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STK-001 Gains FDA Breakthrough Designation as Potential Disease-Modifying Treatment for Dravet Syndrome
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Key Takeaways
- STK-001 targets NaV1.1 protein restoration, addressing Dravet syndrome's underlying cause and reducing seizures and comorbidities.
- Phase 1/2 studies showed significant seizure reduction and quality of life improvements in patients with Dravet syndrome.
Stoke Therapeutics is preparing for a phase 3 registrational study to further assess STK-001, with results from open-label extensions showing sustained seizure reductions and a well-tolerated safety profile.
Shamim Ruff, chief regulatory affairs officer at Stoke
The FDA has granted breakthrough therapy designation to Stoke Therapeutics investigational antisense agent STK-001 for the treatment of genetically confirmed Dravet syndrome (DS), a rare epilepsy disorder. The company remains in discussions with the agency for plans on a phase 3 registrational study, which are expected to be released by the end of this year.1
Also known as zorevunersen, the agent is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. To date, there have been more than 600 doses of the medication administered to patients, with some currently on the drug for more than 3 years.
"The FDA’s Breakthrough Therapy designation for zorevunersen is supported by promising clinical data that suggest that zorevunersen has the potential to demonstrate substantial improvement over current treatments for Dravet syndrome," Shamim Ruff, chief regulatory affairs officer at Stoke, said in a statement.1 "By helping the body restore naturally occurring NaV1.1 protein levels, zorevunersen is designed to treat the underlying cause of the disease. We thank the FDA for their support and look forward to continuing to work together closely to efficiently advance zorevunersen into a registrational Phase 3 study."
To date, the agent has shown promising disease-modifying impacts on patients with DS across a number of phase 1/2 studies, which include MONARCH (NCT04740476) and ADMIRAL (NCT04442295), as well as their extensions, SWALLOWTAIL and LONGWING. At the 15th European Epilepsy Congress, held September 7-11, in Rome, Italy, Stoke presented several different analyses from these studies, each highlighting the agent’s impacts on seizure control and other areas like cognition, behavior, quality of life, and overall clinical status.2,3
Mary Anne Meskis
"This designation brings new hope to the many patients with Dravet syndrome who continue to experience treatment-resistant seizures and a myriad of health and quality of life complications despite the availability of symptomatic treatments," Mary Anne Meskis, executive director at the Dravet Syndrome Foundation, said in a statement.1 "Our organization has been engaging with the FDA to ensure greater awareness and understanding of Dravet syndrome. We are encouraged by the Agency’s shared sense of urgency for the development of innovative new medicines that could help address the gaps left by current treatments by treating the underlying cause of the disease."
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Across the MONARCH and ADMIRAL trials, 81 patients with DS were enrolled from an initial screening of 97. The US-based MONARCH trial included single-ascending dose (SAD) and multiple ascending dose (MAD) phases, while the UK-based ADMIRAL trial focused on a MAD phase with doses of STK-001 up to 70 mg. Over 85% of participants were taking 3 or more antiseizure medications, such as clobazam, stiripentol, and fenfluramine, yet had a baseline median convulsive seizure frequency of 17 per 28 days, underscoring the refractory nature of their seizures. Patients who received 2 or 3 doses of 70 mg of STK-001 achieved median seizure reductions of 85% at 3 months and 74% at 6 months post-treatment, compared with baseline.
Within 36 weeks of treatment with zorevunersen, data showed significant improvements in clinical status and quality of life. In the 70 mg SAD and MAD cohorts of the MONARCH and ADMIRAL trials, the predicted improvement rate on the EuroQol 5-Dimension Youth questionnaire was 7.756. Caregivers and clinicians also reported marked improvements on the Caregiver and Clinical Global Impression of Change scales. Additionally, all ADMIRAL cohorts demonstrated gains in Vineland-3 Adaptive Behavior Scale subdomains, including Receptive Communication (5.778), Expressive Communication (3.272), Personal Skills (2.030), Interpersonal Relationships (3.096), Coping Skills (0.700), Gross Motor (3.517), and Fine Motor (1.993).2
In total, 94.7% (54 of 57) and 84.2% (14 of 17) of patients who completed MONARCH and ADMIRAL, respectively, went on to the SWLLOWTAIL and LONGWING extensions. In these open-label extensions (OLE), nearly half (49%; 33 of 68) of patients were concomitantly on fenfluramine. Enrolled patients received STK-001 as an intrathecal slow bolus injection every 16 weeks, with patients currently receiving 45 mg per dose.
Similar to the core studies, results from the extensions showed reductions in convulsive seizure frequency that were sustained throughout week 48. More substantial reductions were observed in the initial 3 patients who received multiple doses of 70 mg STK-001 in the phase 1/2 studies followed by a single dose of 45 mg in the OLE. In terms of safety, the therapy was well-tolerated, with the most common treatment-emergent adverse events (TEAEs) being increased cerebrospinal fluid (CSF) protein, pyrexia, and COVID-19. CSF protein elevation was observed in 74% (50 of 68) of patients, and was considered the only drug-related TEAE that resulted in the study’s only withdrawal.3
