KCNQ2 Cure Alliance Joins Epilepsy Foundation Research Roundtable

On March 21-22, I had the opportunity to represent the KCNQ2 Cure Alliance at the 2019 Research Roundtable for Epilepsy organized by the Epilepsy Foundation. Now in its fourth year, the annual meeting brings together patient advocacy organizations with leading epilepsy experts from research organizations and pharmaceutical companies with regulators from the Food and Drug Administration and the European Medicines Agency to tackle critical questions around advancing epilepsy treatments. This year, we joined forces with leading voices from other rare diseases, including Dup15q Alliance, Rett Syndrome Foundation, and the TESS Research Foundation to share our reflections on behalf of the rare disease community.

This year, discussions zeroed in on critical challenges and questions around clinical trials. Trials are a major milestone in the development of new drug therapies. They ensure that new compounds work as expected, help to determine dosages, and reveal potential side effects. But they also present some challenges for rare diseases. Is it ethical to use a placebo for a severe rare disease? How can you complete a timely trial when it is difficult to recruit enough patients to study the drug?

The caregiver panel helped to set the stage for the discussions by focusing on how patient communities think about trials, and what considerations affect participation. I shared with the group some aspects of KCNQ2 that may make clinical trials more challenging, including the spectrum of seizure burdens (across children but also over time) and developmental outcomes. And although our community would welcome more effective seizure medicines with fewer side effects, I emphasized our interest in identifying and advancing treatments for all aspects of KCNQ2 encephalopathy. Other discussions focused on different types of trials, how to approach seizure counting during trials, and considerations about dosing.

All of these issues are incredibly important for our community and the discussions were timely given the exciting progress we are seeing in the development of new treatments for KCNQ2. Later this year, Xenon Pharmaceuticals will enter a Phase 3 trial, the first with KCNQ2 children, to test its drug therapy, XEN496, which is a pediatric formulation of ezogabine, previously marketed under the name Potiga. Although Potiga had some important potential side effects, this drug was used with success by KCNQ2 children, before it was taken off the market in 2017. In parallel Xenon is also developing a second potassium channel modulator, called XEN1101, which is expected to enter Phase 2 trials later this year.

And earlier this year, Knopp Biosciences announced a new collaboration with Ed Cooper at Baylor University. Knopp has a number of drug compounds that are designed to activate the potassium channel in the brain and will work with Dr. Cooper’s lab to learn whether these compounds could be used as successful treatments for KCNQ2 epilepsy.

We’re working closely with our partners to make sure that our community is ready to support and participate in trials to advance treatments for KCNQ2 epilepsy, including through our natural history study led by Dr. Ann Poduri at Harvard and Boston Children’s Hospital, the Early Recognition of Genetic Epilepsy in Neonates (ERGENT) program to provide free testing to infants suspected to have KCNQ2, and working closely with other efforts including a new Center Without Walls epilepsy program that will be led by Al George at Northwestern University.

We know that together with our partners we have a long way to go in our journey to a cure for KCNQ2 encephalopathy, but with each step we remember, “If you want to go fast, go alone. If you want to go far, go together.” Please join us. — Megan Roberts, KCNQ2 Cure Alliance

KCNQ2: What’s in the Alphabet Soup?

kcnq2_defExperts have known for some time what the KCNQ2 gene does, and it was named accordingly – “K” for the scientific symbol for potassium, “CN” as an abbreviation for channel, and “Q2” for the subtype Q2. But even scientists only recently understood the wide range of different variations in the “source” of the mutations and in outcomes for affected patients.

KCNQ2 benign familial neonatal epilepsy

The KCNQ2 mutation can come from a variety of sources. It can be inherited from an affected parent that has the mutation, it can be inherited from a parent who carries the mutation in some of his/her cells (called mosaicism) but does not display the severity symptoms that would expect to be caused by that mutation, or can be a new or random mutation (de novo) occurring for the first time in the affected patient.

The KCNQ2 mutation was first recognized by experts as the source of Benign Familial Neonatal Epilepsy (BFNE) in 1998. In the years prior to that, scientists had followed generations of families who had experienced seizures as infants, but that generally resolved and developed normally. These individuals went on to have children of their own, some of whom inherited the mutation in the KCNQ2 gene coding for this mild variation of the disease. Until recently, when doctors saw seizures in the first days of life, or when testing showed a KCNQ2 mutation, they assumed it was likely a benign seizure disorder, BFNE.

KCNQ2 encephalopathy

However, as experts studied more patients, they saw some children who were more severely affected than their parents and began to wonder why. In these cases, the parents had developed normally because only some of their cells carried the mutation (they were mosaic), but passed on the severe mutation from the subset of their cells that were affected. So, in these cases, even though the parent seems to have the benign form of KCNQ2, it is possible for them to have a child with the more significant symptoms of KCNQ2 encephalopathy. In 2011, experts began to realize that KCNQ2 mutations can also cause the more significant developmental delays and more lasting seizures associated with KCNQ2 encephalopathy.

Original study discovering KCNQ2 encephalopathy :

KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy.

With this knowledge and with greater availability of genetic testing, doctors have been able to identify more severely affected patients with KCNQ2 mutations, even when there is no family history. In fact, in the majority of the cases of KCNQ2 encephalopathy – mutations causing the more severe form of the disease – the mutation is not inherited, but is de novo, or “new”. This makes sense when you consider that a severely affected person is unlikely to have offspring, so the specific variants that cause a severe outcome are not usually passed down through a family (unless only some cells are affected, as in the mosaic cases discussed above). Now that genetic testing is more available, doctors have also found that there are some de novo cases of benign epilepsy, in which a spontaneous KCNQ2 mutation causes a more benign outcome, which in turn may be passed on to subsequent generations as BFNE.

So what does this mean?

Historically, the severity of the outcomes was labeled according to the mode of inheritance, with “familial” or inherited being associated with benign variants and de novo being associated with more significant encephalopathies. Now that the genetic basis for the different outcomes is better understood, it is clear that the specific variant of the mutation is more important than whether or not it was inherited.