Summary Basis of Decision for Xcopri

Clinical Pharmacology

The medicinal ingredient in Xcopri is cenobamate. Non-clinical data suggest that cenobamate reduces repetitive neuronal firing by inhibiting the voltage-gated sodium currents. It also appears to act as a positive allosteric modulator of high-affinity gamma-aminobutyric acid type A (GABA_A) receptors by binding to a non-benzodiazepine binding site. The precise mechanism of action by which cenobamate exerts its antiseizure effects in patients with partial onset seizures is unknown.

After oral administration, almost 90% of cenobamate is absorbed. The median time at which the maximum plasma concentration (C_max) of cenobamate is observed (T_max) is between 0.75 and 4 hours. The apparent volume of distribution is approximately 40 to 50 L, and the plasma protein binding is 60%.

Cenobamate is extensively metabolized in the liver, primarily by glucuronidation catalyzed by uridine 5’-diphospho-glucuronosyltransferase (UGT) enzyme UGT2B7 and to a lesser extent by UGT2B4. Minor metabolic pathways include oxidation by cytochrome P450 (CYP) enzymes CYP2E1, CYP2A6, and CYP2B6, and to a lesser extent by CYP2C19 and CYP3A4/5.

Studies of radiolabelled cenobamate demonstrate that unchanged cenobamate accounts for over 98% of the area under the concentration-time curve (AUC) of total radioactivity in plasma. A mean of 93% of the total radioactive dose was recovered in urine and feces (approximately 88% and 5%, respectively).

Other studies indicate that, over a dose range of 100 to 400 mg/day, the apparent terminal half-life of cenobamate is 50 to 60 hours and the apparent oral clearance is approximately 0.45 to 0.66 L/hour. Steady-state plasma levels of cenobamate were generally reached by about 14 days of once-daily dosing. Age, gender, race/ethnicity, and body weight did not have a clinically significant effect on cenobamate exposure.

In healthy subjects, cenobamate induced a dose-dependent shortening of the QT interval corrected for heart rate using Fridericia’s formula (QTcF). Accordingly, Xcopri should be used with caution in patients who take other drugs that can potentially shorten the QT interval, lead to cardiac arrythmia, or cause other similar adverse cardiac events. Moreover, the use of Xcopri is contraindicated in patients with familial short QT syndrome or a family history of the syndrome and in patients with the presence or history of a short QT interval.

Data from drug-drug interaction clinical studies and population pharmacokinetic analyses indicate that cenobamate may interact with several other antiepileptic drugs (e.g., carbamazepine, lamotrigine, phenytoin, phenobarbital, clobazam). In addition, cenobamate may affect plasma levels of drugs that are CYP2B6 substrates (e.g., bupropion), CYP3A substrates (e.g., midazolam), or CYP2C19 substrates (e.g., omeprazole). Doses of these drugs may need to be adjusted accordingly. Cenobamate may also affect plasma levels of oral hormonal contraceptives. Therefore, at least one other, reliable non-hormonal method of contraception is recommended during treatment with Xcopri and for at least 21 days after discontinuing treatment. The potential effects of cenobamate on the exposure of concomitantly used drugs, along with appropriate recommendations, are listed in the Drug-Drug Interactions section of the Xcopri Product Monograph.

Based on pharmacokinetic studies of cenobamate in patients with mild or moderate hepatic impairment and patients with mild, moderate, or severe renal impairment, dose reductions should be considered for these populations and the maximum recommended dose of Xcopri is 200 mg once daily. The pharmacokinetics of cenobamate in patients with severe hepatic impairment, patients with end-stage renal disease or those undergoing dialysis has not been studied. Accordingly, the use of Xcopri in these populations should be avoided.

Overall, the submitted clinical pharmacology data support the use of Xcopri for the specified indication.

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

Clinical Efficacy

The efficacy of Xcopri as adjunctive therapy in the management of partial-onset seizures in adults with epilepsy is supported by data derived from two randomized, double-blind, placebo-controlled studies (C017 and C013).

The studies included patients who had partial-onset seizures with or without secondary generalization that were not adequately controlled with one to three concomitant antiepileptic drugs. The median age of patients was 38 years (range: 19 to 70 years) in Study C017 and 36 years (range: 18 to 61 years) in Study C013. Approximately 50% of patients were women. Patients had a mean duration of epilepsy of approximately 24 years and a median baseline seizure frequency of 8.5 seizures per 28 days (assessed during an 8-week baseline period). After the baseline period, randomized patients entered a double-blind treatment period including a 6-week titration phase and a maintenance phase that lasted 12 weeks in Study C017 and 6 weeks in Study C013. In Study C017, patients were randomized to receive Xcopri at a target maintenance dose of 100 mg/day, 200 mg/day, or 400 mg/day or placebo. In Study C013, patients were randomized to receive Xcopri at a target maintenance dose of 200 mg/day or placebo. Overall, there were 441 patients in the Xcopri groups and 214 patients in the placebo groups. All patients continued receiving their background antiepileptic drugs.

In both studies, the primary efficacy endpoint was the percent change from baseline in seizure frequency per 28 days in the double-blind treatment period (18 weeks and 12 weeks in duration in Study C017 and Study C013, respectively). The key secondary endpoint was the responder rate, defined as the proportion of patients with at least 50% reduction in seizure frequency in the double-blind treatment period.

In Study C017, among patients treated with Xcopri at the recommended maintenance dose of 200 mg/day, the median percent reduction from baseline in seizure frequency per 28 days at the end of the double-blind period was 55%, compared to 24% among those receiving placebo. The treatment difference was statistically significant (p<0.001). This finding was supported by the results of the key secondary endpoint. The responder rate achieved with Xcopri 200 mg/day was 57.8% versus 21.7% in the placebo-treated group (p<0.001). The results achieved in the Xcopri 200 mg/day group translate into placebo-subtracted values of 31% for the primary efficacy endpoint and 36.1% for the key secondary efficacy endpoint.

Efficacy results reported for the primary and key secondary endpoints in the Xcopri 200 mg/day group of Study C013 support the efficacy findings of Study C017. The median percent reduction from baseline in seizure frequency per 28 days at the end of the double-blind period was 55.6% in the Xcopri 200 mg/day group compared to 21.5% in the placebo-treated group (p<0.0001). The responder rate in the double-blind period for the Xcopri 200 mg/day group was 50.4% compared to 22.2% in the placebo group (p<0.0001). Accordingly, the placebo-subtracted values were 34.1% and 28.2% for the primary and key secondary efficacy endpoints, respectively.

During the 12-week maintenance phase of Study C017, 12.1% of all patients across the three Xcopri groups achieved seizure freedom, in a dose-related fashion (i.e., 3.9%, 11.2%, and 21.1% of patients in the 100 mg/day, 200 mg/day, and 400 mg/day groups, respectively, versus 1.0% of placebo-treated patients). In Study C013, 28.3% of Xcopri-treated patients became seizure-free during the 6-week maintenance phase versus 8.8% in the placebo-treated group. Based on the totality of the data, this level of efficacy of Xcopri, as adjunctive treatment in adult patients with partial-onset seizures, is acceptable and is generally in line with the documented efficacy of several other currently marketed antiepileptic drugs.

The efficacy findings reported for the 100 mg daily maintenance dose of Xcopri were shown to be statistically and marginally clinically significant in comparison to placebo. This dose may be sufficiently effective for a segment of the intended patient population. However, 200 mg is the recommended daily maintenance dose of Xcopri. The maximum recommended daily dose is 400 mg, which is reserved for patients who do not respond to lower doses and can tolerate the 400 mg dose. In controlled trials, the 400 mg daily dose of Xcopri was associated with a higher frequency of severe adverse events and treatment discontinuations due to adverse events.

Indication

The New Drug Submission for Xcopri was filed by the sponsor with the following indication:

Xcopri (cenobamate tablets) is indicated as an adjunctive therapy for the management of partial-onset seizures in adults with epilepsy who are not satisfactorily controlled with conventional therapy.

Upon minor revisions, Health Canada approved the following indication:

Xcopri (cenobamate tablets) is indicated as adjunctive therapy in the management of partial-onset seizures in adults with epilepsy who are not satisfactorily controlled with conventional therapy.

For more information, refer to the Xcopri Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Xcopri in adult patients with partial-onset seizures was primarily evaluated in two randomized, double-blind, placebo-controlled studies, C017 and C013 (described in the Clinical Efficacy section). In the double-blind periods of these studies, across the three Xcopri doses (100, 200, and 400 mg/day), there was a dose-related increase in the overall frequency of treatment-emergent adverse events. The most frequently reported treatment-emergent adverse events included gastrointestinal system disorders and nervous system disorders, followed by eye and psychiatric disorders. Some of the most frequently reported adverse events included somnolence, dizziness, fatigue, diplopia, and balance disorder. The Xcopri 400 mg/day dose was associated with a higher frequency of several treatment-emergent adverse events (e.g., gait disturbance, ataxia) as compared to lower doses. Among the adverse events that occurred with the highest frequency in the Xcopri 400 mg/day treatment group were also constipation, blurred vision, balance disorder, increased alanine aminotransferase, and increased aspartate aminotransferase. The observed dose-related increase in the frequency of adverse events suggests a higher probability of a causal relationship between Xcopri and the adverse events.

Twenty-five serious adverse events were reported in the Xcopri groups of the double-blind periods of studies C013 and C017, including somnolence, dizziness, ataxia, and nystagmus. In addition, one case of status epilepticus and one case of drug reaction with eosinophilia and systemic symptoms (DRESS) were reported in the Xcopri 200 mg/day group.

Discontinuation rates due to adverse events were approximately 11%, 9%, and 21% in Xcopri 100, 200, and 400 mg/day groups, respectively (versus 4% in the placebo group). Adverse events that led to discontinuation included somnolence, dizziness, diplopia, nystagmus, and vertigo.

The long-term safety of Xcopri was evaluated in 1,844 patients in three open-label studies, including the extensions of studies C013 and C017, and the long-term study C021. Patients were treated with Xcopri 100, 200, or 400 mg/day for up to 36 months. Some of the most frequently reported adverse events in the open-label extension studies were dizziness, somnolence, nystagmus, balance disorder, and ataxia. Overall, long-term treatment with Xcopri does not appear to result in the emergence of new adverse events or in a markedly higher incidence of previously observed adverse events. In Study C021, serious adverse events included appendicitis (7 cases or 0.5%), hyponatremia (6 cases or 0.4%), dizziness (5 cases or 0.4%), seizure/seizure cluster (32 cases or 2.4%), status epilepticus (7 cases or 0.5%), and suicide ideation/attempt (10 cases or 0.8%). The most commonly reported adverse events leading to study discontinuation in the three open-label studies included nervous system disorders (ataxia [0.4%], dizziness [1.2%], headache [0.4%], somnolence [0.5%]), psychiatric disorders (aggression [0.2%], anxiety [0.3%], irritability [0.3%]), and rash (0.5%). The safety profile of Xcopri during the long-term studies appears to be similar to that observed in the two controlled studies.

Across clinical studies of Xcopri, three cases of DRESS were reported, including one case with fatal outcome in a healthy volunteer who participated in a Phase I safety study. There is a strong suspicion that the occurrence of DRESS was linked to the high initial dose and/or rapid titration of Xcopri. Although a causal relationship could not be definitively proven, the occurrence of DRESS warranted the inclusion of a Serious Warnings and Precautions box in the Xcopri Product Monograph to advise prescribers of closely adhering to the recommended low initial dose and slow titration scheme, and of not exceeding the maximum recommended daily dose.

A dose-dependent shortening of the QT interval corrected for heart rate (QTc) using Fridericia’s formula (QTcF), by as much as 75 ms, has been observed with Xcopri in a placebo-controlled QT study in healthy subjects. Also, a higher percentage of Xcopri-treated subjects had a QT shortening of greater than 20 ms compared to those treated with placebo. Reductions of the QTc interval below 300 ms were not observed in this study. Based on these findings, the use of Xcopri is contraindicated in patients with familial short QT syndrome or a family history of the syndrome, and in patients with the presence or history of short QT interval.

Nine serious cases of appendicitis were reported across Xcopri clinical studies, which represented a markedly higher rate than the expected background rate of appendicitis in the general population (2.9 per 1,000 versus 1.1 per 1,000 patient-years of exposure). However, as stated in the Xcopri Product Monograph, the significance of this finding is currently unknown.

Appropriate warnings and precautions are in place in the approved Xcopri Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box highlights the risk of DRESS, which can be life-threatening or fatal.

For more information, refer to the Xcopri Product Monograph, approved by Health Canada and available through the Drug Product Database.

In non-clinical studies, cenobamate, the medicinal ingredient in Xcopri, has been demonstrated to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents. Cenobamate is also a positive allosteric modulator of the gamma-aminobutyric acid type A (GABA_A) ion channels. However, the precise mechanism by which cenobamate exerts its therapeutic effects in patients with partial onset seizures is unknown.

Cenobamate is highly soluble in water. The non-clinical studies demonstrated high oral bioavailability and low clearance of cenobamate in mice, rats, and monkeys. In rats and monkeys, systemic exposure to cenobamate generally increased in a dose-proportional manner. There was minimal accumulation of cenobamate after multiple dosing.

In all species examined (mouse, rat, rabbit, dog, monkey, human), cenobamate was extensively metabolized. N-glucuronidation represented the major clearance pathway for cenobamate in monkeys and humans. Glucuronidation of cenobamate was catalyzed predominantly by uridine 5’-diphospho-glucuronosyltransferase (UGT) 2B7. In addition, the enzymes cytochrome P450 (CYP) 2E1 (CYP2E1), CYP2A6, and CYP2B6 were found to be major contributors to the CYP-mediated oxidation of cenobamate in humans.

Single- and repeated-dose toxicity studies of cenobamate were conducted in mice, rats, and monkeys.

In single-dose toxicity studies, a single oral administration of cenobamate induced dose-dependent neurologic effects including changes in activity and gait in animals and was lethal at doses higher than 150 mg/kg.

Maximum doses in repeated-dose toxicity studies of cenobamate were limited by adverse effects on the central nervous system (including hypoactivity, uncoordinated gait, hypothermia, and tremor). In a 13-week repeated-dose toxicity study in mice, mortality and neurologic clinical signs were observed at oral doses greater than or equal to 60 mg/kg/day of cenobamate. The no-observed-adverse-effect level (NOAEL) was 30 mg/kg/day, which corresponded to 1.5 times and 2.5 times the maximum plasma concentration in humans at the intended clinical doses of 200 mg/day and 400 mg/day, respectively. In a 26-week repeated-dose toxicity study in rats, the NOAEL was found to correspond to 0.2 to 0.7 times the human exposure associated with the clinical doses of 200 mg/day and 400 mg/day. The NOAEL in a 52-week repeated-dose toxicity study in monkeys was determined to correspond to 0.8 to 2.6 times the human exposure associated with the intended clinical doses of 200 mg/day and 400 mg/day.

Cenobamate was not genotoxic. In carcinogenicity studies, cenobamate did not increase the incidence of neoplastic lesions. However, plasma exposure at the highest dose tested in rats was lower than that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.

Oral administration of cenobamate to male and female rats prior to and throughout the mating period and continuing in females to Day 6 of gestation, at doses which resulted in systemic exposure below the human exposure at the MRHD of 400 mg/day, did not produce adverse effects on fertility, general reproductive performance, or early embryonic development. Cenobamate did not show teratogenic potential up to the dose of 50 mg/kg/day when administered to female rats during gestation.

Oral administration of cenobamate to female rats throughout pregnancy and lactation resulted in neurobehavioral impairment (learning and memory deficit and increased auditory startle response) in the offspring at all doses used. Cenobamate was present in the amniotic fluid, fetal blood, and the milk of lactating rats.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Xcopri Product Monograph. In view of the intended use of Xcopri, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Xcopri Product Monograph, approved by Health Canada and available through the Drug Product Database.

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. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable. Based on the stability data submitted, the proposed shelf life of 60 months for the 12.5 mg and 25 mg tablets and 48 months for the 50 mg, 100 mg, 150 mg, and 200 mg tablets is considered acceptable, when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified, i.e., within the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits or qualified from toxicological studies.

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The excipient lactose monohydrate is of animal origin. It is derived from milk obtained from healthy animals under the same conditions as milk collected for human consumption. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents. The other excipients used in the formulation of Xcopri are not of human or animal origin.