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
Externally publishedYes

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Reflex Epilepsy
Lorazepam
Photic Stimulation
gamma-Aminobutyric Acid
Anticonvulsants
Placebos
GABA-A Receptors
Least-Squares Analysis
Benzodiazepines
Cross-Over Studies
Epilepsy

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Gurrell, R., Gorman, D., Whitlock, M., Ogden, A., Reynolds, D. S., DiVentura, B., ... 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

Photosensitive epilepsy : Robust clinical efficacy of a selective GABA potentiator. / 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.

In: Neurology, Vol. 92, No. 15, 09.04.2019, p. e1786-e1795.

Research output: Contribution to journalArticle

Gurrell, R, Gorman, D, Whitlock, M, Ogden, A, Reynolds, DS, DiVentura, B, Abou-Khalil, B, Gelfand, M, Pollard, J, Hogan, RE, Krauss, G, Sperling, M, Vazquez, B, Wechsler, RT, Friedman, D, Butt, RP & French, J 2019, 'Photosensitive epilepsy: Robust clinical efficacy of a selective GABA potentiator', Neurology, vol. 92, no. 15, pp. e1786-e1795. https://doi.org/10.1212/WNL.0000000000007271
Gurrell R, Gorman D, Whitlock M, Ogden A, Reynolds DS, DiVentura B et al. Photosensitive epilepsy: Robust clinical efficacy of a selective GABA potentiator. Neurology. 2019 Apr 9;92(15):e1786-e1795. https://doi.org/10.1212/WNL.0000000000007271
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. / Photosensitive epilepsy : Robust clinical efficacy of a selective GABA potentiator. In: Neurology. 2019 ; Vol. 92, No. 15. pp. e1786-e1795.
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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

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