Epilepsy

Adjunctive cenobamate for uncontrolled focal epilepsy in adults: phase II trial results

A double-blind, randomised, placebo-controlled phase II study of adjunctive cenobamate in adults with uncontrolled focal epilepsy showed high rates of total seizure-freedom over 12 weeks.

The need for more effective antiseizure medicines (ASMs) is urgent. Cenobamate, also known as YKP3089, is a putative modulator of GABA-A receptor function and inhibitor of sodium channel currents. Preclinical studies suggest it has broad-spectrum anticonvulsant activity.  

Krauss et al. recently reported the results of a second phase II trial (publication of the first is pending).  This large, double-blind, randomised, dose-response study conducted across 107 centres in 16 countries evaluated the safety, efficacy and tolerability of adjunctive cenobamate compared to placebo in adults with uncontrolled focal epilepsy. Patients were assigned to adjunctive once daily oral cenobamate (at 100 mg, 200 mg or 400 mg) or placebo (ratio of 1:1:1:1). A modified intention-to-treat analysis was undertaken.    

322/437 (74%) patients took 2-3 concomitant ASMs at enrolment. Those treated with cenobamate demonstrated a significant reduction in median seizure frequency (35.5% for the 100 mg group, and 55% for both the 200 mg and 400 mg groups), compared to placebo (24%).  

Responder rates (>=50% seizure reduction) for the cenobamate-treated groups were 40% (100 mg), 56% (200 mg) and 90% (400 mg) versus 25% for those taking placebo.  

A post-hoc analysis revealed surprisingly high rates of total seizure-freedom for the 400mg cenobamate group of 21% over 12 weeks (1% in the placebo group).  

The most commonly reported cenobamate-associated adverse events (somnolence, dizziness and fatigue) were dose-related and mild or moderate in severity. 

The US Food and Drug Administration approved cenobamate for the adjunctive treatment of uncontrolled focal epilepsy in adults in November 2019. Real-world, long-term data will be important to collate.  

 

Key points:

  • Cenobamate is a novel broad-spectrum antiseizure medicine with a putative mechanism of action involving GABA-A receptor modulation and sodium channel current inhibition. 
  • In this double-blind, randomised, placebo-controlled study of uncontrolled focal epilepsy in adults, adjunctive cenobamate treatment satisfied primary outcomes regarding responder rates and reduction in median seizure frequency.  Cenobamate also showed high rates of total seizure-freedom over 12 weeks.
  • Cenobamate may be a useful adjunctive therapy for adults with difficult-to-control epilepsy if the study results are replicated over the long-term in a real-world clinical setting
  • The US Food and Drug Administration approved cenobamate for the adjunctive treatment of uncontrolled focal epilepsy in adults in November 2019. 

References:

Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Krauss GL, Klein P, Brandt C et al. Lancet Neurol. 2020 Jan;19(1):38-48. doi: 10.1016/S1474-4422(19)30399-0. PMID: 31734103.