Kyowa Kirin’s KHK4951 Eye Drop Misses Phase 2 Endpoint in Neovascular AMD

Kyowa Kirin’s investigational tivozanib eye drop-maintained vision in many patients with neovascular age-related macular degeneration (nAMD) after initial anti-VEGF treatment, but its Phase 2 study failed to demonstrate the predefined treatment-group difference required for the primary endpoint.

Phase 2 Study Tests Topical Maintenance After Anti-VEGF Therapy

The global Phase 2 trial, Study 4951-002, evaluated KHK4951, a nanocrystal ophthalmic suspension of tivozanib, as a non-invasive maintenance treatment for patients with nAMD. The randomized, double-masked, multicenter study enrolled patients who responded favorably to an initial anti-VEGF run-in with three intravitreal injections of aflibercept 2 mg. Participants were then randomized to three treatment arms:

• KHK4951 0.5% once daily (QD)
• KHK4951 2.0% once daily (QD)
• KHK4951 2.0% twice daily (BID)

Across the three dosing groups, approximately 65% to 69% of patients avoided the composite event of losing 15 or more letters in best-corrected visual acuity (BCVA) or requiring rescue treatment through Week 52. However, the high-dose 2.0% BID regimen did not outperform the low-dose 0.5% QD regimen, and the primary endpoint was not met.

Vision Maintained, but Dose Separation Was Absent

At Week 52, the proportion of patients experiencing the composite event of a loss of 15 or more BCVA letters or requiring rescue treatment was 31.8% in the 0.5% QD arm, 34.9% in the 2.0% QD arm, and 31.1% in the 2.0% BID arm. No statistical difference was observed between the high- and low-dose groups.

Kaplan-Meier analyses showed that approximately 62% to 67% of patients avoided a loss of 15 or more letters or rescue treatment between Week 8 and Week 52. Among study completers, mean BCVA and central subfield thickness (CST) remained generally stable throughout the observation period. However, because the study lacked a true control group, these maintenance outcomes cannot be attributed to KHK4951 alone.

Topical Delivery of VEGF Tyrosine Kinase Inhibition

KHK4951 contains tivozanib, a small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors VEGFR-1, VEGFR-2, and VEGFR-3. Kyowa Kirin developed the nanocrystal formulation to facilitate non-invasive delivery of tivozanib to posterior ocular tissues.

The approach addresses a major challenge in chronic retinal care. Current nAMD treatment relies on intravitreal anti-VEGF injections, which require repeated administration and ongoing clinical visits, creating a substantial burden for patients, caregivers, and healthcare systems.

Favorable Tolerability and Next Steps

KHK4951 was generally well tolerated at doses up to 2.0% BID, with no new safety signals identified. Dry eye and punctate keratitis occurred in some patients. The study also found no clinically meaningful trend toward blood pressure elevation, an important consideration for a therapy targeting the VEGF pathway.

Dante Pieramici, M.D., Medical Director of Clinical Research at California Retina Consultants, said the lack of a true control group remains a key limitation but noted that the findings provide insight into topical maintenance following initial anti-VEGF treatment. Kyowa Kirin Chief Medical Officer Yoshifumi Torii, M.D., Ph.D., highlighted the generally stable BCVA and CST findings despite the absence of the predefined dose-response relationship.

Kyowa Kirin is also evaluating KHK4951 in diabetic macular edema (DME). The candidate remains investigational and has not received regulatory approval in any country or region; its safety and efficacy have not been established.

Reference

Kyowa Kirin Announces Topline Results from Phase 2 Global Study of KHK4951 Eye Drops for Neovascular Age-Related Macular Degeneration, Kyowa Kirin, 08 September 2026