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

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.

• Authors: 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
• Journal: Neurology (Neurology) Vol. 92 Issue 15 Pg. e1786-e1795 (04 09 2019) ISSN: 1526-632X [Electronic] United States
• PMID: 30877186 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 American Academy of Neurology.

Chemical References

• Anticonvulsants
• GABA Modulators
• GABA-A Receptor Agonists
• Imidazoles
• PF-06372865
• Pyridazines
• Lorazepam

Topics

• Adolescent
• Adult
• Anticonvulsants (adverse effects, pharmacokinetics, 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, pharmacokinetics, therapeutic use)
• Humans
• Imidazoles (adverse effects, pharmacokinetics, therapeutic use)
• Lorazepam (therapeutic use)
• Male
• Middle Aged
• Pyridazines (adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome
• Young Adult