• 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, and Jacqueline French.
• From Pfizer Inc. (R.G., D.G., M.W., D.S.R., R.P.B.), Cambridge, UK; Pfizer Inc. (A.O.), Groton, CT; The Epilepsy Study Consortium (B.D.), Reston, VA; Department of Neurology (B.A.-K.), Vanderbilt University Medical Center, Nashville, TN; University of Pennsylvania (M.G., J.P.), Philadelphia; Washington University in St. Louis (R.E.H.), MO; Johns Hopkins Hospital (G.K.), Baltimore, MD; Thomas Jefferson University (M.S.), Philadelphia, PA; Comprehensive Epilepsy Center (B.V., D.F., J.F.), Department of Neurology, New York University, New York; and Consultants in Epilepsy and Neurology PLLC (R.T.W.), Boise, ID. Rachel.Gurrell@Pfizer.com.
• Neurology. 2019 Apr 9; 92 (15): e1786-e1795.

ObjectiveThe 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.MethodsSeven 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.ResultsBoth 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.ConclusionPF-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 IdentifierNCT02564029.Classification Of EvidenceThis study provides Class II evidence that for people with a stable photoparoxysmal response to intermittent photic stimulation, PF-06372865 reduces the SPR.© 2019 American Academy of Neurology.

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