The Epilepsy Therapy Project, a not-for-profit corporation with the stated goal of bringing academia, industry, investors, and the public together to advance the development of new epilepsy therapies, held its Epilepsy Pipeline Update: Portal Into CNS conference on March 13th in San Francisco. Noted researchers including John Krystal, MD, Deputy Chairman for Research, Department of Psychiatry, Yale University School of Medicine, Steven Schachter, MD, Director of Research, Department of Neurology, Harvard Medical School, Jacqueline French, MD, Professor of Neurology, NYU Comprehensive Epilepsy Center, and Michael Rogawski, MD, PhD, Chairman, Department of Neurology, University of California, Davis discussed the development of currently approved anti-epileptic drugs (AEDs), their successes and shortcomings, and strategies and platforms for the development of future therapies.

The modern era of seizure treatment began in 1857 when Queen Victoria's physician began administering potassium bromide to patients. This was followed by the development of phenobarbital in 1912, phenytoin in 1938, and sixteen other drugs in the first wave of drug development which lasted from 1946 to 1978, during which time many of today's stalwarts including carbamazepine, valproate, and ethosuximide were approved. The second wave of drug development, which began in 1993 and is still ongoing, has seen ten new drugs approved to date including UCB's (UCB, Not Rated) Keppra and Pfizer's (PFE, Not Rated) Neurontin. Although the 50 million patients worldwide with seizures, including up to 2.8 million Americans, have had enormous improvements in seizure control and quality of life throughout these peak and trough years of drug development, one-third still remain refractory to medical treatment while another third suffer from serious side effects. Although there are some potential revolutionary treatments which may pan out in the long-term, in the short and medium-term, most improvements are most likely to be evolutionary, with modifications of current medications leading the way. Of the multitude of anti-epileptic drugs (AEDs) undergoing development, many are established drugs with molecular modifications including Novartis's (NVS, Not Rated) licarbazepine, a derivative of carbamazepine and UCB's brivaracetam and seletracetam, derivatives of Keppra. Each has been modified in the hopes of improved bioavailability and efficacy and a reduction in side effects, which today include hepatotoxicity, tertatogenicity, hyponatremia, and aplastic anemia among many others.

Icagen (ICGN, Market Outperform) presented an overview of ICA-105665, which unlike the earlier sodium channel-targeting AEDs, is a KCNQ potassium channel agonist and potential first-in-class small molecule. The activation of these potassium channels facilitates the M-current, a movement of ions in the brain which attenuates neuronal excitability and epileptiform activity. The compound is currently in a Phase I trial, initiated following positive preclinical pharmacokinetic and toxicity data. A competitor's drug, namely Valeant Pharmaceutical's (VRX, Not Rated) Retigabine, was also discussed at the conference. Retigabine is the only other KCNQ potassium channel agonist according to our research. Phase III data from the RESTORE I trial released in February showed a 44.3% reduction in seizure frequency compared to 17.5% for placebo in the intention to treat population, which was a highly refractory patient group.

In addition to the modification of existing compounds and the activation of potassium channels, entirely new sites within the neuronal synapse, the essential location where neurological and epileptiform activity originates, are being targeted. New technologies to alert a patient prior to a seizure occurring as well as improved means to deliver medications more directly to the brain are being developed. The pharmacology of seizure treatment and multiple psychiatric diseases continues to converge. As the treatable population grows and industry interest continues to rise, epilepsy focused companies, such as Icagen among others, have the potential to thrive.

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