Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial

Autor: R. Zanin, A. Seferian, N. Brolatti, A. Govoni, L. Edel, A. Jollet, M. Del Sole, Arseniy Lavrov, M.T. Arnoldi, E. De Vos, Eugenio Mercuri, L. Antonaci, G. Coratti, M. Pedemonte, Haojun Ouyang, K. Groves, O. Schneider, M. Foa, Volker Straub, A.C. Defeldre, G. Comi, Stefania Corti, V. Parente, A. Jonas, R.M. Lofra, Laurent Servais, Riccardo Masson, L. Buscemi, Nicolas Deconinck, S. De Lucia, Aurore Daron, M.C. Pera, Claudio Bruno, E. Pagliano, S. Mouffak, Nuno Mendonca, A. Vanlander, Deepa H. Chand, E. Thompson, H. Van Ruiten, V. Tahon, Giovanni Baranello, S. Tachibana, M. Pane, S. Morando, Francesco Muntoni, R. de Sanctis, V. Schembri, F. Dal Farra, A. Mandelli, Odile Boespflug-Tanguy, Sitra Tauscher-Wisniewski, M. Scoto, F. Abel, F. Magri
Rok vydání: 2021
Předmět:
Zdroj: The Lancet Neurology. 20:832-841
ISSN: 1474-4422
0346-1289
DOI: 10.1016/s1474-4422(21)00251-9
Popis: Summary Background Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. Methods STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov , NCT03461289 (completed). Findings From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p Interpretation STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline. Funding Novartis Gene Therapies.
Databáze: OpenAIRE
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