Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABA_A receptor positive allosteric modulator PF‐06372865

Abstract

PF-06372865 has a unique clinical pharmacology profile and a highly predictive translational data package from preclinical species to the clinical setting.

Pronounced antiepileptic activity of the subtype‐selective GABAA‐positive allosteric modulator PF‐06372865 in the GAERS absence epilepsy model

“…The lowest dose of PF‐06372865 (0.3 mg kg −1 ) did not significantly reduce SWDs compared to vehicle at any time period tested, and the intermediate dose of 1 mg kg −1 showed a significant reduction in the number of SWDs between 30 and 90 minutes postadministration ( P < 0.0001). Interestingly, the two highest doses of PF‐06372865 tested (3 and 10 mg kg −1 ) significantly reduced the incidence of SWDs at all time periods after dosing, with full suppression observed between 30 and 90 minutes postrecording ( P < 0.0001), which is consistent with expected pharmacokinetic parameters previously reported …”

“…At 10 mg kg −1 , the mean plasma exposure at 1 hour postadministration was 1840 ng mL −1 (SD ± 602 ng mL −1 ), which was within 2‐fold of that previously reported . All the GAERS enrolled in this study showed prototypical cortical SWDs at 3 months of age .…”

“…Delayed efficacy was noted with the 1 mg kg −1 dose (~50% RO), while the two highest doses (3 and 10 mg kg −1 , resulting in ~65% and ~80% RO, respectively) resulted in a significant reduction in SWDs at the early time points that persisted throughout the experiment. To examine the effect of PF‐06372865 over time was not feasible within this study, however, there is further indication in the GAERS model, as with other pharmacodynamic data with this compound, that efficacy is closely related to receptor occupancy . Moreover, the analysis of the baseline recordings over the crossover design did not show any long‐lasting effect of PF‐06372865.…”

“…The compound has demonstrated antiseizure activity in animal models, including amygdala kindling in rat and pentylenetetrazol in mice, and clinically in a proof‐of‐principle study in patients with photosensitive epilepsy . Additionally, PF‐06372865 has been shown to be safe and well tolerated in both healthy volunteers and patients in the clinic . In this study, we examine whether subtype‐selective potentiation of GABA A receptors is efficacious in reducing the occurrence of SWDs in the GAERS model using PF‐06372865.…”

Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet syndrome

“…; Nickolls et al . ), although none of these is currently in clinical use as an AED. The commonly prescribed AED and anxiolytic medication CLB is a 1,5‐BDZ that is known to be metabolized in vivo to active N ‐desmethyl clobazam (N‐CLB) which has modest preference for α 2 /α 3 containing receptors (Ralvenius et al .…”