Life-Changing Potential

Just like other 4-year-olds, Sophia Cope enjoys being outside and watching Elmo. Her favorite colors are red, blue and green. But in one crucial way, she is one of a kind.

Sophia is one of about 1,000 known cases of epilepsy — a disorder that causes seizures — caused by a mutation in the SCN2A gene. And now she is a participant in a clinical trial of the first medication to target this gene directly.

If determined to be effective, this medication has the potential to change the lives of children with her diagnosis.

“This is the first time we have a therapy that we think can address the underlying cause to improve seizures and start seeing developmental improvement,” said James Wheless, MD, co-director of Le Bonheur’s Neuroscience Institute and principal investigator of the study. “If we can prove that it works, we can identify children who need intervention in the first week of life to stop developmental decline as early as possible.”

Le Bonheur Children’s is the only site in the world to enroll children in this phase of the EMBRAVE study for the medication PRAX-222 from Praxis Precision Medicines, Inc., with the goal of improving seizure control and development for children with this rare genetic epilepsy. Preliminary data has already shown success for patients with a 43% median reduction in seizures vs. baseline, an increased number of days without seizures and significant seizure reduction after just one dose.

A Devastating Epilepsy 

When Sophia was born in Jonesboro, Ark., her parents Aaron and Michaela knew that something was not right. She was having trouble breathing and constantly shaking and shivering. At just hours old, she was transferred to Le Bonheur’s Neonatal Intensive Care Unit (NICU) where an EEG showed that Sophia’s brain was in a state of one continuous seizure.

With her brain imaging clear of brain bleeds, her geneticist at Le Bonheur, Eniko Pivnick, MD, sent off genetic testing in an attempt to find out what was going on. The results: Sophia had a rare genetic mutation to her SCN2A gene that caused a devastating form of epilepsy with no approved treatment options.

“The genetic testing showed that she was the first child to ever be documented with this specific genetic variant of SCN2A,” said Aaron. “It was causing her to have seizures all over her brain.”

SCN2A is the gene that directs the creation of sodium channel proteins in the brain, which control the flow of sodium ions to neurons. Mutations in the gene can cause too many or too few sodium ions to flow through the channels, causing epilepsy and developmental delay. In Sophia’s case, the gene caused her brain to overproduce sodium ions.

Children with an SCN2A mutation are typically born with no symptoms but start seizing within the first few days of life. Mutation of the gene can also lead to developmental delays that are further exacerbated by the presence of drug-resistant seizures.

“This is a really tough form of epilepsy. As kids get older, not only do they continue to have seizures, but their development declines significantly,” said Wheless. “In the past we have been stuck. All we could do is use seizure medications we thought would work and try to help development with therapy. But none of that changes the underlying genetic problem.”

Sophia spent her first 81 days of life in the NICU at Le Bonheur. She returned at 4 months old for a 71-day stay where she received a gastrostomy tube and a tracheostomy. During this second stay, Sophia’s heart stopped four different times.

The Copes leaned heavily on the support of families whose children also have SCN2A mutations by connecting with the Families SCN2A Foundation. It was through this Foundation that the Copes also heard that a new option for Sophia might be on the horizon.

“It was trial and error for treatment going down the list of sodium channel blockers and medications for infantile spasms that didn’t work,” said Michaela. “We heard about the potential for a new drug, but thought it would be 10 years coming.”

Thanks to the Families SCN2A Foundation, the Copes learned about the EMBRAVE trial that might address the underlying genetic mutation causing Sophia’s medical conditions. And the only place in the world to participate in the trial was the hospital where their current neurologist, Amy McGregor, MD, was located — Le Bonheur Children’s.

Genetic Target

The EMBRAVE study is investigating the efficacy and safety of the medication PRAX-222. This drug is a novel treatment called an anti-sense oligonucleotide (ASO), which targets genes at the mRNA level to affect protein expression. In this case, the ASO hopes to target the SCN2A gene to decrease its expression, which would then decrease the sodium ions causing the symptoms.

Delivered by intrathecal injection, trial participants will receive a dose of one milligram of PRAX-222 each month for four months. Patients are observed inpatient for at least 24 hours after the injection. Once this phase of the trial is complete, the U.S. Food & Drug Administration (FDA) will reevaluate PRAX-222 to determine if it can continue to the next phase of clinical trials.

For the current phase of the trial, Le Bonheur Children’s is the only hospital in the world delivering the medication.

“We have a deep track record of research in pediatric epilepsy, including intimate knowledge of taking a pre-commercial product and walking it through the regulatory phases required by the FDA,” said Wheless. “We also have a system for caring for children in a clinical trial with a very well-developed multidisciplinary program and experience delivering other ASO-based therapies for genetic epilepsies.”

If PRAX-222 is proved to impact the expression of the SCN2A gene, it has massive implications for children like Sophia. The drug could address the intractable seizures that occur multiple times a day. If diagnosed and treated early enough, the medication has the potential to drastically slow the developmental decline that is also associated with this gene’s mutation.

“We hope that it will provide enough of a fix for Sophia that she can still grow and reach what we call ‘inch-stones,’ sitting up, getting rid of her trach and becoming more active,” said Michaela. “It’s great to think about how this can impact my child, but it’s also great to be a part of something that could get answers to help others.”

Future Hope

Proving the safety and efficacy of PRAX-222 would be a major change in the lives of children and families who deal with SCN2A mutations. But this ASO delivery system continues to open the door for children with other genetic epilepsies as well, says Wheless. While these genetic epilepsies can be individually rare, the total number of children with some form of genetic epilepsy is not insignificant, with more than 100 children with genetic epilepsies in Le Bonheur clinics alone. Wheless looks forward to the day when the same hope presented by PRAX-222 for treatment will exist for other genetic epilepsies.

“When I started practicing, we didn’t even have the genetic test to make a diagnosis for SCN2A epilepsies. Now we can tell you exactly what’s causing it down to the gene with a tailored precise therapy to target it,” said Wheless. “It’s amazing to think of that progress compared to where we were not long ago in how we cared for these children.”

The Cope family says that they have already seen a reduction in the number and intensity of Sophia’s seizures and that she is awake more and very alert.

“Sophia has become more vocal as well — I believe that she has found her voice!” said Michaela. “She has made sounds before, but not often at all. Now we get to hear her on a daily basis and even several times a day.”

“We know God gave us Sophia for a reason,” adds Aaron. “Of course I hope my kid excels on this medication, but this has implications for so many other diseases and children who need medication coded to specific genes, too.”