Intrathecal Onasemnogene Abeparvovec Demonstrates Favorable Safety and Motor Function Stabilization in Treatment-Experienced Patients With SMA

Jennifer Kwon, MD, MPH

(Credit: University of Wisconsin)

Recently presented findings from the phase 3b STRENGTH study (NCT05386680) suggested that intrathecal onasemnogene abeparvovec (Novartis), known as OAV101IT, was safe and resulted in stabilized motor function in patients with spinal muscular atrophy (SMA) previously treated with nusinersen (Spinraza; Biogen) or risdiplam (Evrysdi; Genentech). Presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19 in Dallas, Texas, these findings support the continued exploration of OAV101IT for SMA management, particularly in patients transitioning from other disease-modifying therapies.¹

The single-arm, open-label study enrolled 27 patients aged 2 to at least 18 years who had discontinued prior SMA treatments. Over the 52-week study period, OAV101IT’s safety and tolerability remained consistent with expectations, with no adverse events (AEs) leading to death or study discontinuation. Secondary efficacy measures, including the Hammersmith Functional Motor Scale–Expanded (HFMSE), Revised Upper Limb Module (RULM), and caregiver-reported outcomes, indicated that most participants maintained or improved their motor milestones.

Conducted by lead author Jennifer Kwon, MD MPH, professor of child neurology at the University of Wisconsin School of Medicine and Public Health, the study cohort had a mean age of 7.4 years at the time of OAV101IT infusion, with prior treatment durations averaging 3.0 years for risdiplam and 4.3 years for nusinersen. All participants experienced at least 1 treatment-emergent adverse event (TEAE), with the most common being nasopharyngitis, pyrexia, and vomiting. Serious TEAEs were largely infection-related, but none resulted in study discontinuation.

Efficacy assessments over the 52-week period showed that motor function remained stable across HFMSE and RULM scores, with no major declines observed. Additionally, caregiver-reported experiences suggested a maintenance of functional abilities. The majority of patients either preserved their motor milestones or achieved new ones, reinforcing the potential of OAV101IT as a treatment option for this patient population.

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Complementing the STRENGTH study findings, previous results from the phase 1 STRONG trial (NCT03381729) provided additional evidence that OAV101IT may offer motor function benefits in patients with SMA who are ineligible for weight-based intravenous dosing. The STRONG study evaluated the safety, tolerability, and efficacy of a single intrathecal dose of OAV101IT in sitting, patients with nonambulatory SMA who had 3 copies of SMN2.²

Published in Journal of Neuromuscular Diseases, patients were stratified by age (6 to less than 24 months and 24 to less than 60 months) and received low, medium, or high doses. Despite that safety outcomes were consistent with prior research, efficacy findings varied by age group, with younger patients demonstrating limited independent standing ability and older patients experiencing significant HFMSE score improvements.

A total of 32 patients completed the study, with 25 receiving the medium dose. All participants experienced at least one TEAE, though only 1 serious TEAE —transaminase elevations—was reported. Investigators noted no deaths occurred during the study.

In the younger cohort treated with the medium dose, 1 of 13 patients (7.7%) achieved independent standing for at least three seconds. However, in the older group receiving the same dose, HFMSE scores at 12 months significantly improved compared with historical SMA controls (P <.01), suggesting potential motor function benefits beyond what is typically observed in untreated patients.

Together, the findings from STRONG and STRENGTH reinforce the potential of intrathecal OAV101IT in SMA management, particularly for patients who may not qualify for intravenous administration because of weight restrictions. Ongoing research may be crucial in determining optimal dosing strategies and long-term functional outcomes.

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REFERENCES
1. Kwon J, Munell F, Le Goff L, et al. Intrathecal Onasemnogene Abeparvovec for Treatment-Experienced Patients with Spinal Muscular Atrophy: Phase 3b, Open-Label STRENGTH Study. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. Abstract LB449.
2. Finkel RS, Darras BT, Mendell JR, et al. Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG). J Neuromuscul Dis. 2023;10(3):389-404. doi:10.3233/JND-221560