Phase I Study of Tivozanib Eye Drops in Healthy Volunteers and Patients with Neovascular Age-Related Macular Degeneration.

Purpose: To evaluate the safety, pharmacokinetics, and exploratory efficacy of tivozanib eye drops in healthy volunteers and patients with neovascular age-related macular degeneration (nAMD). Design: This multicenter group-sequential dose escalation phase I study consisted of a placebo-controlled double-masked study of healthy volunteers (cohorts 1 and 2) and an open-label study of patients with nAMD (cohort 3). Participants: Healthy volunteers: Japanese or White men aged 20 to <50 years. Patients with nAMD with central subfield thickness (CST) ≥300 μm and best-corrected visual acuity score ≥23 letters in the study eye. Methods: In the single-dose cohort of healthy men (cohort 1: steps 1-5), 1 or 2 tivozanib eye drops (30 μL/drop, 5-minute interval; 0.5, 1.0, and 2.0 w/v%) or placebo were administered in 1 eye once. In the multiple-dose cohort of healthy men (cohort 2: steps 1-6), 1 or 2 tivozanib eye drops (0.5, 1.0, and 2.0 w/v%) or placebo were administered 3 times daily in 1 eye for 21 days. In the multiple-dose cohort of patients with nAMD (cohort 3, steps 1-3), 1 or 2 tivozanib eye drops (0.5 and 1.0 w/v%) were administered 3 times daily in 1 affected eye for 21 days. Main Outcome Measures: The safety outcome measures included adverse events (AEs). The pharmacokinetic outcome was serum tivozanib concentration. Among the exploratory efficacy outcomes, CST was evaluated. Results: In total, 40, 48, and 28 participants were enrolled in cohorts 1, 2, and 3, respectively. Serious AEs did not occur in cohorts 1 to 3. The most frequent AE in multiple-dose cohorts was reversible punctate keratitis: placebo arm, 8.3% (healthy men, 1/12); tivozanib arm, 47.2% (healthy men, 17/36) and 14.3% (nAMD, 4/28). Serum tivozanib exposure increased dose-dependently and was similar in healthy men and patients with nAMD. In patients with nAMD, mean CST changes from baseline to day 22 were -27.6 ± 54.88 (0.5 w/v%; 1 drop, 3 times daily), -35.6 ± 49.64 (1.0 w/v%; 1 drop, 3 times daily), and -43.7 ± 55.19 μm (1.0 w/v%; 2 drops, 3 times daily). Conclusions: Tivozanib eye drops showed a favorable safety profile in healthy Japanese and White men and Japanese patients with nAMD. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.