Novel antiepileptic drugs: Something old, something new in the therapeutic pipeline

Promising new antiepileptic agents are on the horizon. For the most part, these are orphan drugs or repurposed older agents that were belatedly found to have previously unrecognized antiseizure effects. Some of these investigational antiepileptic drugs (AEDs) may even be disease-modifying agents.

In Bangkok, at the recent International Epilepsy Congress sponsored by the International League Against Epilepsy, J. Helen Cross, MD, OBE, highlighted several drugs in the developmental pipeline, many of them now in or successfully through phase 3 clinical trials.

Cenobamate

The novel oral agent cenobamate has been evaluated in more than 1,900 patients in clinical trials. Now under consideration by the U.S. Food and Drug Administration for marketing approval for partial-onset seizures in adults, cenobamate is believed to have two separate mechanisms of action. One involves upregulation of gamma-aminobutyric acid-A (GABA-_A) receptors and the other involves modulation of voltage-gated sodium channels.

In one phase 3 trial, roughly 400 adults with focal epilepsy were randomized to placebo or to cenobamate at 100, 200, or 400 mg/day. A 75% or greater reduction in seizure frequency was seen in 10%, 17%, 32%, and 47% of the study patients, respectively. Notably, seizure-free status was achieved by 1% of placebo-treated controls, compared to 4%, 11%, and 21% of patients on the escalating doses of cenobamate.

“So often when we’re looking at newer treatments, we’re looking at response rates, when really what we want to think about is seizure freedom – and indeed, a 100% reduction in seizures was reported with cenobamate in a substantial proportion of patients in this and other studies,” commented Dr. Cross, professor of pediatric neurology and head of the developmental neurosciences program at University College London – Great Ormond Street Institute of Child Health.

As is so often the case with novel drugs, cenobamate, which is being developed by SK Life Science, must first pass muster in terms of safety and efficacy in adults before it can be formally studied in children.

“This is very much a ‘watch this space’ drug in the pipeline that we may be able to consider in the future for the children we treat,” she said.

Fenfluramine

Decades ago, fenfluramine was a widely prescribed appetite suppressant used for weight loss. The drug was eventually removed from the market because of its alarming association with cardiac valvular thickening and pulmonary hypertension. But it has been resurrected as a novel AED. First, French investigators discovered fenfluramine appeared to have therapeutic benefit in photosensitive epilepsy (N Engl J Med. 1985 Nov 28;313[22]:1419).

Subsequently, Belgian neurologists observed that the drug seemed to be spectacularly effective as add-on therapy in 12 patients with Dravet syndrome, a treatment-resistant and devastating form of epilepsy (Epilepsia. 2012 Jul;53(7):1131-9). 

Two pivotal phase 3, double-blind, randomized, placebo-controlled clinical trials in children and young adults with Dravet syndrome have now been completed. No clinically meaningful toxicities, cardiac or otherwise, were noted. Dr. Cross, who was involved in the studies, characterized the placebo-subtracted 64% reduction in mean monthly seizures at the top dose of 0.8 mg/kg per day as “very exciting in this difficult group.” The sponsor, Zogenix, plans to apply for marketing approval soon.

Ganaxolone

This oral synthetic analog of allopregnanolone binds to both synaptic and extra-synaptic GABA-_A receptors, modulating GABA activity and reducing tonic inhibition in the presence of active neuronal firing. Unlike other GABA modulators, development of tolerance doesn’t seem to be an issue with ganaxolone. In a small pilot study, ganaxolone showed impressive efficacy in young patients with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder, a rare genetic epileptic encephalopathy characterized by severe neurodevelopmental impairment and seizures that are typically refractory to existing AEDs and the ketogenic diet. Not only did the drug result in a nearly 80% increase in seizure-free days as well as significant improvement in secondary endpoints related to attention and sleep disruption, but it did so without any serious side effects.