30 GHP / April 2017 , 1703GH11 Discovering and Developing Drugs to Genetic Epilepsies Epygenix Therapeutics, Inc. is a precisionmedicine-based biopharmaceutical company focused on discovering and developing drugs to treat rare and intractable genetic epilepsy, such as Dravet syndrome. We invited Hahn-Jun Lee, M.Sc., Ph.D., President/CEO and Scott C. Baraban, PhDwho is a Professor of Neurological Surgery andWilliamK. Bowes Jr. Endowed Chair inNeuroscience Research at UCSF. Hahn-Jun Lee is a serial entrepreneur who founded Epygenix Therapeutics, Inc. to develop precision medicine for rare intractable genetic epilepsy. Scott C. Baraban, is a Professor of Neurological Surgery and William K. Bowes Jr. Endowed Chair in Neuroscience Research at UCSF where he directs an epilepsy research laboratory in the Department of Neurological Surgery. Having started up in July 2016, the company may still be young, however, they are rapidly and efficiently advancing an NRDO (No Research, Development Only) biotech strategy. The cutting-edge preclinical research on which the company was founded was completed in Dr. Baraban’s UCSF lab. EpyGenix has licensed the intellectual property associated with the development of medications for Dravet syndrome from UCSF. Dravet Syndrome, is a catastrophic childhood genetic epilepsy, which is associated with severe intellectual disability, impaired social development, persistent drug-resistant seizures and a high risk of sudden unexpected death in epilepsy (SUDEP). These children suffer with life-threatening seizures that cannot be adequately controlled by available medications. Dr. Baraban tells us about the zebrafish models they have developed within his lab at UCSF to identify new treatments for these children. “Our unique phenotype-based zebrafish drug screening system is versatile to rapidly test efficacy and toxicity of any compound. Zebrafish are very suitable for the screening of drug candidates for genetic disease, because zebrafish harbor 82% of human disease-associated targets and drug metabolism pathways are common with humans. This makes zebrafish perfect for a precision medicine based drug discovery program” “Over the past decade, the Baraban laboratory has developed zebrafish models designed to mimic paediatric forms of epilepsy, primarily genetic forms known as catastrophic epilepsies of childhood.” “This zebrafish platform has allowed us to look for drugs that might treat the seizures and the symptoms associated with them. We’ve already screened over 3,000 drugs. From that we have identified several serotonin drugs that we have licensed to Epygenix. This research from the aquarium-to-the-clinic is unique in the drug discovery arena. Specifically, the concept of modelling a disease in a zebrafish, identifying lead compounds from repurposed drug libraries in these fish, and then moving straight to clinical trials and FDA approvals.” From its inception through to this present day, Epygenix is solely dedicated to identify and develop new medications for Dravet syndrome, as Hahn-Jun explains. “Currently, we are preparing to file IND (Investigational New Drug) for PI/ II trial using EPX-100. EPX-100 is a first- generation antihistamine which was safely used to treat itch in the 1950s/1960s. It is currently not manufactured or available anywhere in the world. EPX- 100 was found to be a powerful suppressor of spontaneous convulsive behaviour and electrographic seizures in zebrafish disease models for Dravet Syndrome. EPX-100 antiepileptic action, however, is not through a histaminergic mechanism of action, but via modulation of serotonin (5HT) signaling pathways. Alongside this, EPX-200, a second drug identified in the zebrafish assay, has already been successfully tested in five Dravet patients at the University of Colorado Hospital. With our colleague, Dr. Kelly Knupp, compassionate use off-label trials with EPX-200 showed an an ability to reduce seizure frequency in these children. These results were published in the world-renowned journal Brain. “EPX-200 is an FDA-approved weight gain management drug which acts via modulation of serotonin (5HT) signaling pathways.” For any company to have a great success within their respected field, it is important that there is a strong team supporting the work. Led by Hahn-Jun, the EpyGenix Therapeutics team are developing new ground breaking precision medications for Dravet syndrome.