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In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
In addition, “high rates of seizure freedom were observed with doses of 200 mg and 400 mg,” investigators reported in the Lancet Neurology.
During a 12-week maintenance phase, 21% of patients who received cenobamate 400 mg/day and 11% who received cenobamate 200 mg/day were seizure free, compared with 1% who received placebo. “These data suggest that cenobamate might be a safe and effective treatment option in patients with uncontrolled focal (partial)-onset seizures,” the authors wrote.
On Nov. 21, 2019, the Food and Drug Administration approved cenobamate tablets, marketed as Xcopri, to treat focal-onset seizures in adults. The agency noted that hypersensitivity reactions have occurred with cenobamate in two randomized, controlled studies and that one patient died when the drug was titrated rapidly during one of the studies that has not been published yet.
Researchers think that cenobamate, a novel tetrazole alkyl carbamate derivative, reduces neuronal excitability “by enhancing the fast and slow inactivation of sodium channels and by inhibiting the persistent component of the sodium channel current,” wrote Gregory L. Krauss, MD, a professor of neurology at Johns Hopkins University, Baltimore, and colleagues.
The rates of seizure freedom with adjunctive cenobamate in the published trial are “a remarkable finding,” wrote Stephan Arnold, MD, an epilepsy specialist at Neurozentrum Nymphenburg in Munich, in an accompanying commentary. Twenty of 95 patients in the 400-mg/day group and 11 of 98 patients in the 200-mg/day group “had no seizures during the 12-week maintenance phase, whereas only 1 patient (1%) of the placebo group remained free of seizures during this period,” Dr. Arnold wrote. “To my knowledge, a seizure freedom rate of 20% or higher has not yet been reported in a placebo-controlled, double-blind trial of anticonvulsive drugs.”
Still, clinical trials in general are limited by their inclusion and exclusion criteria, relatively short maintenance phases, and the need to keep the dosage of concomitant drugs unchanged during the study, Dr. Arnold noted. “Thus, future findings under real-life conditions will reveal the clinical relevance of cenobamate.”
Hypersensitivity reactions led to protocol adjustments
During the trial, the investigators amended the protocol to lower the starting dose of cenobamate and slow the rate of up-titration to address a risk of allergic drug reactions. “Three hypersensitivity reactions, characterized as rash with involvement of at least one other body system, were reported in three patients” who were assigned to receive cenobamate 200 mg/day, the authors wrote. One case of pruritic rash accompanied by pyrexia occurred on day 10 during the initial faster titration protocol. In another case, “a rash and facial swelling occurred on day 57 in a patient who underwent the amended titration protocol.” These two patients discontinued treatment, and the rashes resolved.
“The third hypersensitivity reaction was a serious case of drug reaction with eosinophilia and systemic symptoms that occurred starting on day 24 of treatment in a patient randomly assigned to receive 200 mg/day of cenobamate during the faster initial titration protocol,” the authors wrote. “Treatment was discontinued and the patient was treated with corticosteroids and recovered within 2 months.”
The most common treatment-emergent adverse events included somnolence, dizziness, and fatigue. Most events were mild or moderate. The rate of titration and an inability to adjust the dose of concomitant medications may have contributed to the rate of adverse events, the researchers noted. Treatment-emergent adverse events were most frequent in the 400-mg/day group and led to treatment discontinuation in 20% of patients in this group. An ongoing phase 3 study is assessing a lower starting dose and slower titration rate.
A double-blind, randomized, placebo-controlled trial
The 18-week, double-blind, randomized trial published in Lancet Neurology is one of two phase 2 clinical trials of cenobamate. The other phase 2 study, which lasted 12 weeks, is pending publication. For the 18-week study, researchers at 107 centers in 16 countries enrolled more than 430 adults aged 18-70 years with uncontrolled focal epilepsy. Patients were taking one to three concomitant antiepileptic drugs at stable doses for at least 4 weeks before screening. Patients completed an 8-week baseline assessment, followed by a 6-week titration phase and a 12-week maintenance phase.
“During the 8-week baseline assessment, patients had to have eight or more focal aware (simple partial) seizures with a motor component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalized) seizures, with a seizure-free interval of less than 25 days,” Dr. Krauss and colleagues wrote. In addition, participants had to have at least three of these seizures during the first 4 weeks of the baseline assessment and at least three during the last 4 weeks.
The investigators excluded patients who were taking diazepam, phenytoin, or phenobarbital within 1 month of screening because of a potential drug-drug interaction with cenobamate. Other exclusion criteria included clinically significant psychiatric illness and status epilepticus within 3 months of screening.
The researchers assigned patients 1:1:1:1 to receive cenobamate 100 mg/day, cenobamate 200 mg/day, cenobamate 400 mg/day, or placebo. Percentage change from baseline in focal seizure frequency averaged over 28 days during the 18-week treatment period was the primary efficacy outcome for the FDA. The responder rate (the percentage of patients with at least a 50% reduction from baseline in focal seizure frequency) during the 12-week maintenance phase was the primary efficacy outcome for the European Medicines Agency.
The investigators screened 533 patients and assigned 437 to treatment groups. The modified intention-to-treat population included 434 patients, the modified intention-to-treat maintenance-phase population included 397 patients, and the safety population included 437 patients. The most frequently used concomitant medications were levetiracetam (43%), lamotrigine (32%), and carbamazepine (28%).
The median percentage change from baseline in focal seizure frequency per 28 days during treatment was –24% for the placebo group and –35.5% for the cenobamate 100-mg group. The cenobamate 200 mg group and the cenobamate 400-mg/day group each had a change of –55%.
Responder rates during the maintenance phase were 25% for the placebo group, 40% for the 100-mg group, 56% for the 200-mg group, and 64% for the 400-mg group.
The implications of seizure freedom
The authors acknowledged that it is “difficult to interpret seizure freedom in clinical trials given the constraints of the study designs ... which do not reflect real-life practice. Nonetheless, seizure freedom is of great clinical significance to patient quality of life and the rates reported in this study are notable relative to all other pivotal studies of antiepileptic drug treatment in uncontrolled focal seizures over the past 25 years.”
Rates of seizure freedom represent a crucial outcome measure, Dr. Arnold wrote in his commentary.
“For individual patients, it is not a seizure reduction of 50% or even higher that counts, since this effect will not allow them to drive a car or to work under circumstances bearing increased health risks,” he wrote. “Even when seizure are infrequent, patients nevertheless face the risks of falls, fractures, drowning, and sudden unexpected death in epilepsy. It is complete seizure control that gives rise for hope of an independent lifestyle.”
The study was funded by SK Life Science, the developer of cenobamate. One of the study authors is an employee of SK Life Science. Dr. Krauss is a consultant or advisor for Eisai, Otsuka, and Shire and has received research support from Biogen, SK Life Science, and UCB. Dr. Arnold had no competing interests.
SOURCE: Krauss GL et al. Lancet Neurol. 2019 Nov 13. doi: 10.1016/S1474-4422(19)30399-0.
FROM LANCET NEUROLOGY