To evaluate the efficacy of selective T-type calcium channel (TTCC) modulators in the GAERS genetic model of spontaneous epilepsy.

TTCCs regulate neuronal excitability and are implicated in the pathogenesis of generalized epilepsy. Approved drugs zonisamide and ethosuximide have non-selective TTCC antagonist activity and show evidence of efficacy in clinical studies, although many patients experience lack of efficacy or intolerable side effects resulting in treatment discontinuation. Thus, selective targeting of TTCCs with potent, brain penetrant and state-dependent small molecules has the potential to improve efficacy and tolerability.

TTCC modulators CX-8998 and CX-5395 (vehicle, 1, 3 and 10 mg/kg) and ethosuximide (100 mg/kg) were administered by oral gavage. EEG recordings were collected from 20 minutes pre-dose through 90 minutes post-dose in a cross-over design. Recordings were scored by a blinded reviewer and number and time spent in spike-wave-discharges (SWD) was summarized. Data were analyzed by ANOVA with a significance level of p<0.05. When significant, paired comparisons vs. baseline, vehicle and reference compound were conducted.  Blood samples were collected to quantify test compound plasma levels.

Ethosuximide induced reduction in number and cumulative duration of SWD (60%; p<0.0001 vs. vehicle).  CX-8998 showed a dose dependent reduction of both number and cumulative duration of SWD with equivalent effects to ethosuximide at 3 mg/kg (p<0.0001 vs. vehicle) and near complete suppression of seizure activity at 10 mg/kg (99%; p<0.0001 vs. vehicle; p<0.001 vs. ethosuximide).  CX-5395 showed similar results, consistent with its shorter half-life in rodents.  Exposure-response analysis confirms effective concentrations are achievable in humans.

Potent, highly selective TTCC modulators CX-8998 and CX-5395 show dose dependent efficacy in the GAERS model with near full suppression of seizures by CX-8998 at the highest dose. These results support further investigation of CX-8998 in a Phase 2 clinical study in medically-resistant generalized epilepsy syndromes with absences seizures (NCT03406702).