Abstracts

Rationale: TAK-935 is a selective cholesterol 24S-hydroxylase inhibitor currently under development for the treatment of rare epilepsies. Antiepileptic drugs are known to impact cognition negatively.¹  In a phase I multiple-ascending-dose study to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-935 in healthy subjects (reported at AES 2017), cognitive effects were explored with Cogstate tests. Methods: In this phase I, randomized, double-blind, placebo-controlled study, 40 subjects (8 [6 active and 2 placebo] per each of the 5 cohorts) received ascending oral doses of TAK-935 100, 300, 400, or 600 mg once daily (QD) or 300 mg twice daily (BID) for 14 days. The effect of TAK-935 on cognition was assessed with Cogstate tests at baseline and on days 1 (at 1 and 3 hours post dose), 11, and 14. The Cogstate battery used in this study is a validated computerized assessment of cognitive function that includes tests of executive function (Groton Maze Learning Task), working memory (One Back Task), learning (One Card Learning Task), psychomotor speed (Detection Task), and attention (Identification Task) administered via a standard computer system.² The battery takes ˜20 minutes to complete. Results: Cognitive performance generally remained stable across all assessments for each of the cognitive tests across the 100 mg, 300 mg, and 400 mg QD and 300 mg BID cohorts, suggesting that for these cohorts, there was no evidence of cognitive decline post dose. Data from the 600 mg cohort suggested decline on measures of psychomotor speed (Detection Task), attention (Identification Task), and working memory (One Back Test) at day 11. On measures of learning and executive function, there was no evidence of cognitive decline post dose. The observed decline in performance in the 600 mg cohort was attributable to a single subject who had a documented drug-related adverse event of psychosis on day 10 and was subsequently withdrawn from the study on day 11.  Conclusions: These data suggest that TAK-935 doses of 300 mg BID or less are not associated with effects on cognition in healthy adults. The observed decline in cognitive performance in the 600 mg QD cohort was attributable to an episode of psychosis experienced by a single subject, and the drug had no direct adverse effect on cognition. This latter point is supported by the absence of any negative cognitive sequelae in the 300 mg BID cohort. In ongoing studies in rare epilepsies, TAK- 935 is being administered at doses up to 300 mg BID.¹Mula M. Recent and future antiepileptic drugs and their impact on cognition: what can we expect? Expert Rev Neurother. 2012;12:667–71.²Collie A, Maruff P, Snyder PJ, Darekar MA, Huggins JP. Cognitive testing in early phase clinical trials: outcome according to adverse event profile in a phase I study. Hum Psychopharmacol. 2006;21:481-8. Funding: Research funded by Takeda Pharmaceuticals.