Photosensitive epilepsy: Robust clinical efficacy of a selective GABA potentiator

• Published in: Neurology Vol. 92; no. 15; p. e1786
• Main Authors: Gurrell, Rachel, Gorman, Donal, Whitlock, Mark, Ogden, Adam, Reynolds, David S, DiVentura, Bree, Abou-Khalil, Bassel, Gelfand, Michael, Pollard, John, Hogan, R Edward, Krauss, Gregory, Sperling, Michael, Vazquez, Blanca, Wechsler, Robert T, Friedman, Daniel, Butt, Richard P, French, Jacqueline
• Format: Journal Article
• Language: English
• Published: United States 09.04.2019
• Subjects: Adolescent; Adult; Anticonvulsants - adverse effects; Anticonvulsants - pharmacokinetics; Anticonvulsants - therapeutic use; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Epilepsy, Reflex - drug therapy; Female; GABA Modulators - therapeutic use; GABA-A Receptor Agonists - adverse effects; GABA-A Receptor Agonists - pharmacokinetics; GABA-A Receptor Agonists - therapeutic use; Humans; Imidazoles - adverse effects; Imidazoles - pharmacokinetics; Imidazoles - therapeutic use; Lorazepam - therapeutic use; Male; Middle Aged; Pyridazines - adverse effects; Pyridazines - pharmacokinetics; Pyridazines - therapeutic use; Treatment Outcome; Young Adult
• ISSN: 1526-632X
• DOI: 10.1212/WNL.0000000000007271

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 GABA 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. 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. 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. PF-06372865 demonstrated highly robust efficacy. This demonstrates anticonvulsant activity of a novel α2/3/5-subtype selective GABA PAM in humans. Further study of the antiepileptic properties of PF-06372865 is warranted. NCT02564029. This study provides Class II evidence that for people with a stable photoparoxysmal response to intermittent photic stimulation, PF-06372865 reduces the SPR.