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(Abst. 2.273), 2017

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of TAK-935 in Healthy Subjects
Authors: Shining Wang, Takeda Pharmaceuticals; Grace Chen, Takeda Pharmaceuticals; Tolga Uz, Takeda Pharmaceuticals; and John Affinito, Takeda Pharmaceuticals
Content: Rationale: TAK-935 is a selective cholesterol 24S-hydroxylase inhibitor, currently under development for the treatment of rare epilepsies. The objectives of this study were to determine the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of TAK-935 following multiple ascending doses in healthy subjects. Methods: In this Phase 1, randomized, double-blind, placebo-controlled study, 40 subjects (8 subjects [6 active and 2 placebo] per each of the five cohorts) received ascending oral doses of 100, 300, 400, or 600 mg once daily (QD) or 300 mg twice daily (BID) TAK-935 for 14 days. Serial blood and urine PK samples were collected up to 24 hours (hr) postdose on Days 1 and 14, and a trough blood PK sample was collected at predose on Days 7, 11, 12 and 13. Serial blood PD samples were collected on Day -1 and up to 24 hr postdose on Days 1 and 14, and a trough blood PD sample was collected at predose on Days 7, 12 and 13 for the determination of plasma 24S-hydroxycholesterol (24HC) concentrations. Safety was evaluated throughout the study by adverse event (AE) monitoring, clinical laboratory tests, vital signs, electrocardiograms (ECGs), physical examinations, cognitive battery tests, Columbia Suicide Severity Rating Scale (C-SSRS), and psychiatric assessments. Results: Overall, TAK-935 was well tolerated up to 400 mg QD with the most common TEAEs being headache and disturbance in attention.Two subjects discontinued treatment at the highest doses tested due to AEs: one on 600mg QD reported acute psychosis and one on 300mg BID reported confusional state.  Both events resolved after treatment discontinuation. There was no apparent accumulation after multiple QD dose administrations. At steady-state, PK of TAK-935 was characterized by slightly greater than dose-proportional exposure (mean maximum plasma concentration [Cmax] and area under the plasma concentration-time curve during a dosing interval [AUCτ] increased approximately 6-fold over a 4-fold dose increase), rapid absorption (median time of occurrence of Cmax [tmax] between 0.33 and 0.42 hr), and negligible renal excretion (≤ 0.25% of dose) following 100 to 400 mg QD doses for 14 days (Figure 1). TAK-935 had rapid elimination with mean terminal disposition phase half-life [t1/2] of 3.49 to 4.83 hr across the dose range of 100 to 600 mg on Day 1 or Day 14. Plasma 24HC concentrations generally decreased dose dependently, with the steady-state being reached by Day 7 of dosing. Time-matched area under the effect-time curve from time 0 to 24 hr (AUEC24) on Day 14 decreased from Baseline by 47% to 63% across the dose range of 100 to 400 mg QD (Figure 2).  Conclusions: In this study TAK-935 was safe and well tolerated following QD doses up to 400 for 14 days in healthy subjects. Exposure to TAK-935 increased slightly greater than dose-proportionally over the dose range of 100 to 400 mg QD. Plasma 24HC concentrations generally decreased with increasing TAK-935 doses. Funding: Takeda Pharmaceuticals
Figure 1
Figure 2