ANTISENSE OLIGONUCLEOTIDE THERAPY FOR DRAVET SYNDROME: A CRITICAL REVIEW OF THE EVIDENCE FOR DISEASE MODIFICATION WITH ZOREVUNERSEN
DOI:
https://doi.org/10.31435/ijitss.3(51).2026.6603Keywords:
Dravet Syndrome, SCN1A, Antisense Oligonucleotide, Zorevunersen, Disease ModificationAbstract
Dravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency, and no approved disease-modifying therapy addresses its underlying channelopathy. Zorevunersen, an intrathecal splice-modulating antisense oligonucleotide, is designed to increase NaV1.1 expression. This critical narrative review appraises the available human evidence for disease modification using explicit operational criteria and a documented, provenance-based search. The peer-reviewed evidence base centers on two open-label phases 1–2a studies (MONARCH and ADMIRAL; n=81) and their open-label extensions (SWALLOWTAIL and LONGWING; n=75; data cut May 30, 2025). In descriptive analyses, median convulsive-seizure reductions ranged from −58.8% to −90.9% across one-month intervals through Month 20 in the 70-mg subgroup, and at Month 36 both clinicians and caregivers rated 94.7% of patients with available assessments as at least minimally improved; least-squares mean Vineland-3 raw-score changes were 7.56 (expressive) and 6.06 (receptive). Dose-group comparisons were post hoc; confidence intervals were not adjusted for multiplicity, and late extension outcomes were based on available data without a concurrent control. We conclude that current human evidence supports a hypothesis of disease modification but does not establish it, and we delineate what the randomized, sham-controlled EMPEROR trial can and cannot confirm, with implications for patients, clinicians, and the communication of preliminary results.
References
Baethge, C., Goldbeck-Wood, S., & Mertens, S. (2019). SANRA—a scale for the quality assessment of narrative review articles. Research Integrity and Peer Review, 4, Article 5. https://doi.org/10.1186/s41073-019-0064-8
Carvill, G. L., Engel, K. L., Ramamurthy, A., Cochran, J. N., Roovers, J., Stamberger, H., Lim, N., Schneider, A. L., Hollingsworth, G., Holder, D. H., Regan, B. M., Lawlor, J., Lagae, L., Ceulemans, B., Bebin, E. M., Nguyen, J., EuroEPINOMICS Rare Epilepsy Syndrome, Myoclonic-Astatic Epilepsy, and Dravet Working Group, Barsh, G. S., Weckhuysen, S., … Mefford, H. C. (2018). Aberrant inclusion of a poison exon causes Dravet syndrome and related SCN1A-associated genetic epilepsies. The American Journal of Human Genetics, 103(6), 1022–1029. https://doi.org/10.1016/j.ajhg.2018.10.023
Catterall, W. A., Kalume, F., & Oakley, J. C. (2010). NaV1.1 channels and epilepsy. The Journal of Physiology, 588(11), 1849–1859. https://doi.org/10.1113/jphysiol.2010.187484
Chiron, C., Marchand, M. C., Tran, A., Rey, E., d'Athis, P., Vincent, J., Dulac, O., & Pons, G. (2000). Stiripentol in severe myoclonic epilepsy in infancy: A randomised placebo-controlled syndrome-dedicated trial. The Lancet, 356(9242), 1638–1642. https://doi.org/10.1016/S0140-6736(00)03157-3
Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., & De Jonghe, P. (2001). De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. The American Journal of Human Genetics, 68(6), 1327–1332. https://doi.org/10.1086/320609
Condon, C., Parkerson, K. A., Dandurand, A., Wang, F., Howse, C., Mayhew, M., Whyman, S., Ventola, P., Meskis, M. A., Sullivan, J., Knupp, K. G., Gater, A., & Mahon-Smith, A. (2025). Qualitative evaluation of meaningful change in Dravet syndrome as measured by the Vineland-3: Caregiver and clinician perspectives. Epilepsy & Behavior, 167, 110381. https://doi.org/10.1016/j.yebeh.2025.110381
Cooper, M. S., McIntosh, A., Crompton, D. E., McMahon, J. M., Schneider, A., Farrell, K., Ganesan, V., Gill, D., Kivity, S., Lerman-Sagie, T., McLellan, A., Pelekanos, J., Ramesh, V., Sadleir, L., Wirrell, E., & Scheffer, I. E. (2016). Mortality in Dravet syndrome. Epilepsy Research, 128, 43–47. https://doi.org/10.1016/j.eplepsyres.2016.10.006
Cross, J. H., & Lagae, L. (2020). The concept of disease modification. European Journal of Paediatric Neurology, 24, 43–46. https://doi.org/10.1016/j.ejpn.2019.12.005
Devinsky, O., Cross, J. H., Laux, L., Marsh, E., Miller, I., Nabbout, R., Scheffer, I. E., Thiele, E. A., & Wright, S. (2017). Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. The New England Journal of Medicine, 376(21), 2011–2020. https://doi.org/10.1056/NEJMoa1611618
Encoded Therapeutics. (2026, May 13). Encoded Therapeutics presents new clinical data from POLARIS phase 1/2 trials of ETX101 gene therapy in Dravet syndrome at the ASGCT 2026 Presidential Symposium [Press release]. https://encoded.com/press-releases/encoded-therapeutics-presents-new-clinical-data-from-polaris-phase-1-2-trials-of-etx101-gene-therapy-in-dravet-syndrome-at-the-asgct-2026-presidential-symposium/
Finkel, R. S., Mercuri, E., Darras, B. T., Connolly, A. M., Kuntz, N. L., Kirschner, J., Chiriboga, C. A., Saito, K., Servais, L., Tizzano, E. F., Topaloglu, H., Tulinius, M., Montes, J., Glanzman, A. M., Bishop, K., Zhong, Z. J., Gheuens, S., Bennett, C. F., Schneider, E., … De Vivo, D. C. (2017). Nusinersen versus sham control in infantile-onset spinal muscular atrophy. The New England Journal of Medicine, 377(18), 1723–1732. https://doi.org/10.1056/NEJMoa1702752
Han, Z., Chen, C., Christiansen, A., Ji, S., Lin, Q., Anumonwo, C., Liu, C., Leiser, S. C., Meena, Aznarez, I., Liau, G., & Isom, L. L. (2020). Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome. Science Translational Medicine, 12(558), eaaz6100. https://doi.org/10.1126/scitranslmed.aaz6100
Juandó-Prats, C., James, E., Bilder, D. A., McNair, L., Kenneally, N., Helfer, J., Huang, N., Vila, M. C., Sullivan, J., Wirrell, E., & Rico, S. (2021). DRAVET ENGAGE. Parent caregivers of children with Dravet syndrome—Perspectives, needs, and opportunities for clinical research. Epilepsy & Behavior, 122, 108198. https://doi.org/10.1016/j.yebeh.2021.108198
Lagae, L., Sullivan, J., Knupp, K., Laux, L., Polster, T., Nikanorova, M., Devinsky, O., Cross, J. H., Guerrini, R., Talwar, D., Miller, I., Farfel, G., Galer, B. S., Gammaitoni, A., Mistry, A., Morrison, G., Lock, M., Agarwal, A., Lai, W. W., & Ceulemans, B. (2019). Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A randomised, double-blind, placebo-controlled trial. The Lancet, 394(10216), 2243–2254. https://doi.org/10.1016/S0140-6736(19)32500-0
Laux, L., Sullivan, J., Perry, M. S., Brunklaus, A., Desurkar, A., Schreiber, J. M., Roberts, C. M., Knupp, K. G., Wheless, J. W., Wirrell, E. C., Ventola, P., Wang, F., Meena, Lynch, J., Parkerson, K. A., Ticho, B., & Cross, J. H. (2026). Zorevunersen in children and adolescents with Dravet syndrome. The New England Journal of Medicine, 394(10), 969–982. https://doi.org/10.1056/NEJMoa2506295
Lim, K. H., Han, Z., Jeon, H. Y., Kach, J., Jing, E., Weyn-Vanhentenryck, S., Downs, M., Corrionero, A., Oh, R., Scharner, J., Venkatesh, A., Ji, S., Liau, G., Ticho, B., Nash, H., & Aznarez, I. (2020). Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression. Nature Communications, 11, Article 3501. https://doi.org/10.1038/s41467-020-17093-9
Miller, T. M., Cudkowicz, M. E., Genge, A., Shaw, P. J., Sobue, G., Bucelli, R. C., Chiò, A., Van Damme, P., Ludolph, A. C., Glass, J. D., Andrews, J. A., Babu, S., Benatar, M., McDermott, C. J., Cochrane, T., Chary, S., Chew, S., Zhu, H., Wu, F., … Fradette, S. (2022). Trial of antisense oligonucleotide tofersen for SOD1 ALS. The New England Journal of Medicine, 387(12), 1099–1110. https://doi.org/10.1056/NEJMoa2204705
Ogiwara, I., Miyamoto, H., Morita, N., Atapour, N., Mazaki, E., Inoue, I., Takeuchi, T., Itohara, S., Yanagawa, Y., Obata, K., Furuichi, T., Hensch, T. K., & Yamakawa, K. (2007). Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: A circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. The Journal of Neuroscience, 27(22), 5903–5914. https://doi.org/10.1523/JNEUROSCI.5270-06.2007
Perry, M. S., Scheffer, I. E., Sullivan, J., Brunklaus, A., Boronat, S., Wheless, J. W., Laux, L., Patel, A. D., Roberts, C. M., Dlugos, D., Holder, D., Knupp, K. G., Lallas, M., Phillips, S., Segal, E., Smeyers, P., Lal, D., Wirrell, E., Zuberi, S., … Rico, S. (2024). Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study. Epilepsia, 65(2), 322–337. https://doi.org/10.1111/epi.17850
Sparrow, S. S., Cicchetti, D. V., & Saulnier, C. A. (2016). Vineland Adaptive Behavior Scales, Third Edition (Vineland-3). Pearson.
Stoke Therapeutics. (2026c, March 4). The New England Journal of Medicine publishes first data to demonstrate the potential for disease modification in Dravet syndrome [Press release]. https://investor.stoketherapeutics.com/news-releases/news-release-details/new-england-journal-medicine-publishes-first-data-demonstrate
Stoke Therapeutics. (2026a, June 30). Stoke Therapeutics announces completion of enrollment of 162 patients into the Phase 3 EMPEROR study of zorevunersen, an investigational medicine for the treatment of Dravet syndrome [Press release]. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-announces-completion-enrollment-162-patients/
Sullivan, J., Deighton, A. M., Vila, M. C., Szabo, S. M., Maru, B., Gofshteyn, J. S., James, E. S., Rico, S., & Zuberi, S. M. (2022). The clinical, economic, and humanistic burden of Dravet syndrome—A systematic literature review. Epilepsy & Behavior, 130, 108661. https://doi.org/10.1016/j.yebeh.2022.108661
Sullivan, J., Perry, M. S., Scheffer, I. E., Wheless, J., Boronat, S., Brunklaus, A., Laux, L., Patel, A. D., Roberts, C., Dlugos, D., Holder, D., Knupp, K., Lallas, M., Phillips, S., Segal, E., Lal, D., Wirrell, E., Zuberi, S., Gioia, G., … Rico, S. (2026). Cognitive stagnation and executive function deficits in young children with SCN1A+ Dravet syndrome: Detailed characterization of onset, progression, and impact in the ENVISION natural history study. Epilepsia, 67(3), 1284–1302. https://doi.org/10.1111/epi.70015
Sullivan, J., Wirrell, E. C., Knupp, K. G., Ciliberto, M., Ziobro, J., Chen, D. Y., Flamini, J. R., Zafar, M., LaVallee, N., Stepanians, M., Ventola, P., Chavan, T. S., Wang, F., Parkerson, K. A., & Ticho, B. (2025). Natural history of children and adolescents with Dravet syndrome: A 24-month follow-up. Neurology, 105(11), e214388. https://doi.org/10.1212/WNL.0000000000214388
Sullivan, J., Wirrell, E., Zafar, M., Chen, D., Flamini, R., Knupp, K. G., Ventola, P., Brathwaite, C., Condon, C., Wang, F., Parkerson, K. A., & Ticho, B. (2024). 24-month analysis of BUTTERFLY: A prospective, observational study to investigate seizures and comorbidities in children and adolescents with Dravet syndrome [Poster presentation]. 15th European Epilepsy Congress, Rome, Italy. https://www.stoketherapeutics.com/wp-content/uploads/24-Month-Analysis-of-BUTTERFLY-A-Prospective-Observational-Study-to-Investigate-Cognition-and-Other-Non-seizure-Comorbidities-in-Children-Adolescents-with-Dravet-Syndrome-1.pdf
Sveinsson, O., Andersson, T., Carlsson, S., & Tomson, T. (2017). The incidence of SUDEP: A nationwide population-based cohort study. Neurology, 89(2), 170–177. https://doi.org/10.1212/WNL.0000000000004094
Tanenhaus, A., Stowe, T., Young, A., McLaughlin, J., Aeran, R., Lin, I. W., Li, J., Hosur, R., Chen, M., Leedy, J., Chou, T., Pillay, S., Vila, M. C., Kearney, J. A., Moorhead, M., Belle, A., & Tagliatela, S. (2022). Cell-selective adeno-associated virus-mediated SCN1A gene regulation therapy rescues mortality and seizure phenotypes in a Dravet syndrome mouse model and is well tolerated in nonhuman primates. Human Gene Therapy, 33(11–12), 579–597. https://doi.org/10.1089/hum.2022.037
U.S. Food and Drug Administration. (n.d.). Accelerated approval program. Retrieved August 23, 2026, from https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program
DailyMed. (2024, November 13). Qalsody (tofersen) injection [Prescribing information]. U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=81356b45-1cb7-4eef-88ea-e44cc18b47c5
ClinicalTrials.gov. (2026). A double-blind study evaluating the efficacy, safety, and tolerability of zorevunersen in patients with Dravet syndrome (NCT06872125). U.S. National Library of Medicine. Retrieved August 23, 2026, from https://clinicaltrials.gov/study/NCT06872125
Villas, N., Meskis, M. A., & Goodliffe, S. (2017). Dravet syndrome: Characteristics, comorbidities, and caregiver concerns. Epilepsy & Behavior, 74, 81–86. https://doi.org/10.1016/j.yebeh.2017.06.031
Wirrell, E. C., Hood, V., Knupp, K. G., Meskis, M. A., Nabbout, R., Scheffer, I. E., Wilmshurst, J., & Sullivan, J. (2022). International consensus on diagnosis and management of Dravet syndrome. Epilepsia, 63(7), 1761–1777. https://doi.org/10.1111/epi.17274
Wu, Y. W., Sullivan, J., McDaniel, S. S., Meisler, M. H., Walsh, E. M., Li, S. X., & Kuzniewicz, M. W. (2015). Incidence of Dravet syndrome in a US population. Pediatrics, 136(5), e1310–e1315. https://doi.org/10.1542/peds.2015-1807
Yu, F. H., Mantegazza, M., Westenbroek, R. E., Robbins, C. A., Kalume, F., Burton, K. A., Spain, W. J., McKnight, G. S., Scheuer, T., & Catterall, W. A. (2006). Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nature Neuroscience, 9(9), 1142–1149. https://doi.org/10.1038/nn1754
Stoke Therapeutics. (2026b, May 7). Stoke Therapeutics announces first quarter 2026 financial results and provides business updates [Press release]. https://investor.stoketherapeutics.com/news-releases/news-release-details/stoke-therapeutics-announces-first-quarter-2026-financial
George, D., Kennedy, J., & Gupta, V. (2026). Zorevunersen in children and adolescents with Dravet syndrome. The New England Journal of Medicine, 394(23), 2383–2384. https://doi.org/10.1056/NEJMc2605256
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Oliwia Żmuda, Anna Halot, Patrycja Walo, Natalia Skórka, Magdalena Tatara, Karolina Skórka, Klaudia Wydra, Jakub Jakubiec, Michał Szubartowski, Adam Szymczyk
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
