Phase 3b STRENGTH Trial Provides Greater Support for Intrathecal SMA Gene Therapy

Weeks after the FDA approved Novartis’ Itvisma, an intrathecal one-time gene transfer therapy for spinal muscular atrophy (SMA), investigators published data from the phase 3b STRENGTH trial (NCT05386680), a 52-week study that was part of the drug’s expanded new drug application (NDA) submission.¹

Published in Nature, STRENGTH was a single-arm, open-label, multicenter trial that comprised 27 patients with SMA aged 2 to 18 years who discontinued nusinersen (Spinraza; Biogen) or risdiplam (Evrysdi; Genentech) treatment before starting intrathecal onasemnogene abeparvovec, later marketed as Itvisma. The trial, primarily focused on safety and tolerability, was the first such study testing this newer intrathecal formulation in patients with SMA who left other FDA-approved SMA treatments.

Coming into the study, most participants (85.2%; n = 23) had 3 copies of the SMN2 gene, while a relatively small amount (14.8%; n = 4) had just 2 copies instead. Prior to initiating gene therapy, the mean duration of treatment was 4.3 (range, 1.86-6.18) years for nusinersen and 3.0 (range, 0.39-6.28) years for risdiplam. Patients were a mean age of 7.4 (range, 2.4-17.7) years at dosing, with a mean baseline Hammersmith Functional Motor Scale-Expanded (HFMSE) of 24.3 (range, 2.0-46.5).

Led by Jennifer Kwon, MD, a professor in the department of neurology at the University of Wisconsin School of Medicine and Public Health, the study found that Itvisma’s safety profile was consistent with findings in treatment-naïve patients. Adverse events (AEs), which occurred in all participants, mostly comprised nasopharyngitis (55.6%; n = 15), pyrexia (51.9%; n = 14), and vomiting (48.1%; n = 13). A closer look revealed that 13 patients had AEs related to the study treatment, most frequently vomiting (22.2%; n = 6), headache (14.8%; n = 4), and pyrexia (11.1%; n = 3).

Itvisma, approved in late November, came years after the FDA’s original approval of Zolgensma, the intravenous infusion formulation of the drug, in 2019. The latest approval was mainly based on data from the phase 3 STEER study (NCT05089656), as well as supportive findings from STRENGTH.²

READ MORE: FDA Approves Inebilizumab for AChR- and MuSK-Positive Generalized Myasthenia Gravis

AEs of special interest (AESI) reported were in the categories of transient thrombocytopenia (n = 8, 29.6%), hepatotoxicity (n = 4, 14.8%) and signs and symptoms that may be suggestive of dorsal root ganglia (DRG) toxicity (n = 2, 7.4%). Of note, the most frequently reported AEs in the transient thrombocytopenia category were epistaxis (11.1%; n = 3) and contusion (7.4%; n = 2), although these events were non-serious, mild or moderate in intensity and resolved.

At week 52, patients showed modest improvements in motor function, with a mean change of 0.17 points in HFMSE scores and a least squares (LS) mean increase of 1.05 points (95% CI, −0.21 to 2.32; Cohen’s d, 0.36). Upper limb function, measured by the revised upper limb module, also showed small gains, with a mean change of 0.29 points and an LS mean increase of 0.59 points (95% CI, −0.56 to 1.73). Caregiver experience scores remained stable ovet this time period, with mean changes of 1.43 points in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) scores.

At the week 52 assessment, most participants maintained the same motor milestones observed at baseline, while a smaller number achieved new gains. Overall, 17 of 24 participants (70.8%) demonstrated milestones consistent with baseline, and 3 participants (12.5%) achieved new milestones, including walking independently (n = 2) and standing or walking with assistance (n = 1). Four participants did not demonstrate a milestone at week 52 that had been observed at baseline, including sitting without support (n = 2), hands-and-knees crawling (n = 1), and standing or walking with assistance (n = 1); however, one of these cases was attributed to recovery from a broken arm, and the remaining milestones were observed at other study visits during the trial.

In a post hoc analysis, the effect of Itvisma on motor function was observed across all age groups, with HFMSE score changes of 0.33 in participants whose symptoms began at 6 months of age or younger and 0.10 in those with symptom onset after 6 months. In a small group of patients who initiated add-on therapy after gene therapy administration (n = 4), the LSM change in HFMSE was 1.02 at week 52 compared with 1.05 in the full analysis set.

REFERENCES
1. Kwon JM, Munell F, Goff LL, et al. Intrathecal onasemnogene abeparvovec for treatment-experienced patients with spinal muscular atrophy: a phase 3b, open-label trial. Nature. Published online December 8, 2025. doi:10.1038/s41591-025-04119-2
2. Novartis receives FDA approval for Itvisma®, the only gene replacement therapy for children two years and older, teens, and adults with spinal muscular atrophy (SMA). News release. Novartis. November 24, 2025. Accessed December 17, 2025. https://www.novartis.com/news/media-releases/novartis-receives-fda-approval-itvisma-only-gene-replacement-therapy-children-two-years-and-older-teens-and-adults-spinal-muscular-atrophy-sma