Novel antiepileptic drugs: Something old, something new in the therapeutic pipeline
By Bruce Jancin
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.
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.
Dr. J. Helen Cross
credit: Bruce Jancin/MDedge News
GABAergic synapse showing the production, release, action and degredation of GABA.
“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.
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;313:1419).
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.
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.
Electroencephalography (EEG) recorded in a 2-year-old girl with CDKL5epileptic encephalopathy. Interictal EEG recorded during sleep and showing diffuse slowing with intermixed frequent high-amplitude generalized bursts of polyspikes, spikes, and waves. Gain, 20 µV/mm; high frequency filter, 70 Hz; paper speed, 15 mm/second.
credit: Reprinted from Fetal and Neonatal Physiology, Vol 2 / Fifth Edition, Maria Roberta Cilio, Francesco Pisani, Electroencephalography in the Preterm and Term Infant, Pages 1362-1389.e4 Copyright 2017, with permission from Elsevier.
Marinus Pharmaceuticals, which is developing ganaxolone, is sponsoring a pivotal phase 3, double-blind, placebo-controlled clinical trial in 70 patients, aged 2-21 years, with confirmed CDKL5 deficiency disorder. The Marigold trial is now enrolling patients with a minimum of 16 major motor or drop seizures per month despite being on up to four conventional AEDs. After a 23-week double-blind phase, a long-term open-label extension will follow. At present there is no approved treatment for CDKL5 deficiency disorder.
Ganaxolone is also in earlier-stage studies for protocadherin 19 (PCDH19)–related epilepsy, another rare and serious epileptic syndrome characterized by early-onset cluster seizures and cognitive and behavioral disturbances.
Everolimus and other mTOR inhibitors
Everolimus (Afinitor), a mammalian target of rapamycin (mTOR) inhibitor, earned FDA approval in 2018 as adjunctive treatment for tuberous sclerosis-associated partial-onset seizures in adults and children age 2 years or older on the strength of its impressive showing in the 25-country, phase-3, double-blind, placebo-controlled EXIST-3 trial. A post hoc analysis of the pediatric participants showed that the seizure response rate was significantly higher in those aged 2-5 years than in those aged 6-18 years (Lancet Child Adolesc Health. 2018 Jul;2(7):495-504).
“Also, tantalizingly, there was a steady improvement over time with the utilization of everolimus, perhaps suggesting a degree of disease modification,” Dr. Cross noted.
Old drugs, new tricks
Early promising anecdotal reports of treatment success using quinidine in drug-resistant epilepsy of infancy with migrating focal seizures caused by potassium channel gene KCNT1 gain-of-function mutations have been followed by mixed results from other investigators. And a small randomized trial of oral quinidine in patients with severe autosomal dominant nocturnal frontal lobe epilepsy due to KCNT1 mutations proved negative (Neurology. 2018 Jan 2;90(1):e67-e72. doi: 10.1212/WNL.0000000000004769. Epub 2017 Dec 1).
An international group of investigators have asserted on the basis of an initial 15-patient series that the sodium-channel blockers carbamazepine and phenytoin should be considered first-line therapy in patients with KCNQ2 encephalopathy. They argued that early recognition and treatment of the disorder may be key to reducing the associated neurodevelopmental impairment (Epilepsia. 2015 May;56:685-91).
Time to reconceptualize epilepsy?
These potential new uses for older drugs, along with the success of everolimus and ganaxolone in targeting specific genetically based seizure disorders, put Dr. Cross in a frame of mind to revisit the conventional concept of epilepsy.
“We cannot look at epilepsy as a single disease anymore,” she claimed. “You really need to think of it as a symptom of a group of diseases and look more at the specific underlying causes, not just the electroclinical phenotype.”
This research approach is the way forward to achieve improved outcomes and perhaps even the possibility of cure, according to the pediatric neurologist.
Dr. Cross reported receiving research funding and/or consultant’s fees, all of which go directly to her institution, from nine companies.
Cost And Coping