Abstracts

Rationale: PF-06372865 (now CVL-865) is in development for the treatment of epilepsy. PF-06372865 is a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABAA receptors with minimal activity at α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines (BZDs), including somnolence.The objective of this double-blind, third party open, randomized, placebo-controlled dose escalation study (NCT03351751) was to assess the safety, tolerability and pharmacokinetics (PK) of multiple doses of PF-06372865 in healthy volunteers at doses higher than previously evaluated.  Methods: Eligible, healthy adult subjects received twice-daily (BID) oral doses of PF-06372865 over 21 days. In each of the 2 cohorts, up to 10 subjects (7-8 PF-06372865, 2 placebo) were titrated up in the first 7 days and then the dose was maintained for the following 14 days prior to discontinuation from treatment. In Cohort 1, subjects received 5 mg BID for 3 days, 12.5 mg BID for 4 days and 25 mg BID for 14 days. In Cohort 2, subjects received 5 mg BID for 2 days, 12.5 mg BID for 2 days, 25 mg BID for 3 days and 42.5 mg BID for 14 days. Serial PK samples were collected at selected timepoints on Days 1 and 21. Safety evaluations throughout the study included adverse event (AE) monitoring, clinical laboratory tests, vital signs, electrocardiograms (ECGs) and physical examinations. Results: A total of 19 subjects were assigned to study treatments. Of these, 1 subject was withdrawn from the study at the Principal Investigator's discretion due to unacceptable behaviour. The remaining 18 subjects completed study treatment.PF-06372865 was rapidly absorbed with Cmax achieved at a median Tmax of 1 to 2 hours following both single-and multiple-dose administration. Mean t½ on Day 21 was 11.2 hours (25 mg BID) and 11.5 hours (42.5 mg BID). All reported AEs were mild and there were no SAEs. The most frequently reported AE was dizziness, which was reported by 6 subjects (1 placebo subject, 2 subjects titrated to 25 mg BID, and 3 subjects titrated to 42.5 mg BID). No subjects reported somnolence after dosing with 42.5 mg BID.There were no clinically significant findings in the clinical laboratory, vital signs, ECG data, or physical examinations. Additionally, there were no withdrawal symptoms on discontinuation of treatment. Conclusions: These results demonstrate that PF-06372865 is safe and well tolerated. There was a lack of somnolence following titration, and lack of withdrawal following abrupt discontinuation, despite achieving α2 receptor occupancy of approximately 80%. In contrast, α1-mediated adverse effects following administration of BZDs are observed at low levels of receptor occupancy (<10%). PF-06372865 has a differentiated profile from a BZD and this data supports continued clinical development in epilepsy. Funding: Pfizer Ltd