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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.
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.
Glossary
- 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
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work as co–last authors.
Class of Evidence: NPub.org/coe
- Received June 26, 2018.
- Accepted in final form December 17, 2018.
- © 2019 American Academy of Neurology
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