Regulatory Decision Summary for Xcopri

This New Drug Submission – New Active Substance (NDS-NAS) was filed to obtain market authorization for Xcopri (cenobamate) as adjunctive therapy in the management of partial-onset seizures in adults with epilepsy.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

Xcopri (cenobamate) is a new active substance. Based on animal studies, this drug is a sodium channel blocker and an enhancer of ү-Aminobutyric acid type A (GABA_A) ion channel.

Evidence to support Xcopri was provided by two randomized, double-blind, placebo-controlled, safety and efficacy studies (C013 and C017). Both studies had a 6-week titration period, followed by maintenance periods of 6 weeks (Study C013) and 12 weeks (Study C017). In these studies, a total of 441 participants received Xcopri 100, 200, or 400 mg/day (placebo: 214 participants). At baseline, participants reported a median frequency of 8.5 attacks per 28 days, which was similar across treatment groups. In both studies, the primary efficacy endpoint was to compare Xcopri and placebo with respect to median percent reduction in seizure frequency per 28 days in the treatment period vs baseline. In Study C017, the primary efficacy endpoint in the recommended maintenance dose of Xcopri 200 mg/day showed a placebo-subtracted value of 31%. This was supported by the results of the key secondary endpoint of greater than 50% Responder Rate (placebo-subtracted value of 36%). Efficacy results of the single 200 mg/day arm of the supportive Study C013 confirmed the efficacy findings of Study C017 (placebo-subtracted values of 34% and 28% for the primary and key secondary endpoints, respectively). In Study C013, approximately 28.3% of Xcopri-treated participants became seizure-free during the trial (placebo: 8.8%), whereas in Study C017, 12.1% reported seizure-free status, in a dose-dependent fashion, across the three Xcopri arms (placebo: 1%).

The most common treatment-emergent adverse events (TEAEs) in Xcopri treatment arms of the two controlled studies were somnolence, dizziness, nystagmus, vision-related adverse events (AE) (e.g., blurred vision, diplopia), and balance-related AEs (e.g., gait disturbance, ataxia). Other events such as increase in the levels of transaminases did also occur. Some of the AEs that led to study discontinuation across Xcopri arms included dizziness, somnolence, ataxia, nystagmus, and diplopia.

Long-term safety of Xcopri was assessed in three open-label trials (N = 1,845), which collectively demonstrated a similar safety profile of Xcopri to what was observed in controlled studies. There were no new safety signals or unexpected AEs in open-label trials. A total of 9 serious cases of appendicitis were reported across Xcopri studies which was markedly higher than the rate in the general population. The significance of this finding is currently unknown. Appendicitis, as well as hyperkalemia and elevation of transaminases (none suggestive of Hy’s Law) have been included in the product monograph (PM).

Data from an abuse potential study suggest that such risk does exist and participants with history of drug/alcohol abuse should be monitored for signs of misuse/abuse.

Xcopri can lead to the shortening of QT interval, by as much as 75 msec, in a dose-dependent manner. A contraindication has been added to Xcopri PM for patients with Familial Short QT syndrome, a family history of the syndrome, and presence or history of short QT interval.

Three cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) were reported in Xcopri clinical trials, including one in a healthy volunteer who participated in a Phase I safety study. There is strong suspicion that the occurrence of DRESS was linked to the high initial dose and/or rapid titration of Xcopri. Although this could not be definitely proven, it warranted the inclusion of a box warning to advise prescribers of closely adhering to the recommended low initial dose and slow titration scheme and to not exceed the recommended limits.

Notable uncertainties included a limited number of elderly participants across studies (N = 48), use of Xcopri in pregnant or lactating individuals, participants with hepatic impairment, and those with end stage renal disease/undergoing dialysis, all of which have been addressed in the approved PM.

Upon review, the Risk Management Plan (RMP) was considered acceptable with some revisions. As an additional pharmacovigilance activity, the prospective Pregnancy Exposure Registry and Pregnancy Outcomes Study will be included in the Canadian RMP.

Following review of the labels provided for Xcopri, the final labelling and PM were considered to be acceptable.

The chemistry and manufacturing information submitted for Xcopri has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Based on the data currently available to Health Canada, the benefit of Xcopri therapy in adults with epilepsy outweighs the risks associated with the use of this product. Therefore, the Benefit-Harm-uncertainty (BHU) assessment for the use of Xcopri in the management of partial-onset seizures in adult patients with epilepsy is positive and favorable.

For further details about Xcopri, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.