Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of TAK-935 in Healthy Subjects (P5.262)

Objective: To determine the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of TAK-935 following multiple ascending doses of TAK-935 in healthy subjects. Background: TAK-935 is a selective cholesterol 24 S -hydroxylase inhibitor, under development for the treatment of rare epilepsies. Design/Methods: In this Phase 1, randomized, double-blind, placebo-controlled study, 40 subjects (6 active and 2 placebo per cohort) received ascending oral doses of 100, 300, 400, and 600 mg once daily (QD) and 300 mg twice daily (BID) TAK-935 for 10–14 days. Serial plasma and urine samples were collected to determine TAK-935 concentrations and plasma 24 S -hydroxycholesterol (24HC) concentrations. Safety was evaluated by adverse event (AE) monitoring, clinical laboratory tests, electrocardiograms, physical examinations, cognitive battery tests, Columbia Suicide Severity Rating Scale, and psychiatric assessments. Results: TAK-935 C max was reached rapidly at 0.33 to 0.5 hours across the dose range studied. Over the dose range of 100 to 400 mg QD after multiple-dose administration, mean TAK-935 C max and AUC ⊤ on Day 14 increased 6.08- and 6.12-fold, respectively. There was no apparent exposure accumulation after multiple doses. Approximately 0.08% to 0.25% of the TAK-935 dose was excreted in urine across dose groups. Plasma 24HC concentrations decreased dose dependently, with steady-state reached by Day 7. Time-matched area under the effect-time curve for 24HC from 0 to 24 hr on Day 14 decreased from Baseline by 47% to 63% across the dose range of 100 to 400 mg QD. Two subjects discontinued treatment due to AEs: one on 600 mg QD reported acute psychosis and one on 300 mg BID reported confusional state. Both events resolved after treatment discontinuation. Conclusions: TAK-935 was safe and well tolerated following QD doses up to 400 mg for 14 days in healthy subjects. Exposure to TAK-935 increased slightly greater than dose-proportional over the dose range of 100 to 400 mg QD. Plasma 24HC concentrations generally decreased with increasing TAK-935 doses. Study Supported by: Takeda Pharmaceuticals Disclosure: Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Takeda Pharmaceuticals (employer). Dr. Cheng has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Takeda Pharmaceuticals (employer). Dr. Uz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Takeda Pharmaceuticals (employer). Dr. Affinito has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Takeda Pharmaceuticals (employer).