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Clinical Trial
. 2025 Jan 28;104(2):e210268.
doi: 10.1212/WNL.0000000000210268. Epub 2024 Dec 30.

Safety and Efficacy of IV Onasemnogene Abeparvovec for Pediatric Patients With Spinal Muscular Atrophy: The Phase 3b SMART Study

Hugh J McMillan  1 , Giovanni Baranello  2   3 , Michelle A Farrar  4   5 , Craig M Zaidman  6 , Teresa Moreno  7 , Liesbeth De Waele  8   9 , Yuh-Jyh Jong  10   11   12 , Vincent Laugel  13 , Susana Quijano-Roy  14   15 , Eugenio Mercuri  16   17 , Yin-Hsiu Chien  18 , Volker Straub  19 , Basil T Darras  20 , Julia Seibert  21 , Roberto Bernardo Escudero  22 , Iulian Alecu  21 , Frank Freischläger  23 , Francesco Muntoni  2   3 ; SMART Study Group
Collaborators, Affiliations
Clinical Trial

Safety and Efficacy of IV Onasemnogene Abeparvovec for Pediatric Patients With Spinal Muscular Atrophy: The Phase 3b SMART Study

Hugh J McMillan et al. Neurology. .

Abstract

Background and objectives: Safety and efficacy of IV onasemnogene abeparvovec has been demonstrated for patients with spinal muscular atrophy (SMA) weighing <8.5 kg. SMART was the first clinical trial to evaluate onasemnogene abeparvovec for participants weighing 8.5-21 kg.

Methods: SMART was an open-label, multicenter, phase 3b study conducted across 13 sites in 9 countries (NCT04851873). Symptomatic pediatric participants with SMA (any type; treatment-naïve or had discontinued prior treatment) were stratified into 3 weight cohorts (≥8.5-13, >13-17, and >17-21 kg), administered onasemnogene abeparvovec, and followed for 52 weeks. Corticosteroids were initiated 24 hours before infusion with dose increases in response to adverse events (AEs) and subsequent tapering at investigator discretion. The primary objective was safety. Secondary objective was efficacy (motor function/motor milestones).

Results: Twenty-four participants were enrolled; the majority had SMA type 2 (n = 11), 3 SMN2 copies (n = 18), and prior treatment (n = 21). All participants completed the study; no deaths occurred. All participants had ≥1 treatment-related AE(s), 7 of 24 (29%) had serious treatment-related AEs, and 23 of 24 (96%) had ≥1 AE of special interest. Twenty of 24 participants (83%) had asymptomatic hepatotoxicity events, which were primarily transaminase elevations. No participant had bilirubin elevations >2× upper limit of normal, developed symptomatic hepatotoxicity, or met Hy law criteria. Transient asymptomatic thrombocytopenia events were reported in 17 of 24 participants (71%); all resolved spontaneously with no related bleeding events reported. Three of 24 participants (13%) had cardiac AEs (all unrelated to treatment). No thrombotic microangiopathy or dorsal root ganglionopathy-related AEs were reported. AE frequency and severity were similar across weight groups, although corticosteroid exposure was greater for the 2 heavier cohorts (median 135.0, 201.0, and 194.0 days, respectively) with 37% and 33% still on corticosteroids at the study end. By week 52, most participants maintained or improved motor function (Hammersmith Functional Motor Scale-Expanded 16/18; Revised Upper Limb Module 15/17); 4 participants (all 3 SMN2 copies) achieved new motor milestones.

Discussion: Onasemnogene abeparvovec safety profile was similar across weight groups in this heterogenous participant population. Frequency and duration of asymptomatic aminotransferase elevations and thrombocytopenia are notable findings. Most participants demonstrated maintenance or improvement of motor function, suggesting clinical benefit for patients with SMA weighing up to 21 kg.

Trial registration information: ClinicalTrials.gov identifier (NCT04851873, clinicaltrials.gov/study/NCT04851873) submitted April 19, 2021. First participant enrolled on September 8, 2021.

Classification of evidence: This study provides Class IV evidence that intravenous onasemnogene abeparvovec is safe in pediatric patients with SMA who weigh 8.5-21 kg.

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Conflict of interest statement

H.J. McMillan has participated in clinical trials with Roche, PTC Therapeutics, ReveraGen, Catabasis, Novartis, and Sarepta, and has been a consultant for and received honoraria from Novartis Gene Therapies Inc. and Hoffman La-Roche Ltd. G. Baranello has participated in clinical trials sponsored by Roche, Novartis, Sarepta, Pfizer, NS Pharma, ReveraGen, and Scholar Rock, and has received speaker and/or consulting fees from Sarepta, PTC Therapeutics, Pfizer, Biogen, Novartis Gene Therapies Inc. (AveXis), and Roche and grants from Sarepta, Roche, and Novartis Gene Therapies Inc. M.A. Farrar has received honoraria for scientific advisory boards from Novartis Gene Therapies Inc., Biogen, and Roche and research grants from Biogen. C.M. Zaidman has received research support from Biogen and Novartis and speaking fees from Sarepta, Chugai, and the France Foundation. T. Moreno received speaker and consulting fees for scientific advisory boards from Biogen, Novartis Gene Therapies Inc. (AveXis), Pfizer, and Roche. L. De Waele has received speaker and consulting fees from Novartis Gene Therapies Inc. (AveXis), Biogen, and Roche; has worked as a principal investigator of SMA studies sponsored by Novartis Gene Therapies Inc., Roche, Scholar Rock, and Biohaven; has received research grants from Novartis Gene Therapies Inc., Roche, and Biogen; and is a member of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). Y.-J. Jong has participated in clinical trials with Biogen, Novartis, Roche, PTC, Sarepta, Pfizer; received speaker and/or consulting fees from Biogen, Novartis, Roche, and Pfizer; and received research grants from Biogen. V. Laugel has participated in clinical trials with Roche, Novartis, Wave Life Sciences, FibroGen, and Genethon, and reports consulting honoraria from Roche, Biogen, Novartis, Sarepta, Alexion, PTC Therapeutics, Genethon, Pfizer, and Italfarmaco. S. Quijano-Roy has participated in clinical trials sponsored by Roche, Novartis, and Biogen and has received speaker and/or consulting fees from Biogen, Novartis Gene Therapies Inc. (AveXis), Sanofi, UCB, and Roche; has received research support from the European Commission, INSERM-Health Ministry, and the Association Française des Myopathies (AFM); is the scientific coordinator of the Registre SMA FRANCE for the French neuromuscular network (FILNEMUS) (filnemus.fr); and is coordinator of the Garches-Necker-Creteil Health Care Provider for the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD). E. Mercuri has participated in SMA clinical trials sponsored by Roche, Novartis, Biogen Epirium, and Scholar Rock and has received speaker and/or consulting fees from Biogen, Novartis Gene Therapies Inc. (AveXis), and Roche, and has received grants to the institution from Biogen, Roche, and Novartis Gene Therapies Inc. Y.-H. Chien has served in an advisory role for Sanofi and Amicus Therapeutics, has received consulting fees from Sanofi, BioMarin, Amicus Therapeutics, Biogen, Novartis, PTC Therapeutics, DHKS, Pfizer, Regeneron, Recordati, and Takeda, and has received research funding from Sanofi and Biogen. V. Straub has served on advisory boards for Astellas Gene Therapies, Biogen, Edgewise Therapeutics, Ipsen, Kate Therapeutics, ML Bio Solutions, Novartis Gene Therapies, PepGen, Roche, Sanofi, Sarepta Therapeutics, Vertex Pharmaceuticals, and Wave Therapeutics; has received speaking fees/honoraria from Novartis Gene Therapies Inc., Pfizer, Roche, Sanofi, and Sarepta Therapeutics; and has received grants for clinical research from Sarepta Therapeutics and Sanofi. B.T. Darras has served as an ad hoc scientific advisory board member for AveXis/Novartis Gene Therapies, Biogen, Sarepta, Scholar Rock, and Roche/Genentech; as Steering Committee Chair/member for Roche FIREFISH and MANATEE studies; and as a DSMB member for Amicus Inc., argenX BV, and Lexeo Therapeutics (he has no financial interests in these companies); has received research support from the NIH/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the Spinal Muscular Atrophy Foundation, CureSMA, and Working on Walking Fund; and has received grants from Ionis Pharmaceuticals Inc. for the ENDEAR, CHERISH, CS1/CS2/CS12 studies, from Biogen for CS11, and from Sarepta Pharmaceuticals, Novartis (AveXis), PTC Therapeutics, Roche, Scholar Rock, and Fibrogen. J. Seibert, R. Bernardo Escudero, and I. Alecu are employees of Novartis and own stock/other equities. F. Freischläger is a paid statistical consultant under contract with Novartis Gene Therapies Inc. F. Muntoni reports personal compensation for serving as a consultant for Sarepta, on a scientific advisory/data safety monitoring board for Pfizer, as a clinical expert with the UK NICE Committee, and on speakers' bureaus for Novartis, Biogen, Pfizer, Roche, and Sarepta; and has received research support from the European Commission, the Medical Research Council, Biogen, Roche, Novartis, Muscular Dystrophy UK, MDA USA, Sarepta, and the Association Française des Myopathies. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. CONSORT Diagram of Trial Profile
Figure 2
Figure 2. ALT and AST Elevations During the SMART Study (Primary Endpoint)
(A) Multiple of ULN in ALT per participant over time (log scale). (B) Multiple of ULN in AST per participant over time (log scale). (C) Maximum postbaseline multiple of ULN in ALT by body weight at screening per participant. Gray lines indicate 1× ULN and 3× ULN. ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.
Figure 3
Figure 3. HFMSE Total Score Over Time (Secondary Endpoint)
(A) Total score changes over time and (B) change from baseline. Green lines, ≥8.5–13 kg; blue lines, >13–17 kg; red lines, >17–21 kg. Gray line indicates maximum score for HFMSE of 66 points. HFMSE = Hammersmith Functional Motor Scale–Expanded.
Figure 4
Figure 4. RULM Total Score Over Time (Secondary Endpoint)
(A) Total score changes over time and (B) change from baseline. Green lines, ≥8.5–13 kg; blue lines, >13–17 kg; red lines, >17–21 kg. Gray line indicates maximum score for RULM of 37 points. RULM = Revised Upper Limb Module.
See this image and copyright information in PMC

References

    1. Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20(4):284-293. doi: 10.1016/S1474-4422(21)00001-6 - DOI - PubMed
    1. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713-1722. doi: 10.1056/NEJMoa1706198 - DOI - PubMed
    1. Al-Zaidy SA, Kolb SJ, Lowes L, et al. AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort. J Neuromuscul Dis. 2019;6(3):307-317. doi: 10.3233/JND-190403 - DOI - PubMed
    1. Mercuri E, Muntoni F, Baranello G, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20(10):832-841. doi: 10.1016/S1474-4422(21)00251-9 - DOI - PubMed
    1. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nat Med. 2022;28(7):1381-1389. doi: 10.1038/s41591-022-01866-4 - DOI - PMC - PubMed

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