8-K: Stoke & Biogen Zorevunersen Data Boost Dravet Syndrome Hope

Stoke Therapeutics and Biogen presented new data at the AES Annual Meeting, further supporting zorevunersen's potential as a disease-modifying medicine for Dravet syndrome with durable seizure reductions and cognitive improvements.

Summary

• Long-term Phase 1/2a and open label extension (OLE) data for zorevunersen demonstrated durable seizure reductions, including increases in seizure-free days, and improvements in cognition, behavior, and quality of life in Dravet syndrome patients.
• A propensity score weighted analysis showed statistically significant reductions in major motor seizure frequency at six months for patients receiving two loading doses of zorevunersen (70mg) compared to natural history.
• Improvements in five key assessments of cognition and behavior (Vineland-3) were observed at 18 months with continued 45mg dosing, with several reaching statistical significance.
• Durable effects were demonstrated through 24 months, the longest evaluable timepoint in the BUTTERFLY natural history study.
• EEG analysis highlighted dose-dependent effects of zorevunersen in decreasing abnormal brain activity, which was associated with an increased probability of achieving meaningful seizure reduction.
• Zorevunersen was generally well tolerated across Phase 1/2a and OLE studies, with 81 patients receiving at least one dose and over 800 doses administered.
• Study drug related treatment emergent adverse events (TEAEs) were observed in 30% (24/81) of Phase 1/2a patients and 53% (40/75) of OLE patients.
• The most common study drug related TEAE was CSF protein elevations, reported in 14% (11/81) of Phase 1/2a patients and 45% (33/75) of OLE patients.
• CSF protein elevations (>50 mg/dL) occurred in 42% (34/81) of Phase 1/2a patients and 86% (62/72) of OLE patients, with one patient discontinuing treatment due to elevated levels, but no related clinical manifestations observed.
• Treatment-emergent serious adverse events (TESAEs) were reported in 22% (18/81) and 29% (22/75) of patients in Phase 1/2a and OLE studies, with one patient experiencing SUSARs assessed as related.
• Three patient deaths occurred (two from sudden unexpected death in epilepsy (SUDEP) and one from malnutrition), all assessed as unrelated to zorevunersen.

Sentiment

Score: 9

Explanation: The filing presents strong, statistically significant positive clinical data for zorevunersen in Dravet syndrome, showing durable seizure reductions and improvements in cognition and behavior. The drug was generally well-tolerated, and the data supports its potential as a disease-modifying therapy, which is a significant advancement for this severe condition. The collaboration with Biogen further de-risks development and commercialization.

Positives

• Durable seizure reductions, including increases in seizure-free days, observed in long-term Phase 1/2a and OLE studies.
• Improvements in cognition, behavior, and quality of life demonstrated in treated patients.
• Statistically significant reductions in major motor seizure frequency at six months (70mg loading doses) compared to natural history.
• Statistically significant improvements in five key assessments of cognition and behavior (Vineland-3) at 18 months (45mg continued dosing).
• Durable effects shown through 24 months, the longest evaluable timepoint in the BUTTERFLY natural history study.
• EEG analysis supports a dose-dependent decrease in abnormal brain activity, correlating with seizure reduction.
• Zorevunersen was generally well tolerated across studies, with over 800 doses administered to 81 patients.
• The data aligns with and supports the ongoing Phase 3 EMPEROR study's primary and secondary endpoints.

Negatives

• Study drug related treatment emergent adverse events (TEAEs) were observed in 30% (24/81) of Phase 1/2a patients and 53% (40/75) of OLE patients.
• CSF protein elevations were common, reported in 14% (11/81) of Phase 1/2a patients and 45% (33/75) of OLE patients, with levels >50 mg/dL in 42% (34/81) and 86% (62/72) respectively.
• One patient discontinued treatment due to elevated CSF protein levels, although no related clinical manifestations were observed.
• Treatment-emergent serious adverse events (TESAEs) were reported in 22% (18/81) and 29% (22/75) of patients in Phase 1/2a and OLE studies, with one patient experiencing SUSARs assessed as related.
• Three patient deaths occurred, though all were assessed as unrelated to zorevunersen.

Risks

• Ability to advance, obtain regulatory approval, and commercialize product candidates.
• Risk of Biogen breaching or terminating the collaboration, leading to loss of anticipated financial or other benefits.
• Possibility that Stoke and Biogen may not successfully develop or commercialize zorevunersen.
• Positive results in early-stage clinical trials may not be replicated in subsequent trials or predictive of later-stage results.
• Ability to protect intellectual property.
• Ability to fund development activities and achieve development goals.
• Drug development and commercialization involve a high degree of risk, with only a small number of programs resulting in commercialization.
• Regulatory authorities may require additional information or further studies, or may fail to approve or delay approval of drug candidates.
• Occurrence of adverse safety events, restrictions on use, or product liability claims.

Future Outlook

The data presented further supports zorevunersen's potential as a disease-modifying medicine for Dravet syndrome. The ongoing Phase 3 EMPEROR study is progressing, with expectations for safety and efficacy data from this larger, sham-controlled study to provide additional confidence in zorevunersen's potential to improve debilitating symptoms like seizures and cognitive impairment by addressing the underlying cause of Dravet syndrome.

Management Comments

• "Over the last four years we have gained an increasing appreciation for the potential to change the course of Dravet syndrome with new disease-modifying medicines. Open-label data from the zorevunersen clinical studies have been highly encouraging, bringing hope and anticipation to the Dravet community." M. Scott Perry, M.D., Head of Neurosciences and Director of the Jane and John Justin Institute for Mind Health and Medical Director of the Genetic Epilepsy Clinic at Cook Childrens Medical Center.
• "The new propensity score weighted analysis comparing zorevunersen treatment to patients treated with the current standard of care gives us further context for the improvements we’re seeing in patients living with this devastating disease." M. Scott Perry, M.D.
• "Data from this analysis, which allows us to match patients treated with zorevunersen directly to natural history, add to a growing body of information shaping our understanding of Dravet syndrome and the effects of zorevunersen over time." Barry Ticho, M.D., Ph.D., Chief Medical Officer of Stoke Therapeutics.
• "As we continue to progress our Phase 3 EMPEROR program and await safety and efficacy data from this larger, sham-controlled study, results presented at AES give us additional confidence in what zorevunersen may one day offer to patients and their families." Barry Ticho, M.D., Ph.D.
• "In addition to these important efficacy findings, we are also encouraged by the accumulating long-term safety data, with some patients treated with up to 15 doses over more than four years." Katherine Dawson, M.D., Head of the Therapeutics Development Unit at Biogen.
• "The totality of clinical data, in addition to the new EEG findings, demonstrates zorevunersen’s potential to restore protein function and address the underlying cause of Dravet syndrome to improve debilitating symptoms like seizures and cognitive impairment." Katherine Dawson, M.D.

Industry Context

Dravet syndrome is a severe developmental and epileptic encephalopathy caused by SCN1A gene mutations, leading to insufficient NaV1.1 protein. Current anti-seizure medicines (ASMs) are often insufficient, with up to 57% of patients not achieving 50% seizure reduction. Zorevunersen, an investigational antisense oligonucleotide, aims to be a disease-modifying therapy by increasing functional NaV1.1 protein, potentially offering a significant advancement beyond symptomatic treatment in a market with no approved disease-modifying therapies.

Comparison to Industry Standards

• Zorevunersen demonstrated statistically significant reductions in major motor seizure frequency at six months compared to natural history, a benchmark for untreated disease progression.
• Improvements in cognition and behavior were observed with zorevunersen, contrasting with the significant cognitive and behavioral impairments characteristic of Dravet syndrome, even with standard of care.
• The efficacy and safety data from Phase 1/2a and OLE studies are consistent with and support the design and endpoints of the ongoing Phase 3 EMPEROR study, which is a global, double-blind, sham-controlled trial, representing a high standard for clinical validation.
• The mechanism of action, aiming to restore protein function and address the underlying cause, differentiates zorevunersen from existing anti-seizure medicines that primarily manage symptoms.

Stakeholder Impact

• Shareholders: Positive clinical data for zorevunersen could significantly increase the company's valuation and future revenue potential, especially given the large market for Dravet syndrome and the lack of disease-modifying therapies.
• Patients with Dravet Syndrome: The investigational medicine offers hope for a disease-modifying treatment that could not only reduce seizures but also improve cognitive and behavioral impairments, significantly enhancing quality of life.
• Caregivers: Potential for improved patient outcomes could alleviate some of the significant burden and challenges faced by caregivers of individuals with Dravet syndrome.
• Medical Community: The data supports a novel mechanism of action (TANGO approach) and could lead to a new standard of care for Dravet syndrome, influencing treatment paradigms.

Next Steps

• Continue enrollment and progression of the global Phase 3 EMPEROR study (NCT06872125).
• Await safety and efficacy data from the larger, sham-controlled Phase 3 EMPEROR study.
• Eligible participants from the EMPEROR study will be offered ongoing treatment in an Open Label Extension (OLE) study.

Key Dates

Recommendation

The filing provides compelling, statistically significant clinical data from long-term Phase 1/2a and OLE studies, demonstrating zorevunersen's potential as a disease-modifying therapy for Dravet syndrome. The observed durable reductions in major motor seizures and improvements in cognition and behavior, coupled with a generally well-tolerated safety profile, are highly encouraging. The data aligns with and supports the ongoing Phase 3 EMPEROR study, significantly de-risking the development pathway. Given the high unmet medical need in Dravet syndrome and zorevunersen's differentiated mechanism of action, these results position the company for substantial future growth and market penetration, making it a strong investment opportunity.

Keywords

Dravet syndrome, zorevunersen, antisense oligonucleotide, SCN1A gene, epilepsy, clinical trial, Phase 1/2a, OLE, Phase 3 EMPEROR, Biogen, Stoke Therapeutics, neurological disorder, rare disease, orphan drug, Breakthrough Therapy Designation, EEG, seizure reduction, cognition, behavior