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

Abstract

PurposeTo evaluate the safety, pharmacokinetics, and exploratory efficacy of tivozanib eye drops in healthy volunteers and patients with neovascular age-related macular degeneration (nAMD). DesignThis multicenter, group-sequential dose escalation phase 1 study consisted of a placebo-controlled, double-masked study of healthy volunteers (Cohorts 1 and 2) and an open-label study of nAMD patients (Cohort 3). ParticipantsHealthy volunteers: Japanese or White men aged 20 to <50 years. Patients with nAMD with central subfield thickness ≥300 μm and best-corrected visual acuity score ≥23 letters in the study eye. MethodsIn 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 (TID) in 1 eye for 21 days. In the multiple-dose cohort of nAMD patients (Cohort 3, Steps 1–3), 1 or 2 tivozanib eye drops (0.5 and 1.0 w/v%) were administered TID in 1 affected eye for 21 days. Main Outcome MeasuresThe safety outcome measures included adverse events (AEs). The pharmacokinetic outcome was serum tivozanib concentration. Among the exploratory efficacy outcomes, central subfield thickness (CST) was evaluated. ResultsIn total, 40, 48, and 28 participants were enrolled in Cohorts 1, 2, and 3, respectively. Serious AEs did not occur in Cohorts 1–3. 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, TID), −35.6 ± 49.64 (1.0 w/v%; 1 drop, TID), and −43.7 ± 55.19 μm (1.0 w/v%; 2 drops, TID). ConclusionsTivozanib eye drops showed a favorable safety profile in healthy Japanese and White men and Japanese patients with nAMD.