8-K: Stoke & Biogen Dose First Patient in Phase 3 Dravet Study

Stoke Therapeutics and Biogen announced the dosing of the first patient in the global Phase 3 EMPEROR study for zorevunersen, a potential disease-modifying treatment for Dravet syndrome.

Summary

• The first patient has been dosed in the global Phase 3 EMPEROR study of zorevunersen for the treatment of Dravet syndrome.
• Zorevunersen is an investigational antisense oligonucleotide (ASO) with the potential to be the first disease-modifying treatment for Dravet syndrome.
• Dravet syndrome is a rare genetic disease characterized by refractory seizures and neurodevelopmental impairments, with no currently approved medicines addressing the underlying cause.
• Previous Phase 1/2 and open-label extension studies provided data supporting substantial and durable reductions in seizures and continuing improvements in cognition and behavior.
• The EMPEROR study will enroll patients with Dravet syndrome aged 2 to under 18 years with a confirmed SCN1A gene variant not associated with gain of function.
• Participants will be randomized 1:1 to receive either zorevunersen or sham for a 52-week treatment period, following an 8-week baseline period.
• Active treatment arm patients will receive two 70mg loading doses (Day 1 and Week 8) followed by two 45mg maintenance doses (Week 24 and Week 40), alongside standard of care medicines.
• The primary endpoint is the change in major motor seizure frequency measured at Week 28.
• Key secondary endpoints include change in major motor seizure frequency at Week 52 and changes in behavior and cognition (Vineland-3 subdomains) at Week 52.
• Eligible participants will be offered ongoing treatment with zorevunersen as part of an open-label extension (OLE) study.
• The EMPEROR clinical trial has initiated in the United States, United Kingdom, Japan, and is planned for Europe.
• Stoke Therapeutics retains exclusive rights for zorevunersen in the United States, Canada, and Mexico, while Biogen receives exclusive rest-of-world commercialization rights.
• Dravet syndrome is estimated to affect up to 38,000 people in the U.S. (~16,000), UK, EU-4, and Japan.
• Zorevunersen is designed to increase NaV1.1 protein production from the non-mutated (wild-type) copy of the SCN1A gene.
• Zorevunersen has been granted Orphan Drug Designation by the FDA and EMA, and Rare Pediatric Disease Designation and Breakthrough Therapy Designation by the FDA.

Sentiment

Score: 8

Explanation: The announcement of the first patient dosed in a pivotal Phase 3 study for a potential disease-modifying treatment for a severe rare genetic disease, supported by positive prior data and regulatory designations, is a significant positive milestone for the company and its collaboration partner. It indicates strong progress in a high-impact therapeutic area.

Positives

• Initiation of the global Phase 3 EMPEROR study is a critical milestone in zorevunersen's development.
• Zorevunersen has the potential to be the first disease-modifying treatment for Dravet syndrome, addressing the underlying genetic cause.
• Prior Phase 1/2 and open-label extension studies demonstrated substantial and durable reductions in seizures and improvements in cognition and behavior.
• The drug has received significant regulatory designations, including Orphan Drug Designation (FDA, EMA), Rare Pediatric Disease Designation (FDA), and Breakthrough Therapy Designation (FDA).
• The strategic collaboration with Biogen provides extensive resources and global commercialization capabilities.
• There is a high degree of interest in the EMPEROR study, indicating significant unmet medical need and potential market acceptance.

Risks

• Ability to advance, obtain regulatory approval, and ultimately commercialize product candidates.
• Risk that collaborators (Biogen) may breach or terminate agreements, leading to loss of anticipated financial or other benefits.
• Possibility that Stoke and Biogen may not be successful in their development of zorevunersen, or unable to successfully commercialize it even if developed.
• Positive results in early-stage clinical trials may not be replicated in subsequent or later-stage trials.
• Ability to protect intellectual property.
• Ability to fund development activities and achieve development goals through mid-2028.
• Risks associated with clinical trials, including managing clinical activities, unexpected concerns from additional data, regulatory authorities requiring more information or studies, or delays/failures in approval.
• Occurrence of adverse safety events, restrictions on product use, or product liability claims.

Future Outlook

The global Phase 3 EMPEROR study aims to evaluate the efficacy and safety of zorevunersen as a potential first disease-modifying treatment for Dravet syndrome, with primary endpoint data expected at Week 28 and key secondary endpoints at Week 52. Eligible participants will be offered ongoing treatment in an open-label extension study.

Management Comments

• Barry Ticho, M.D., Ph.D., Chief Medical Officer of Stoke Therapeutics: "Our Phase 1/2 and open-label extension studies have provided a large dataset to support our understanding of zorevunersen and guide the EMPEROR study design, including dosing, duration and selection and powering of the endpoints. Given the severity of this disease and the limitations of current treatments, the substantial and durable reductions in seizures and continuing improvements in cognition and behavior support our belief that zorevunersen may improve outcomes for patients with Dravet syndrome."
• Katherine Dawson, M.D., Head of the Therapeutics Development Unit at Biogen: "The initiation of the EMPEROR study is a critical milestone in zorevunersens development. Despite treatment with available anti-seizure medicines, no approved medications currently address the underlying cognitive and behavioral aspects of this rare, genetic disease. Together with Stoke, we look forward to working in collaboration with the hope of bringing forward zorevunersen as the first disease-modifying treatment option, if approved, for Dravet syndrome."
• Joseph Sullivan, M.D., FAES, principal investigator: "Dravet syndrome is one of the most well studied genetic epilepsies so we know the significant and life-altering effects it can have on patients and their caregivers. Providing additional relief from seizures remains an important clinical outcome, but the potential to address the underlying genetic cause to also address neurodevelopmental symptoms signals a fundamentally new way of treating the disease. The urgent need for treatments is evident in the high degree of interest in the EMPEROR study."

Industry Context

This announcement highlights the ongoing efforts in the biotechnology and pharmaceutical industries to develop targeted therapies for rare genetic diseases, particularly those with significant unmet medical needs like Dravet syndrome. The collaboration between Stoke Therapeutics, a company focused on RNA medicine, and Biogen, a leading biotechnology company, reflects a common strategy to combine specialized expertise with broader development and commercialization capabilities to accelerate drug development for complex conditions. The focus on a disease-modifying treatment for Dravet syndrome, which currently lacks therapies addressing its underlying genetic cause, positions zorevunersen as a potentially significant advancement in the neurodevelopmental disorder space.

Comparison to Industry Standards

• Dravet syndrome affects up to 38,000 people in the U.S. (~16,000), UK, EU-4, and Japan, indicating a significant unmet medical need for a disease-modifying treatment, as current anti-seizure medicines do not address the underlying cognitive and behavioral aspects.
• Zorevunersen's mechanism of action, increasing NaV1.1 protein production from the non-mutated SCN1A gene, represents a novel approach compared to existing symptomatic anti-seizure medications, aiming for disease modification rather than just symptom management.
• The receipt of Orphan Drug Designation, Rare Pediatric Disease Designation, and Breakthrough Therapy Designation from the FDA and EMA indicates recognition by regulatory bodies of the significant unmet need and potential benefit of zorevunersen, aligning with industry efforts to expedite development for rare and severe conditions.
• The global Phase 3 EMPEROR study design, including a sham-controlled arm and specific endpoints for seizure frequency, behavior, and cognition (Vineland-3), is consistent with rigorous clinical trial standards for neurological disorders, aiming to provide robust evidence for regulatory approval.

Stakeholder Impact

• Shareholders: Positive impact due to advancement of a key pipeline asset into pivotal Phase 3, potentially increasing company valuation and future revenue prospects if successful.
• Patients with Dravet Syndrome and Caregivers: Significant potential for improved quality of life through a disease-modifying treatment that addresses underlying genetic cause and neurodevelopmental symptoms, beyond just seizure control.
• Employees: Positive impact on morale and strategic direction, validating research and development efforts.
• Healthcare Providers: Potential new treatment option for a challenging condition, offering a fundamentally new way of treating the disease.

Next Steps

• Continue patient enrollment in the global Phase 3 EMPEROR study across the United States, Japan, United Kingdom, and Europe.
• Evaluate primary endpoint (change in major motor seizure frequency) at Week 28.
• Evaluate key secondary endpoints (change in major motor seizure frequency, behavior, and cognition) at Week 52.
• Offer eligible participants ongoing treatment with zorevunersen in an open-label extension (OLE) study.

Key Dates

Recommendation

The initiation of the pivotal Phase 3 EMPEROR study for zorevunersen, a potential first-in-class disease-modifying treatment for Dravet syndrome, represents a significant de-risking event and a major value inflection point for Stoke Therapeutics. Supported by promising Phase 1/2 data, multiple regulatory designations (Orphan Drug, Rare Pediatric Disease, Breakthrough Therapy), and a strategic collaboration with Biogen, this advancement positions the company for substantial long-term growth if the trial is successful. The high unmet medical need in Dravet syndrome further enhances the commercial potential. This milestone warrants a 'buy' recommendation for investors seeking exposure to innovative rare disease therapies.

Keywords

Dravet syndrome, zorevunersen, Phase 3 clinical trial, biotechnology, Stoke Therapeutics, Biogen, rare disease, neurology, antisense oligonucleotide, genetic epilepsy, SCN1A gene, clinical development