2

Efficacy and safety of intravitreal sozinibercept were assessed in two global, fully enrolled pivotal Phase 3 clinical trials (COAST and ShORe) investigating combination therapy versus anti-VEGF-A monotherapy in the treatment of wet AMD. The COAST trial assessed 2 mg sozinibercept every 4 (Q4W) or 8 weeks (Q8W) in combination with on-label 2 mg aflibercept every 8 weeks after a loading phase.

Participants with minimally classic and occult lesions treated with sozinibercept combination therapy at dosing regimens of Q4W (n = 296) or Q8W (n = 297) achieved mean BCVA improvements of 13.2 letters (P = .59) and 13.2 letters (P = .62) from baseline at 52 weeks, respectively. The aflibercept monotherapy (n = 299) group achieved improvements of 13.8 letters at 52 weeks.

For the overall population, sozinibercept combination therapy at a dosing regimen of Q4W (n = 333) or Q8W (n = 330) demonstrated a mean BCVA change of 13.5 (P =.86) and 12.8 (P =.42) letters at 52 weeks, respectively, versus 13.7 letters with aflibercept monotherapy (n = 299).

The release indicated no numerical differences were identified for the key secondary endpoints, while safety analyses showed sozinibercept combination therapy remained tolerable in patients with wet AMD.

“Following the receipt of these results, Opthea has undertaken a thorough review of the data to ensure both its accuracy and integrity,” Opthea added. “No anomalies were identified through this process that would cause the Board to adopt an alternative view on the data outlined above.”

The company announced the ShORe trial had completed the enrollment of 986 treatment-naive patients with wet AMD. The trial is set to evaluate ranibizumab Q4W and sozinibercept Q4W, ranibizumab Q4W and sozinibercept Q8W, and ranibizumab Q4W plus sham Q4W.3

In the release, Opthea acknowledged “material uncertainty” as to the company’s ability to continue in light of these negative data for their lead product candidate.1

“As noted above, discussions with the DFA Investors are ongoing and Opthea cannot be certain as to the outcome of those discussions or when that outcome may become known,” Opthea wrote.1

References

1. Opthea announces Coast Phase 3 trial Topline Results. Opthea Limited. March 24, 2025. Accessed March 25, 2025. https://ir.opthea.com/news-releases/news-release-details/opthea-announces-coast-phase-3-trial-topline-results.

2. Opthea’s opt-302 granted FDA Fast Track designation for wet age-related macular degeneration. Opthea Limited. July 6, 2021. Accessed March 25, 2025. https://ir.opthea.com/news-releases/news-release-details/optheas-opt-302-granted-fast-track-wet-amd.

3. Iapoce C. Sozinibercept topline results expected in Q2 after coast trial completion. HCP Live. February 19, 2025. Accessed March 25, 2025. https://www.hcplive.com/view/sozinibercept-topline-results-expected-in-q2-after-coast-trial-completion.