Failure to use new breakthrough treatments for epilepsy.

Despite the approval of ~20 additional antiseizure medications (ASMs) since the 1980's, one-third of epilepsy patients experience seizures despite therapy. Drug-resistant epilepsy (DRE) is associated with cognitive and psychiatric comorbidities, socioeconomic impairment, injuries, and a 9.3-13.4 times higher mortality rate than in seizure-free patients. Improved seizure control can reduce morbidity and mortality. In 2020 two new ASMs were launched in the US, cenobamate for focal epilepsy in adults and fenfluramine for Dravet syndrome (DS). They offer markedly improved efficacy. Cenobamate achieved 21% seizure freedom with the highest dose and decreased tonic-clonic seizures by 93% during maintenance treatment in a randomized clinical trial (RCT). In long-term open label studies, 10-36% of patients were seizure-free for a median duration of approximately 30-45 months. Fenfluramine treatment in DS reduced convulsive seizure frequency by 56% over placebo at the highest dose, with 8% of patients free of convulsive seizures, and 25% with only one convulsive seizure over 14 weeks. These results were sustained for up to 3 years in open label extension studies. Mortality was reduced 5-fold. These results are superior to all other approved ASMs, placing these two drugs among the most effective anti-seizure therapies. The adverse event profiles resemble those of other ASMs. Despite greater efficacy and similar toxicity, these medications are infrequently used. Two years after US market entry, < 5% of either adults with focal DRE or DS patients were treated with either cenobamate or fenfluramine. We believe this is a failure of our medical system, resulting from limited knowledge about these drugs stemming partly from the separation by academia from industry; restrictions to access created by health care payors, hospitals and regulatory agencies; and insufficient post-launch information about their efficacy and safety.