PT  - JOURNAL ARTICLE
AU  - Gurrell, Rachel
AU  - Gorman, Donal
AU  - Whitlock, Mark
AU  - Ogden, Adam
AU  - Reynolds, David S.
AU  - DiVentura, Bree
AU  - Abou-Khalil, Bassel
AU  - Gelfand, Michael
AU  - Pollard, John
AU  - Hogan, R. Edward
AU  - Krauss, Gregory
AU  - Sperling, Michael
AU  - Vazquez, Blanca
AU  - Wechsler, Robert T.
AU  - Friedman, Daniel
AU  - Butt, Richard P.
AU  - French, Jacqueline
TI  - Photosensitive epilepsy
AID  - 10.1212/WNL.0000000000007271
DP  - 2019 Apr 09
TA  - Neurology
PG  - e1786--e1795
VI  - 92
IP  - 15
4099  - http://n.neurology.org/content/92/15/e1786.short
4100  - http://n.neurology.org/content/92/15/e1786.full
SO  - Neurology2019 Apr 09; 92
AB  - 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.Clinicaltrials.gov 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.AE=adverse event; AED=antiepileptic drug; BZD=benzodiazepine; CI=confidence interval; IPS=intermittent photic stimulation; IRT=Interactive Response Technology; LS=least square; PAM=positive allosteric modulator; PK=pharmacokinetic; POP=proof-of-principle; PPR=photoparoxysmal response; SPR=standardized photosensitivity range