Stoke Therapeutics (NASDAQ:STOK) said its Phase III EMPEROR study of zorevunersen for Dravet syndrome has enrolled 162 patients, exceeding its target enrollment of 150, with no patient discontinuations reported to date.
Speaking at a Canaccord Genuity event, Chief Executive Officer Ian Smith said the sham-controlled trial is evaluating zorevunersen in patients who are already receiving stable background anti-seizure medications. The study’s primary endpoint is seizure reduction at week 28, while secondary assessments at week 52 include measures of cognition and behavior.
Trial Design and Retention
The company had incorporated a 15% discontinuation assumption into the trial design, partly because the control arm includes a sham lumbar puncture procedure. Smith said the absence of dropouts so far reflects both trial execution and the drug’s tolerability profile, while noting that some patient retention may also relate to the availability of an open-label extension in which participants can receive treatment after the controlled portion of the trial.
“The drug must be well-tolerated to date. Otherwise, we would have seen dropouts related to the drug,” Smith said. He added that Stoke remains blinded to the trial data.
Stoke expects to provide another update on the EMPEROR study toward the end of the third quarter, Smith said.
Measuring Effects Beyond Seizures
Smith said the U.S. Food and Drug Administration granted breakthrough therapy designation for zorevunersen for the treatment of Dravet syndrome, based on data involving both seizure reductions and outcomes from the Vineland adaptive behavior assessments in earlier studies and an open-label extension.
While EMPEROR’s primary endpoint focuses on seizures, the study is also designed to assess cognitive and behavioral changes through the Vineland-3 assessment. Smith said the measures include receptive and expressive communication, motor skills, interpersonal skills and social functioning.
The trial is powered around the receptive communication endpoint, with Stoke seeking a two- to three-point treatment benefit versus natural history, Smith said. He said natural-history data suggest that patients generally do not gain function over time.
Smith said prior long-term open-label data showed continued gains in cognitive and behavioral measures over four years, in addition to seizure reduction. He described examples of children progressing from non-verbal to verbal or becoming more ambulatory, though these outcomes were discussed in the context of the company’s prior data rather than results from the ongoing Phase III trial.
On seizure reduction, Smith said the Phase III study was powered for a roughly 40% to 45% treatment difference. In prior Phase I/II studies and the open-label extension, he said patients in the higher-dose group experienced seizure reductions of 70% to 80% while receiving zorevunersen on top of standard anti-seizure therapies.
Jason Hoitt, Stoke’s chief patient officer, said persistent seizures remain the primary unmet need cited by caregivers and physicians treating Dravet syndrome, followed by quality-of-life and neurocognitive concerns. He added that seizure reduction is also an important consideration for payers.
Regulatory Submission Plans
Smith said Stoke anticipates beginning a rolling New Drug Application submission in the first quarter of 2027, pending discussion with the FDA at a planned pre-NDA meeting. The company expects to complete the submission in the third quarter of 2027 after completion of the EMPEROR trial.
The company plans to submit chemistry, manufacturing and controls information first, followed by preclinical materials and then clinical data, Smith said. He said Stoke intends to discuss inclusion of its long-term open-label data in the eventual product label as part of its pre-NDA discussions with regulators.
Hoitt said the company has conducted payer research on the potential value proposition for zorevunersen. According to Hoitt, payers indicated that long-term safety and efficacy data would be among the most compelling evidence for a chronic treatment if the therapy reaches approval.
Additional Programs and Biogen Partnership
Beyond Dravet syndrome, Stoke is developing a treatment for autosomal dominant optic atrophy, or ADOA, a genetic disease associated with progressive vision loss. Smith said the company’s Phase I/II OSPREY study is a single-dose, dose-escalation study targeting the OPA1 gene.
The study will assess potential changes in vision using low-contrast visual acuity and fluorescent fundus autofluorescence measures. Smith said Stoke expects potential efficacy data from the third and fourth cohorts in the first half of 2027. If the results support further development, the company expects to discuss a potential registrational study with the FDA.
Smith also discussed Stoke’s partnership with Biogen for territories outside North America. He said the collaboration, which has been in place for roughly 18 months, was designed to expand the company’s capabilities beyond North America and cited Biogen’s experience with antisense oligonucleotide therapies, manufacturing and international commercial footprint.
About Stoke Therapeutics (NASDAQ:STOK)
Stoke Therapeutics, headquartered in Bedford, Massachusetts, is a clinical-stage biopharmaceutical company focused on developing genetic medicines to upregulate protein production for the treatment of rare neuromuscular and neurological disorders. Founded in 2014, the company applies its proprietary Targeted Augmentation of Nuclear Gene Output (TANGO™) platform to design antisense oligonucleotides that selectively modulate RNA splicing and enhance expression of functional proteins.
The company’s lead program, STK-001, is an antisense oligonucleotide therapy designed to increase production of the sodium channel protein SCN1A and is currently in clinical development for Dravet syndrome, a severe childhood-onset epilepsy.
