Abstracts

Rationale: Benzodiazepines (BZs), non-selective positive allosteric modulators (PAMs) of GABAA receptors, are highly effective anticonvulsants across a broad spectrum of epilepsy types. However, BZ use is limited by adverse effects, including cognitive impairment, sedation, withdrawal symptoms, abuse potential and tolerance. PF-06372865 is a partial PAM of a2/3/5 subunit-containing GABAA receptors with minimal activity at a1-containing receptors, which are believed to mediate many of the adverse events associated with BZs. The objective of this Phase 2a study was to assess the activity of PF-06372865 in the photosensitivity model as a proof of principle of efficacy in patients with epilepsy. Methods: A total of 7 subjects (5 female, 2 male) were randomized and all completed the double-blind, 4-period cross-over study examining single doses of placebo, 17.5 and 52.5 mg PF-06372865 and 2 mg lorazepam (active control). Each subject was exposed to intermittent photic stimulation that evoked a generalized photoparoxysmal EEG response. Standard photosensitivity ranges (SPRs) were recorded at screening and at each subsequent active treatment visit pre-administration of study drug and then at 1, 2, 4 and 6 hours post-administration. The primary endpoint was the average least squares mean change in the SPR in the subject’s most sensitive eye condition, over the first 6 hours post treatment. Results: Both doses of PF-06372865 demonstrated superiority over placebo. The average 17.5 mg PF-06372865 response relative to placebo in SPR in the most sensitive eye condition was -6.2 (90% CI: -8.6 to -3.9). The mean effect of 52.5 mg PF-06372865 over placebo in the primary analysis was -5.4 (90% CI: -7.8 to -3.1). The effect of 2 mg Lorazepam relative to placebo on the primary endpoint was -5.2 (90% CI: -7.6 to -2.8). Complete suppression of SPR post-treatment was observed in 6 (of the 7) subjects after administration of 17.5 mg and 52.5 mg of PF-06372865 and 2 mg Lorazepam (Figure 1). In comparison, two subjects (out of 7) had complete suppression post-treatment with placebo.Both doses of PF-06372865 were safe and well tolerated, the most common treatment-related adverse events were dizziness and somnolence. There were no deaths, serious adverse events, or discontinuations during the study. Conclusions: This is the first demonstration of anticonvulsant activity of a novel a2/3/5-subtype selective GABAA partial PAM in the photosensitivity model, with clear suppression of generalized photoparoxysmal EEG response. As such, further study of the antiepileptic properties and tolerability of PF-06372865 are warranted in clinical studies in patients with epilepsy. (ClinicalTrials.gov ID: NCT02564029) Funding: Pfizer Ltd.