Stoke touts early signs of efficacy for Dravet syndrome drug
Two and a half years after driving his antisense oligonucleotide platform to Wall Street, Stoke Therapeutics CEO Ed Kaye is painting a fuller picture of the company’s first clinical data. And though the trial wasn’t powered to detect statistical significance, Kaye says the readout shows early signs of efficacy in kids with a rare, drug-resistant form of epilepsy
STK-001 was well-tolerated in single and multiple doses in 22 Dravet syndrome patients between the ages of 2 and 18 years old, Stoke announced on Friday. What’s more, 12 of the 17 evaluable patients at the time (70.6%) saw reductions from baseline in convulsive seizure frequency, according to the company.
While that reduction wasn’t statistically significant, Kaye explained that it was a small patient population, adding they didn’t expect to see any improvement this early. Median reductions in seizure frequency of 17% to 37% were seen across all cohorts, the company reported.
“Given the numbers, you would have to see a phenomenal change in seizure before you can see a statistical significance. But when we get more patients, we expect that we’ll be able to reassess statistical significance,” Kaye said
Dravet syndrome typically begins within an infant’s first year of life, and persists throughout adulthood. Though it’s characterized by frequent seizures, the disease can also lead to intellectual disability, ataxia or motor abnormalities, behavioral problems, speech impairment and sleep disturbances. It’s caused by mutations to the SCN1A gene, which encodes a protein called Nav1.1.
Patients with Dravet syndrome have one functional gene copy and one mutated copy — what’s called a haploinsufficiency — resulting in half as much protein as needed to maintain normal health. Stoke’s Targeted Augmentation of Nuclear Gene Output (TANGO) platform is designed to address haploinsufficiencies by increasing — or stoking — protein output from healthy genes, thus compensating for the mutant copy of the gene.
The platform itself traces back to Cold Spring Harbor Laboratory’s Adrian Krainer, who is credited as the inventor of Biogen’s spinal muscular atrophy drug Spinraza.
STK-001 binds to pre-mRNA and helps functional (also called wild-type) genes dial up protein production. While anticonvulsants like Zogenix’s Fintepla or GW Pharma’s Epidiolex are designed to prevent seizures by dampening the electrical activity of the brain, Kaye and the team at Stoke believe upregulating Nav1.1 can restore functioning neurons and also treat non-seizure symptoms.
“The problem with giving a patient an anti-epileptic is you’re only treating one of many symptoms of the disease,” Kaye said.
Patients in the open-label Phase I/IIa MONARCH study were given either single doses of up to 30 mg, or 20 mg doses. The antisense oligonucleotide is suspended in saline and delivered via spinal injection. The drug appeared well-tolerated after 12 weeks, with the most common side effects being headache, vomiting, seizure, irritability and back pain. Though five of 22 patients (22.7%) experienced a serious adverse event, none of them were found to be related to the drug, Stoke said.
Patients who were in MONARCH are eligible to continue treatment in the SWALLOWTAIL extension study, which is currently enrolling. Overall, Stoke plans to enroll 90 patients across 20 sites in the US to the MONARCH study.
“One of the things that we want to determine from this study is not only what’s the therapeutic dose that we can reach, but what we also want to know is: Can we give a high enough dose that we can give it infrequently?” Kaye said.
While the estimate is that they’d dose the drug every four months, it’s possible that they could go every six months, he added.
Correction: A previous headline and version of this article incorrectly stated STK-001 missed statistical significance. The story has been updated to clarify that the trial wasn’t powered to detect statistical significance.