Authors :
Presenting Author: Kelly Knupp, MD, MSCS, FAES – University of Colorado, Anschutz Medical Campus
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
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
Colin Roberts, M.D. – Oregon Health & Science University, Doernbecher Children’s Hospital
John Schreiber, M.D. – Children's National Hospital, Washington D.C.
James Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES, FCNS – University of Tennessee Health Science Center and Le Bonheur Children's Hospital
Kimberly A. Parkerson, M.D., Ph.D. – Stoke Therapeutics
Brian Werneburg, Ph.D. – Stoke Therapeutics
Fei Wang, Ph.D. – Stoke Therapeutics
Barry Ticho, M.D., Ph.D. – Stoke Therapeutics
Rationale:
Dravet syndrome (DS) is a developmental and epileptic encephalopathy caused primarily by SCN1A gene haploinsufficiency, resulting in reduced NaV1.1 expression. Despite treatment with best available antiseizure medications (ASMs), patients with DS in the BUTTERFLY natural history study continued to show frequent seizures and widening cognitive and behavioral gaps relative to their neurotypical peers; impacts on quality of life (QoL) were also reported. Zorevunersen is an investigational antisense oligonucleotide that upregulates NaV1.1 by leveraging the wild-type SCN1A copy. Here, we present the effects of zorevunersen on seizures and measures of QoL in patients with DS. 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). Of the 80 completers, 74 (92.5%) continued treatment (≤ 45 mg every 4 months) in the SWALLOWTAIL/LONGWING (NCT04740476 [USA]/2021-005626-14 [UK]) open-label extension (OLE) studies. Seizure frequency (SF), seizure-free days, QoL, overall functioning, and safety were evaluated. Results:
Patients who received multiple doses of 70 mg zorevunersen (n=9) in Phase 1/2a studies experienced a 73.6% reduction in median convulsive SF 6 months after their last dose. They gained a median (range) of 7 (2, 20) convulsive seizure-free days per 28 days between baseline and 6 months after their last dose, leading to a median (range) of 24 (15,28) convulsive seizure-free days per 28 days per patient.
In the OLEs, these patients received maintenance doses of 45 mg every 4 months (n=9) and continued to experience a 53.0% to 87.0% reduction in median convulsive SF per 28 days from naïve baseline through Month 8.
Improvements in QoL were greatest in patients administered 70 mg doses in Phase 1/2a studies, with estimated improvement of 13.62 (95% CI: 7.41, 19.82) health score points on the EuroQol-visual analogue scale from naïve baseline to 9 months after treatment initiation (Figure 1).
The greatest improvements in overall functioning, rated by the Clinical and Caregiver Global Impression of Change scales, were observed in patients who received 70 mg doses, with estimated mean scores of 2.64 (95% CI: 2.06, 3.21) and 2.68 (95% CI: 2.12, 3.24), respectively, at 9 months after treatment initiation (Figure 2).
Zorevunersen was generally well tolerated up to doses ≤ 70 mg. Increased cerebrospinal fluid (CSF) protein was the most common treatment-related adverse event in 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.
Ongoing analysis is underway and will be included in the final presentation.
Conclusions:
Treatment with zorevunersen resulted in durable seizure reduction, increased seizure-free days, and improvements in QoL and overall functioning in patients with DS. These findings support the potential of zorevunersen as a disease-modifying therapy and are further evaluated in the ongoing Phase 3 study. Funding:
Stoke Therapeutics