For children with Dravet syndrome, a rare, severe genetic disease characterized by fever-related seizures and intellectual disability, developmental delays begin after the first few years of normal development. Stoke Therapeutics is developing a drug designed to reduce seizures and restore some of their lost developmental function.
“These children grow neuro-typically up to ages 18 months or 24 [months], but once they reach that period in life, they’re in a stable state—they don’t grow,” Ian Smith, CEO of Stoke Therapeutics, told Fierce Biotech. The company is one of a handful of players with a clinical-stage asset taking aim at the rare disease, with current treatments focused on seizure management and lifestyle modifications.
“So, when you’re 10, 15, 20 years old, you’re still in a two-year-old state,” Smith explained about people living with Dravet syndrome. “You may not be able to talk, you don’t recognize your parents, you can’t acknowledge your name, you can’t take yourself to the toilet.”
“There’s many features of a Dravet child, but it’s like they’re effectively an 18-month to two-year-old all their life, while they may have an adult body,” he added.
Stoke and Biogen’s zorevunersen, an investigational antisense oligonucleotide, is designed to boost functional NaV1.1 protein production in brain cells from the non-mutated copy of the SCN1A gene. The drug is made to treat the underlying cause of Dravet syndrome, which is caused primarily by SCN1A haploinsufficiency.
“I really do believe this medicine not only reduces seizures but actually causes these children, that unfortunately, are flatlining after two years old—they might start to sprout off that flatline of neurotypical development,” Smith said.
“You may have the opportunity to put them on a more neurotypical pathway to develop,” he continued. “There’s not many medicines that give back function in a disease where there is no function after a certain age.”
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In the clinic, Smith said the company is seeing seizure reductions of up to 85% in addition to standard-of-care medicines.
In two open-label phase 1/2 studies, zorevunersen, in combination with standard-of-care antiseizure medicines, demonstrated durable reductions in seizures and improvements across multiple measures of cognition and behavior, according to results published this month in The New England Journal of Medicine.
One of those measures is an assessment known as, Vineland-3, which evaluates changes in adaptive behavior, such as motor skills and receptive communication, among others. These changes can be tied to increased independence and safety for the patients.
Out of 81 total patients enrolled across the two trials, 75 have entered the open-label extension (OLE) program. Looking at the three-year OLE data, Smith said the Vineland scores demonstrate robust improvements.
“Dravet syndrome arrives without warning for families, just as it did for our family more than 25 years ago when my son began having seizures,” Mary Anne Meskis, CEO of the nonprofit Dravet Syndrome Foundation, said in a March 4 release announcing the data publication.
“While awareness, diagnosis and medical care have advanced significantly over the years, the realities of Dravet syndrome remain severe and life-altering for patients and their families,” Meskis explained. “A treatment that could help someone like my son dress himself independently or better communicate with his parents would profoundly change the cadence and quality of our everyday lives.”
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In Stoke’s phase 1/2 studies, most adverse events (AEs) were mild or moderate, with one patient experiencing a suspected unexpected serious AE related to zorevunersen. Another patient withdrew from the study after experiencing an AE.
Two patients died from sudden unexpected death in epilepsy (SUDEP), and one from malnutrition—all unrelated to zorevunersen.
“SUDEP is unfortunately common with this disease,” Smith said, citing the fact that one out of five children with Dravet syndrome don’t reach 18 years of age, largely because of SUDEP.
Stoke has already started a phase 3 program for zorevunersen, in which no SUDEPs have been reported to date, according to Smith.
The path forward
Stoke is currently recruiting patients for the phase 3 study, dubbed Emperor. The biotech anticipates enrolling a total of 150 patients across the U.S., U.K. and Japan to be enrolled by the second quarter of this year, with data expected to support a rolling new drug application slated for mid-2027.
The sham-controlled study’s main goal is to reduce seizures at 28 weeks, with a secondary endpoint based around Vineland scores at Week 52.
“There was an initial anticipation that the study may take a year to 18 months to recruit,” Smith said. “We anticipate fully recruiting all patients into the study by the second quarter of this year, which means it will have taken eight to 10 months.”
The CEO credited Stoke’s strong presence at medical conferences and advocacy work for speeding up the enrollment time.
“The whole timeline for the company over the last year was probably accelerated by close to a year and so, and I think that’s a function of education around the severity of Dravet, but also what our medicine is doing beyond just seizure reductions,” Smith said.
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Zorevunersen has nabbed breakthrough, orphan drug and rare pediatric disease designations from the FDA.
When asked about current controversies surrounding the agency’s rare disease decisions, such as uniQure’s heated back-and-forth over the FDA’s request for another sham-controlled trial in Huntington’s, Smith said he wasn’t concerned about Stoke’s regulatory path.
“I do think that [FDA commissioner Marty] Makary is leading a very progressive FDA in a way that I do think he wants change,” Smith said. “I think he’s very genuine to, you know, having faster approvals, evidence-based medicine, real-world data, doing natural history comparison studies.
That being said, Smith said he believes the agency is “struggling to execute on the ground.”
“Now, I can’t comment on specific examples of different companies, but I can comment on our company because we’ve had interactions with them, and we’ve had all the data on the table with the FDA,” the CEO said. “We have great interactions with them.”
Smith said the agency did exhibit “regulatory flexibility,” asking if Stoke “wanted to move our patients all onto medicine and not have a sham-control trial and measure the endpoints at month six—just seizures.”
“We declined because we wanted to have a label that shows what our medicine does in the kind of a more neurotypical benefit as well,” he said.
Smith’s insight is interesting given the agency’s recent push for placebo- or sham-controlled trials, even in rare diseases that impact very small populations.
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Stoke’s drug is being developed with Biogen, which paid out $165 million cash early last year to gain exclusive rights to commercialize zorevunersen outside of the U.S., Canada and Mexico. Biogen will cover 30% of external clinical development costs and is offering the biotech up to $385 million in milestone payments.
Other players in Dravet syndrome include Encoded Therapeutics’ gene therapy, Harmony Bioscience’s late-stage clemizole hydrochloride and Lundbeck’s oral 5-HT2C receptor superagonist.
Besides pipeline medicines, UCB’s Fintepla and Jazz’s Epidiolex are approved to treat seizures in patients with Dravet syndrome.
