FDA Accepts NDA Submission of Cenobamate for Partial-Onset Seizures

Marc Kamin, MD, the chief medical officer at SK Life Science

Marc Kamin, MD

The FDA has accepted a New Drug Application (NDA) from SK Life Science for cenobamate, its investigational antiepileptic agent for the treatment of partial-onset seizures in adult patients.¹

The submission is based on data from pivotal trials that assessed the efficacy and safety of cenobamate in more than 1900 patients. The results of these trials were presented at the annual meetings of the American Epilepsy Society (AES) and the American Academy of Neurology (AAN).

“We know significant unmet needs remain for patients with CNS disorders, particularly epilepsy. Currently, about one-third of the epilepsy patient population does not achieve adequate seizure control with currently available treatments,” Marc Kamin, MD, the chief medical officer at SK Life Science, told NeurologyLive. “Cenobamate is an investigational compound being developed for the potential treatment of adults with partial-onset seizures and we are hopeful it will provide an additional option for these patients.”

The initial phase 2 studies of cenobamate evaluated close to 1000 individuals, with efficacy demonstrated to the point that the FDA did not require additional efficacy studies.

Three individuals in the early studies developed drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, so this was evaluated further in a phase 3 trial. The trial evaluated if going “low and slow” with cenobamate could possibly mitigate the risk for reactions such as DRESS. Patients were administered gradually increasing doses of cenobamate 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg/day at 2-week intervals. Additionally, biweekly increases of 50 mg/day to increase dosage to 400 mg/day were allowed. No incidences of DRESS were observed in the phase 3 trial.²

“The decision was made, after careful consultation with experts, that the rate of titration of drug is critical in determining the incidence of allergic reactions, particularly for a serious idiosyncratic reaction like DRESS syndrome,” Michael Sperling, MD, the director of the Jefferson Comprehensive Epilepsy Center and the Jefferson Clinical Neurophysiology Laboratory, told NeurologyLive.

In one of the trials presented at the 2018 AAN annual meeting, an 18-week, randomized, double-blind, dose-response study, 437 patients received 100 mg per day of cenobamate (n = 108), 200 mg per day of cenobamate (n = 110), 400 mg per day of cenobamate (n = 111), or placebo (n = 108).

Median seizure frequencies decreased for all doses of cenobamate, with the 100 mg/day experiencing a 35.5% reduction, the 200 mg/day observing a 55.0% reduction, and the 400 mg/day seeing a 55.0% reduction. In comparison, the placebo group experienced a 24.0% reduction.

The median frequencies for simple partial seizures also decreased with all doses of cenobamate—100 mg/day: 48.0%; 200 mg/day: 63.0%; and 400 mg/day: 58.5%—compared with placebo, which showed a 7.0% reduction.

The median frequencies for complex partial seizures and secondary generalized tonic-clonic seizures decreased with the 200 mg per day dose of cenobamate, 55.0% and 91.0%, respectively, as well as the 400 mg per day of cenobamate, 60.0% and 78.0%, respectively. In comparison, the placebo group saw 28.5% and 33.0% reductions, respectively.

The most important issue relates to safety, that slow titration is mandatory to reduce the risk of DRESS syndrome” Sperling said. “The agent is unusually effective, and in my view, well worth trying. It appears to be well tolerated in my patients with very few withdrawals because of side effects.”

When speaking with NeurologyLive, Sperling added a typical caution for physicians. “It is easy to be excited about new agents, and much of what we need to know will be learned over time. Initial enthusiasm is often tempered by experience. That said, I remain optimistic,” he said.

The therapy’s mechanism of action is not completely understood, though investigators believe that it works through 2 mechanisms: enhancing inhibitory currents through positive modulation of GABA-A receptors and decreasing excitatory currents by inhibiting the persistent sodium current.

Cenobamate is the first molecule discovered and developed from inception to NDA submission without partnering or out-licensing from a Korean pharmaceutical company. SK Life Science has stated that it plans to independently commercialize the agent. This, Kamin said, “shows that we are dedicated to building a fully integrated pharmaceutical company with experienced, dedicated individuals committed to doing things differently to change what’s possible for central nervous system treatment.”

REFERENCES

1. SK life science announces FDA acceptance of NDA submission for

cenobamate

, an investigational antiepileptic drug [press release]. Fair Lawn, NJ: SK Life Science; Published February 4, 2019. sklifescienceinc.com/pdf/SKLSI%20NDA%20Acceptance%20Press%20Release%20-FINAL-Updated%202-3-19.pdf. Accessed February 6, 2019.

2. Sperling M, Klein P, Kamin M. Safety of

cenobamate

(YKP3089) as

adjunctive

treatment for uncontrolled partial seizures in a large, multi-center, open-label study. Presented at: American Epilepsy Society Annual Meeting; New Orleans, LA; December 2, 2018. aesnet.org/meetings_events/annual_meeting_abstracts/view/500991.