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(Abst. 2.272), 2017

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Doses of TAK-935 in Healthy Subjects
Authors: Grace Chen, Takeda Pharmaceuticals; Shining Wang, Takeda Pharmaceuticals; Tolga Uz, Takeda Pharmaceuticals; and John Affinito, Takeda Pharmaceuticals
Content: Rationale: TAK-935 is a potent and selective cholesterol 24S-hydroxylase (CH24H) inhibitor that converts brain cholesterol to 24 hydroxycholesterol (24HC), which is a co-agonist at the NMDA receptor. 24-HC can drive glutamatergic over-activation by modulation of astrocytes and N-methyl-D-aspartate (NMDA) channel activity, implying a potential role in CNS diseases such as epilepsy. TAK-935 is currently under development for the treatment of rare epilepsies. The objective of this study was to determine the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of TAK-935 following single ascending doses in healthy subjects. Methods: In this Phase 1, randomized, double-blind, placebo-controlled study, single ascending doses of 15, 50, 200, 600, 900, and 1350 mg of TAK-935 or placebo were administered orally to 48 healthy subjects (8 subjects [6 active and 2 placebo] per cohort) under fasted conditions. Sentinel dosing was used in each cohort. Serial blood and urine samples were collected on Day -1 (PD only, plasma 24S-hydroxycholesterol [24HC] and up to 96 hours (hr) postdose for the PK (plasma and urine TAK-935) and PD  assessment. Safety was evaluated throughout the study by adverse event (AE) monitoring, clinical laboratory tests, vital sign measurements, electrocardiograms (ECGs), physical examinations (including comprehensive eye examinations), cognitive battery tests and Columbia Suicide Severity Rating Scale (C-SSRS) Results: TAK-935 was safe and well tolerated up to a single dose of 1350 mg with the most common TEAEs were headache and nausea. All treatment emergent AEs (TEAEs) were mild in intensity, and no dose dependence was apparent in the incidence of any individual TEAEs. No clinically meaningful changes in clinical laboratory, vital sign, physical examination, comprehensive eye examination, or ECG measurements were observed. Following a single oral administration of TAK-935 via dosing solution, TAK-935 was rapidly absorbed, with median tmax (time of occurrence of maximum plasma concentration [Cmax]) observed between 0.25 and 0.52 hr. Exposure to TAK-935 increased greater than dose-proportionally (mean Cmax and area under the plasma concentration-time curve from time 0 to infinity [AUC∞]) increased by 183- and 581-fold, respectively, over a 90-fold dose increase). Renal excretion of TAK-935 was negligible (≤0.6% of the dose), and terminal disposition phase half-life (t1/2) generally increased with increasing dose from 0.82 to 7.16 hr (Figure 1). The plasma 24HC concentrations generally decreased with increasing dose (Figure 2). Time-matched percent change from baseline in area under the effect-time curve from time 0 to 24 hr (AUEC24) decreased from 3% to 14% across the TAK-935 dose groups.  Conclusions: TAK-935 was safe and well tolerated following a single oral administration up to 1350 mg in healthy subjects. A greater than dose-proportional increase in TAK-935 systemic exposure was observed over the dose range evaluated. There was a trend of dose-dependent decrease in the plasma 24HC concentrations. Funding: Takeda Pharmaceuticals
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