Photosensitive epilepsy: Robust clinical efficacy of a selective GABA potentiator

Rachel Gurrell, Donal Gorman, Mark Whitlock, Adam Ogden, David S. Reynolds, Bree DiVentura, Bassel Abou-Khalil, Michael Gelfand, John Pollard, R. Edward Hogan, Gregory Krauss, Michael Sperling, Blanca Vazquez, Robert T. Wechsler, Daniel Friedman, Richard P. Butt, Jacqueline French

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: The objective of this phase 2a study was to assess the activity of PF-06372865, 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, in the epilepsy photosensitivity model as a proof-of-principle of efficacy. METHODS: Seven participants with a photoparoxysmal response to intermittent photic stimulation (IPS) at baseline were randomized in a double-blind, 4-period cross-over study examining single doses of 17.5 and 52.5 mg PF-06372865, 2 mg lorazepam (active control), and placebo. Standardized photosensitivity ranges (SPRs) to IPS were recorded at screening, predose, and 1, 2, 4, and 6 hours postdose. The primary endpoint was the average least squares mean change in the SPR in the participant's most sensitive eye condition, across all time points. RESULTS: Both doses of PF-06372865 produced a marked and statistically significant mean reduction in SPR compared to placebo, which was similar in degree to lorazepam. There was complete suppression of SPR in 6/7 participants following PF-06372865 or lorazepam administration. PF-06372865 was safe and well-tolerated. CONCLUSION: PF-06372865 demonstrated highly robust efficacy. This demonstrates anticonvulsant activity of a novel α2/3/5-subtype selective GABAA PAM in humans. Further study of the antiepileptic properties of PF-06372865 is warranted. CLINICALTRIALSGOV IDENTIFIER: NCT02564029. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for people with a stable photoparoxysmal response to intermittent photic stimulation, PF-06372865 reduces the SPR.

Original languageEnglish (US)
Pages (from-to)e1786-e1795
JournalNeurology
Volume92
Issue number15
DOIs
StatePublished - Apr 9 2019

ASJC Scopus subject areas

  • Clinical Neurology

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    Gurrell, R., Gorman, D., Whitlock, M., Ogden, A., Reynolds, D. S., DiVentura, B., Abou-Khalil, B., Gelfand, M., Pollard, J., Hogan, R. E., Krauss, G., Sperling, M., Vazquez, B., Wechsler, R. T., Friedman, D., Butt, R. P., & French, J. (2019). Photosensitive epilepsy: Robust clinical efficacy of a selective GABA potentiator. Neurology, 92(15), e1786-e1795. https://doi.org/10.1212/WNL.0000000000007271