Authors :
Presenting Author: Joseph Sullivan, MD – Weill Institute for Neurosciences and Benioff Children’s Hospital, University of California San Francisco
M. Scott Perry, MD – Cook Children’s Physician Network
Andreas Brunklaus, M.D. – University of Glasgow
J. Helen Cross, M.B., Ch.B., PhD – University College London NIHR BRC Great Ormond Street Institute of Child Health
Linda Laux, M.D. – Ann & Robert H. Lurie Children's Hospital of Chicago
John Schreiber, M.D. – Children's National Hospital, Washington D.C.
Kelly Knupp, MD, MSCS, FAES – University of Colorado, Anschutz Medical Campus
Charlene Brathwaite, B.A. – Stoke Therapeutics
Carrie Condon, M.P.H. – Stoke Therapeutics
Ann Dandurand, M.D. – Stoke Therapeutics
Jessie Lynch, B.A. – Stoke Therapeutics
James Stutely, B.A. – Stoke Therapeutics
Fei Wang, Ph.D. – Stoke Therapeutics
Meena N/A, Ph.D. – Stoke Therapeutics
Kimberly A. Parkerson, M.D., Ph.D. – Stoke Therapeutics
Brian Werneburg, Ph.D. – Stoke Therapeutics
Barry Ticho, M.D., Ph.D. – Stoke Therapeutics
Rationale:
Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy that in most patients is caused by sodium voltage-gated channel α subunit 1 (SCN1A) gene haploinsufficiency, resulting in reduced NaV1.1 protein expression. Despite receiving multiple anti-seizure medications (ASMs), patients with DS continue to experience frequent seizures and persistent neurodevelopmental deficits. Zorevunersen is an investigational antisense oligonucleotide designed to upregulate NaV1.1 expression by leveraging the wild-type SCN1A copy. Here, clinical effects and safety of zorevunersen in patients with DS are presented.Methods:
In the MONARCH/ADMIRAL (NCT04442295 [USA]/2020-006016-24 [UK]) Phase 1/2a studies, 81 patients on best available ASMs received single or multiple loading doses of zorevunersen (≤ 70 mg). At the end of Phase 1/2a, 74 patients continued treatment in the SWALLOWTAIL/LONGWING (NCT04740476 [USA]/2021-005626-14 [UK]) open-label extension (OLE) studies and received zorevunersen (≤ 45 mg) every four months. Convulsive seizure frequency (SF), cognition and behavior (Vineland-3), overall functioning, and safety were evaluated.
Results:
Six months after their last dose, patients treated with multiple doses of 70 mg zorevunersen (n=9) experienced a 73.6% (80% confidence interval [CI]: 63.2%–88.7%) reduction in median convulsive SF relative to naïve baseline. Overall, reductions in convulsive SF were sustained across enrolled patients through Month 24 of the OLEs (Figure 1A). Patients who received multiple loading doses of 70 mg followed by maintenance doses of 45 mg in the OLEs (n=9) had reductions in median convulsive SF per 28 days ranging from 50.8% to 89.3% from naïve baseline through Month 8 of the OLEs (Figure 1B). Enrolled patients gained an estimated 3.79 (0.85–6.73) and 5.22 (2.93–7.50), growth scale values (95% CI) in Expressive and Receptive Communication Vineland-3 subdomains, respectively, from OLE baseline to Month 24 in the OLEs (Figure 2). Substantial improvements in overall functioning, as rated by the Clinical and Caregiver Global Impression of Change scales, were observed in the Phase 1/2a and OLE studies.
Single or multiple doses of ≤ 70 mg zorevunersen were generally well tolerated. Increased cerebrospinal fluid protein was the most common treatment-related adverse event in the Phase 1/2a (13.6%, n=11/81) and OLE (27.0%, n=20/74) studies. No patients experienced clinical manifestations of elevated CSF white blood cell count, hydrocephalus, or increased intracranial pressure in relation to increased CSF protein.
Ongoing analysis of seizure and non-seizure outcomes, including Vineland-3 scores, is underway and will be included in the final presentation.
Conclusions:
Patients treated with zorevunersen experienced substantial and durable seizure reductions along with continuing improvements in cognition, behavior and overall functioning despite already receiving the best available ASMs. These findings support the potential of zorevunersen as a disease-modifying therapy and warrant its further evaluation in the ongoing Phase 3 study. Funding:
Stoke Therapeutics