8-K: Stoke Therapeutics and Biogen Announce Positive Zorevunersen Data for Dravet Syndrome, Informing Phase 3 EMPEROR Study Design

Stoke Therapeutics and Biogen presented new data on zorevunersen, an investigational medicine for Dravet syndrome, showing improvements in cognition and behavior at Week 68, which informed the design of the ongoing Phase 3 EMPEROR study.

Summary

• Stoke Therapeutics and Biogen announced the presentation of data from an analysis that informed the design of the Phase 3 EMPEROR study for zorevunersen, an investigational medicine for Dravet syndrome.
• The analysis evaluated the potential effects of the Phase 3 zorevunersen dosing regimen, showing improvements in multiple measures of cognition and behavior at Week 68.
• These findings contrast with outcomes observed in natural history data from patients with Dravet syndrome treated with standard of care medicines.
• Previously presented data from Phase 1/2a and open label extension (OLE) studies showed substantial and durable reductions in major motor seizure frequency and improvements in cognition and behavior through two years of treatment.
• Data indicated responses may be better among patients treated with loading doses of 70mg followed by maintenance doses of 45mg.
• Zorevunersen was generally well-tolerated across these studies.
• Dravet syndrome is a severe neurodevelopmental disorder characterized by recurrent seizures and significant cognitive and behavioral impairments, with an estimated 38,000 people living with the condition in the U.S., UK, EU-4, and Japan.
• Zorevunersen is designed to increase NaV1.1 protein production from the non-mutated SCN1A gene, aiming to reduce seizure frequency and improve neurodevelopment, cognition, and behavior.
• Zorevunersen has received Orphan Drug Designation from the FDA and EMA, and Rare Pediatric Disease Designation and Breakthrough Therapy Designation from the FDA for Dravet syndrome with a confirmed SCN1A gene mutation.

Sentiment

Score: 8

Explanation: The document presents strong positive clinical data for zorevunersen in Dravet syndrome, a severe condition with high unmet medical need. The data supports the Phase 3 study design and indicates potential for disease modification, which is highly favorable for the company and patients. The drug's Breakthrough Therapy Designation further underscores its significance.

Positives

• Zorevunersen demonstrated improvements in cognition and behavior at Week 68, supporting its potential as a disease-modifying therapy.
• The observed improvements contrasted favorably with findings from natural history studies where patients received only standard of care medicines.
• Previous Phase 1/2a and OLE studies showed substantial and durable reductions in major motor seizure frequency and sustained improvements in cognition and behavior over two years.
• The drug was generally well-tolerated across all studies.
• Zorevunersen has been granted Orphan Drug Designation by both the FDA and EMA, and Rare Pediatric Disease Designation and Breakthrough Therapy Designation by the FDA, highlighting its potential and unmet medical need.

Negatives

• Dravet syndrome is a severe neurodevelopmental disorder with significant impacts on patients and their families.
• Most patients with Dravet syndrome continue to experience seizures despite treatment with the best available anti-seizure medicines.
• There are currently no medications approved that address the underlying cognitive and behavioral aspects of Dravet syndrome.
• Patients with Dravet syndrome have a higher risk of sudden unexpected death in epilepsy (SUDEP).

Risks

• Ability to advance, obtain regulatory approval, and ultimately commercialize product candidates.
• Risk that collaborators (Biogen) may breach or terminate their agreements, which would impact anticipated financial or other benefits.
• The possibility that Stoke and Biogen may not be successful in their development of zorevunersen, or unable to successfully commercialize it even if successful in development.
• Positive results in a clinical trial may not be replicated in subsequent trials, and successes in early-stage clinical trials may not be predictive of results in later-stage trials or ensure regulatory approval.
• Ability to protect intellectual property.
• Ability to fund development activities and achieve development goals through mid-2028.

Future Outlook

Stoke Therapeutics and Biogen plan to continue advancing zorevunersen as a potential first-in-class disease-modifying medicine for Dravet syndrome. The Phase 3 EMPEROR study is designed to evaluate the effects of zorevunersen, with key secondary endpoints assessing cognition and behavior, aiming to reduce seizure frequency and improve neurodevelopment, cognition, and behavior.

Management Comments

• Dr. Andreas Brunklaus, Consultant Paediatric Neurologist: "Natural history data shows the limitations of treating this disease with anti-seizure medicines. The zorevunersen data give us early evidence that this new genetically-targeted approach could address the underlying cause of Dravet syndrome, resulting in additional seizure control and offer patients the opportunity to experience improvements in cognition and behavior."
• Barry Ticho, M.D., Ph.D., Chief Medical Officer of Stoke Therapeutics: "Effects on behavior and cognition are a key secondary endpoint in our Phase 3 EMPEROR study. Feedback from caregivers and clinicians, and analyses like this one, give us insight into which assessments have the greatest potential to demonstrate meaningful effects for patients within the year-long treatment period."
• Katherine Dawson, M.D., Head of the Therapeutics Development Unit at Biogen: "Most patients with Dravet syndrome continue to experience seizures despite treatment with the best available anti-seizure medicines, and there are currently no medications approved that address the underlying cognitive and behavioral aspects of the disease. We look forward to continuing to work together to advance zorevunersen as a potential first-in-class disease modifying medicine for Dravet syndrome."

Industry Context

Dravet syndrome represents a significant unmet medical need within the neurology and rare disease sectors, as current standard-of-care anti-seizure medicines are often insufficient and do not address the underlying cognitive and behavioral impairments. Zorevunersen, as a first-in-class, genetically-targeted RNA medicine, positions Stoke Therapeutics and Biogen at the forefront of developing disease-modifying therapies for this complex neurodevelopmental disorder, potentially setting a new standard beyond symptomatic treatment.

Comparison to Industry Standards

• Zorevunersen's observed improvements in cognition and behavior at Week 68 contrasted significantly with findings from the BUTTERFLY natural history study, which tracked patients with Dravet syndrome receiving only standard of care medicines, highlighting the limitations of existing treatments.
• Unlike current anti-seizure medicines that primarily target seizure control, zorevunersen aims to address the underlying cause of Dravet syndrome by increasing NaV1.1 protein production, offering a potential disease-modifying approach that is currently unavailable in the market.

Stakeholder Impact

• **Patients with Dravet syndrome**: Potential for significant improvements in seizure control, cognition, and behavior, addressing the underlying cause of their condition and potentially leading to a better quality of life.
• **Caregivers**: Potential for reduced burden and improved quality of life due to better patient outcomes and a more effective treatment option.
• **Shareholders (Stoke Therapeutics & Biogen)**: Positive clinical data and progression to Phase 3 for a high-need indication could enhance the companies' valuation and future revenue potential.
• **Medical Community**: Introduction of a potential first-in-class, disease-modifying therapy could revolutionize the treatment paradigm for Dravet syndrome, offering a new standard of care.

Next Steps

• Continue the Phase 3 EMPEROR study for zorevunersen.
• Evaluate five specific sub-domains of the Vineland-3 Adaptive Behavior Scales (Receptive Communication, Expressive Communication, Interpersonal Relationships, Coping Skills, and Personal Skills) as key secondary endpoints in the Phase 3 EMPEROR study.
• Advance zorevunersen as a potential first-in-class disease-modifying medicine for Dravet syndrome.

Key Dates

Recommendation

Keywords

Dravet syndrome, Zorevunersen, Stoke Therapeutics, Biogen, Phase 3 EMPEROR study, Clinical trial, RNA medicine, Antisense oligonucleotide, Neurodevelopmental disorder, Cognition, Behavior, Seizure control, Orphan drug, Breakthrough Therapy Designation, SCN1A gene