Kv7.2/7.3 Activators for the Treatment of Epilepsy Disorders

DESCRIPTION provided by applicant Epilepsy is the oldest known and most common serious chronic neurological disorder that is characterized by recurrent seizures It currently affects million people worldwide including million adults and nearly children in the United States People with epilepsy suffer from seizure related disabilities depression and anxiety and have increased mortality compared to the general population Over the last few decades there has been considerable effort and success to bringing new anti seizure drugs to market Despite the availability of several newer medications approximately of patients are treatment resistant Furthermore anti seizure drug therapies are associated with significant adverse effects and often require careful titration to achieve efficacy while minimizing disabling side effects Neuronal potassium channels play a key role in regulating neuronal activities Kv channels are one family of voltage gated potassium channels critical in maintaining the resting membrane potential of excitable cells and neuronal Kv channels act to dampen repetitive firing of neurons Additional interest in Kv and Kv channels come from the discovery of mutations in the Kv or Kv genes found to be associated with some inherited forms of epilepsy Thus small molecule drugs that activate the opening of Kv and Kv channels have potential to treat many neuronal hyperexcitability disorders including epilepsy A recently approved anti seizure drug ezogabine acts primarily by opening Kv channels with activity on the GABAA system as well However in addition to tolerability issues ezogabine use has been associated with serious adverse effects that have limited its utility including retinal and skin discoloration that are likely linked to ezogabineandapos s chemical instability rather thn its Kv activities The goal of this Knopp Biosciences program is to design and develop a Kv activator that fully realizes the potential of this target to address the unmet medical need of treatment resistant epilepsy patients and difficult to treat generalized epilepsy syndromes Such a compound will possess a dramatically improved tolerability and safety profile over that of ezogabine not only via improved intrinsic chemical stability characteristics but also due to reduced Kv activity so as to avoid side effects that may be caused by opening Kv channels present in blood vessels and smooth muscle In addition the next generation Kv activator will remove activity on the GABAA channels To accomplish this Knopp has developed a variety of in vitro screening assays using Kv expressing cell lines and primary neurons These data along with those generated from a battery of in vitro assays testing for metabolism and drug like properties will be used to select compounds for study in acute and chronic animal models of epilepsy We will also evaluate the tolerability of compounds in animals to identify drug candidates that show the best therapeutic window for efficacy with minimal side effects PUBLIC HEALTH RELEVANCE Epilepsy treatment remains a significant unmet medical need and health care burden worldwide with approximately of patients not fully responding to current therapies The goal of this program is to develop a biased Kv potassium channel activator to address such treatment resistant epilepsy patients and difficult to treat generalized epilepsy syndromes A small molecule compound that demonstrates broad efficacy in epilepsy patients along with a significantly improved safety and tolerability profile compared to existing anti epileptic drugs would be a significant addition to the existing treatments