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. 2023;10(3):389-404.
doi: 10.3233/JND-221560.

Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG)

Richard S Finkel  1   2 , Basil T Darras  3 , Jerry R Mendell  4   5 , John W Day  6 , Nancy L Kuntz  7 , Anne M Connolly  4   5   8 , Craig M Zaidman  9 , Thomas O Crawford  10 , Russell J Butterfield  11 , Perry B Shieh  12 , Gihan Tennekoon  13 , John F Brandsema  13 , Susan T Iannaccone  14 , John Shoffner  15   16 , Sarah Kavanagh  15 , Thomas A Macek  15 , Sitra Tauscher-Wisniewski  15
Affiliations

Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG)

Richard S Finkel et al. J Neuromuscul Dis. 2023.

Abstract

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing.

Objective: STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients.

Methods: Sitting, nonambulatory SMA patients (biallelic SMN1 loss, three SMN2 copies, aged 6-<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6-<24 months) and older (24-<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls.

Results: Thirty-two patients were enrolled and completed the study (medium dose, n = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P < 0.01).

Conclusions: Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history.

Keywords: Adeno-associated virus; Hammersmith Functional Motor Scale Expanded; clinical trial; gene therapy; intrathecal administration; motor milestones; neurodegenerative disorders; onasemnogene abeparvovec; spinal muscular atrophy; vector genomes.

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Conflict of interest statement

RSF has received personal compensation for advisory board participation from Novartis Gene Therapies, Inc., Biogen, Roche, and Scholar Rock, and for consulting from Novartis; editorial fees from Elsevier for co-editing a neurology textbook; license fees from the Children’s Hospital of Philadelphia; and research funding from Novartis Gene Therapies, Inc., Biogen, Roche/Genentech, and Scholar Rock. BTD has served as an ad-hoc scientific advisory board member for Audentes, AveXis/Novartis Gene Therapies, Biogen, Pfizer, Sarepta, and Roche/Genentech; as a steering committee chair and member for the Roche FIREFISH and Biogen ASCEND studies, respectively, and data and safety monitoring board member for Amicus Inc.; he has no financial interests in these companies. He has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the Spinal Muscular Atrophy Foundation, Cure SMA, and Working on Walking Fund and has received grants from Ionis Pharmaceuticals, Inc., for the ENDEAR, CHERISH, CS2/CS12 studies; from Biogen for CS11; and from Novartis Gene Therapies, Inc., Sarepta Pharmaceuticals, Novartis, PTC Therapeutics, Roche, Scholar Rock, Fibrogen. He has also received royalties for books and online publications from Elsevier and UpToDate, Inc. JRM has received personal compensation for clinical trial consulting, serving on scientific advisory boards, and research support from Novartis Gene Therapies, Inc. JWD has received consulting fees from NGT, Biogen, Cytokinetics, Ionis Pharmaceuticals, Pfizer, Roche, and Sarepta Therapeutics; license fees or royalty payments from Athena Diagnostics; and research funding from NGT, Biogen, Cytokinetics, Roche, Sanofi-Genzyme, and Sarepta Therapeutics. NLK has served on medical advisory boards for Argentyx, Audentes, Biogen, Cytokinetics, Novartis Gene Therapies, and Sarepta Therapeutics. AMC has received personal fees for serving on advisory boards from Acceleron, Genentech/Roche, Novartis Gene Therapies, NS Pharma, and Sarepta Therapeutics; and has served on a data management safety board for Catabasis. CZ has received research support from Biogen. TOC has received personal compensation from Novartis Gene Therapies and Biogen. RJB has received funding via contracts for clinical trials from AveXis/Novartis, PTC Therapeutics, Sarepta Therapeutics, Pfizer, and Biogen; and served on scientific advisory boards for Sarepta Therapeutics, Biogen, AveXis/Novartis, and Pfizer. PBS has served as a consultant for Alexion, Biogen, Genentech, Novartis Gene Therapies, Inc., and Sarepta, and has served as a speaker for Alexion, Biogen, Genentech, Grifols, Novartis Gene Therapies, Inc., and PTC Therapeutics. GT has nothing to disclose. JFB has been a consultant for Audentes, AveXis/Novartis, Biogen, Cytokinetics, Genentech, Marathon, Momenta/Janssen, NS Pharma, Pfizer, PTC Therapeutics, Sarepta, Scholar Rock, and WaVe; a speaker for AveXis/Novartis and Biogen; a medical advisory council member for Cure SMA; and site investigator for clinical trials with Alexion, Astellas, AveXis/Novartis, Biogen, Catabasis, CSL Behring, Cytokinetics, Fibrogen, Genentech, Ionis, Lilly, Pfizer, PTC Therapeutics, Sarepta, Summit, and WaVe. STI has received personal compensation for service on advisory boards or consulting from Novartis Gene Therapies, Inc., Biogen, Roche-Genentech, and Sarepta; and research support from Novartis Gene Therapies, Inc., Biogen, Capricor, PTC, Scholar Rock, and Sarepta.; JS was an employee of Novartis Gene Therapies, and held stock/other equities, at the time of the study. SK is an employee of Novartis Gene Therapies, Inc., and receives consulting fees from Karuna Therapeutics, Nesos Inc., PharPoint Research, UCB Pharma, and Worldwide Clinical Trials. TAM and ST-W are employees of Novartis Gene Therapies, Inc., and hold stock/other equities. RSF, JRM, and JWD are Editorial Board Members of this journal, but were not involved in the peer-review process nor did they have access to any information regarding its peer review.

Figures

Fig. 1
Fig. 1
Patient disposition. AAV9, adeno-associated virus-9; vg, vector genomes. aOne of the six patients was rescreened under two different patient identifications and failed screening both times.
Fig. 2
Fig. 2
Change from baseline in HFMSE scores up to Month 12 for the older group (ITT population). All patients were treated with 1.2×1014 vg onasemnogene abeparvovec (medium dose) administered via intrathecal administration (N = 12). The PNCR cohort represents the primary PNCR population that contains a subset of 15 patients from the PNCR natural history control population who had SMA types 2 or 3, three copies of SMN2, symptom onset before 12 months of age, diagnosis before 24 months of age, were unable to stand or walk at enrollment (baseline visit), received an HFMSE evaluation between 24 and 60 months of age (“baseline”), and had a follow-up evaluation (HFMS of HFMSE performed between 12 and 14 months following that baseline evaluation. Older group, 24 to <60 months of age at dosing. HFMS, Hammersmith Functional Motor Scale; HFMSE, Hammersmith Functional Motor Scale-Expanded; ITT, intention-to-treat; PNCR, Pediatric Neuromuscular Clinical Research; vg, vector genomes.
See this image and copyright information in PMC

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