AMERICAN EPILEPSY SOCIETY 2018 and KCNQ2

The annual meeting of the American Epilepsy Society (AES) is the premier scientific meeting for the physicians, scientists, pharmaceutical industry, and patient groups engaged in epilepsy and related diseases, such as KCNQ2. Our time at the AES meeting in New Orleans this month was a time of learning, seeing old friends, building new relationships, and advancing our collaborations. Here’s a run-down of some of the things the KCNQ2 Cure team was involved in during the conference.

RARE EPILEPSY NETWORK

During the conference, we always appreciate the roundtable organized by the Rare Epilepsy Network (REN), for which one of our board members is a member of the Steering Committee. REN brings together patient advocates representing various rare epilepsies, such as Lennox Gastaut Syndrome (LGS), Dravet, CDKL5, SCN2a etc, along with physicians who treat those patients. The discussion each year has a theme, and this year focused on the need for Centers of Excellence for the treatment of rare epilepsies like KCNQ2. These centers could bring together the neurologists with expertise in the primary condition affecting our children, along with other experts that patients need to see, in order to get a comprehensive evaluation of the patient at one location and at a single visit. The specialists that would be needed at these centers of excellence could include the neurologist, gastroenterologist, vision specialist, hearing specialist, feeding specialist, etc., along with a coordinator to organize the appointments, all under one roof. Not only would this add convenience for the patients, but it would also bring together a group of physicians who gain deeper experience in their needs and greater insights into their treatment. This network of Centers of Excellence could also serve as the framework for collecting data for a natural history study and conducting clinical trials when for treatments under development. This type of initiative could have significant benefits for our KCNQ2 community, but can only be accomplished through collaborations like REN and our related rare epilepsy community.

DRAVET SYNDROME and KCNQ2

Another good opportunity for collaboration every year is at the Dravet Syndrome Foundation (DSF) roundtable. We are able to learn so much from the work of the DSF, which is focused on one of our “sister” mutations, mutations of the sodium channel that are related to our potassium channel mutation. While there is the biological connection, we also benefit from the DSF’s longer history (this mutation was known for years before KCNQ2 was identified) and larger more established patient population. Not only do many of the same experts treat Dravet and KCNQ2 patients, but many of the scientific discoveries and potential treatments for Dravet have the potential for benefit in the treatment of KCNQ2. One such possibility is a drug which showed good benefit for the treatment of Dravet, Zogenix’s, Fintepla (also known as ZX008, a formulation of fenfluramine), which could be approved for the treatment of Dravet Syndrome and Lennox-Gastaut Syndrome next year. Fintepla works by modulating both the serotonin receptor and the sigma-1 receptor. Because this mechanism is not specific to the sodium channel in its treatment of Dravet, also was effective in LGS, and because of the commonalities between these disorders and KCNQ2, experts we spoke with believe it has potential in the treatment of KCNQ2. In addition to these nearer-term, traditional drug approaches, the Dravet community is looking into gene editing approaches like gene therapy and antisense technology. The research being done, which was presented by Encoded Therapeutics (working on gene regulation and gene therapy approaches for Dravet) and Stoke Therapeutics (on their antisense oligonucleotide technology which they have evaluated in animal models of Dravet), could help provide a roadmap for our own efforts and collaborations in these cutting-edge technologies.

PHARMACEUTICALS and KCNQ2

Many of the biopharmaceutical companies working on treatments for rare epilepsies were also well represented at the AES meeting and we had the opportunity to meet with some of them. Xenon, which has been very involved with KCNQ2 specifically, and presented at the KCNQ2 Cure Summit in September, is continuing to focus on its development of potassium channel modulators. Xenon continues to anticipate having its own pediatric form of retigabine (Potiga), now known as XEN496, ready to start a Phase 3 trial in young patients with KCNQ2 in the middle of 2019. Xenon’s next-generation potassium channel modulator, XEN1101, has had good safety results in healthy individuals, and is advancing into a Phase 2 trial in adults with focal epilepsy early next year (and could also ultimately be effective for KCNQ2). Another company, Marinus Pharmaceuticals, is not currently involved in developing treatments for KCNQ2, but this could be another opportunity in which a treatment being studied in another rare epilepsy could also benefit KCNQ2 patients. Marinus is studying its drug, ganaxolone, in patients with CDKL5 mutations, and has also evaluated it in PCDH19 and other neurological conditions. Ganaxolone works by modulating the GABA receptor (a target known to have anti-anxiety, as well as anti-epileptic activity) and is not specific to a particular channel or mutation, so could also have benefit in KCNQ2.

There are other drug screening approaches that remain of interest for KCNQ2. Just before the AES meeting began, Pairnomix, the precision medicine company with which KCNQ2 Cure has previously collaborated, announced its merger with Q-State Biosciences. In talking to the team from Q-State and Pairnomix, it seems there may be additional opportunities to pursue with this drug screening approach, as Q-State brings to the table a range of new technologies. Q-State has developed human cell-based disease models and an imaging technology, which can more accurately and efficiently assess the activity of potential treatments in the cells grown in the laboratory. They also have the expertise to develop and test their own proprietary compounds in these cells, in addition to existing compounds that could be repurposed for KCNQ2.

RESEARCH and KCNQ2

Our medical and scientific experts have also been busy on our behalf, and we had the chance to host our own, informal, scientific roundtable with many of them. Dr. Ann Poduri of Harvard/Boston Children’s Hospital, who is spearheading our KCNQ2 Natural History Study, is continuing to enroll patients in the study. As part of this study, Dr. Poduri and her team are collecting medical information and samples from KCNQ2 patients that will improve the understanding of this relatively new disease. Many of our KCNQ2 families have already enrolled in this important study, but having broad participation across ages and mutations is key. We have other initiatives ongoing that are also collecting data on KCNQ2. Dr. Anne Berg, of Chicago Lurie Children’s Hospital, is conducting a survey of many of the rare epilepsies, including KCNQ2. At AES we continued our work with Dr. Berg to target this survey at the issues that are most important to our patients with KCNQ2. Many of our KCNQ2 families have already filled out all or part of the survey, but we are looking forward to getting enough families completing the surveys to get an analysis completed over the coming months. Dr. Ingrid Scheffer and her team in Melbourne are continuing their work on the important issue of sleep, which is a challenge for many KCNQ2 patients. Her sleep study is also ongoing and should generate some data that illuminates some of the issues faced.

While our community is growing dramatically, our discussions with experts have confirmed that the majority of cases of KCNQ2 are still not being diagnosed. As we learn more about KCNQ2, targeting treatments are under development, and more treatment options emerge, it is increasingly important to diagnose as many patients as early in their life as possible to get the best outcomes. KCNQ2 Cure Alliance has collaborated with Dr. Ed Cooper at Baylor University, and others, to establish the ERGENT (Early Recognition of Genetic Epilepsy in Neonates) program. ERGENT provides genetic testing, free of charge, for newborns suspected of having a KCNQ2 mutation. We are working on new approaches to spread the word about ERGENT so those affected can benefit from all of the developments in KCNQ2 treatment and care.

CENTER WITHOUT WALLS GRANT (CWoW)

It was exciting to learn the initial details of the CWoW grant award to a multi-center team led by Al George of Northwestern as the primary investigator.

The project will center on further identification of disease-causing mutations in epilepsy with KCNQ2 both being a focus as well as the first gene to be studied. As many of us know, the initial genetics reports provided to families detail a mutation with an unknown significance.

The work of the CWoW team will help to identify more precisely all of the mutations that are disease-causing and characterize the activity of passing potassium through the damaged channel in stem cell models. The hope is this can lead to testing compounds (possibly treatments) to be translational medicine to companies developing those drugs.

In January 2019, KCNQ2 Cure will be hosting a webinar with Al George who will go into more detail about the impact of the CWoW grant on KCNQ2.

While the AES meeting occurs but once a year, the new information and inspiration is setting us on course to pursue new collaborations, new potential treatment options, and we hope, the potential to improve the lives of the patients living with KCNQ2.