Indirect Comparison Suggests Intrathecal Onasemnogene Abeparvovec Comparable to Other SMA Therapies

New data from an indirect comparison analysis suggest that intrathecal onasemnogene abeparvovec (Itvisma; Novartis) demonstrated motor function improvements comparable with currently approved disease-modifying therapies for spinal muscular atrophy (SMA), including nusinersen (Spinraza; Biogen) and risdiplam (Evrysdi; Genentech).¹

Presented at the 2026 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 8-11 in Orlando, Florida, the data provided early comparative effectiveness insights for this recently approved gene therapy, which came to market last November.

Indirect Comparisons Across SMA Trials

The MDA analysis, led by Nick Riley, Director of International HEOR at Novartis, evaluated the relative effectiveness of onasemnogene abeparvovec, or OAV101 IT, using indirect treatment comparison (ITC) methods. Investigators conducted a systematic review of SMA trials and applied statistical approaches including matching-adjusted indirect comparisons (MAICs) and multilevel network meta-regression (ML-NMR).

Individual patient data from the STEER trial (NCT05089656) of intrathecal onasemnogene abeparvovec were compared with summary data from SUNFISH Part 2 (NCT02908685) evaluating risdiplam and CHERISH (NCT02292537) evaluating nusinersen. Additional analyses included patient-level data from the STRENGTH study (NCT05386680) alongside summary data from the placebo arm of SAPPHIRE (NCT05156320), which included patients previously treated with nusinersen or risdiplam.

Across analyses, investigators assessed change from baseline in two commonly used motor function measures: the Hammersmith Functional Motor Scale–Expanded (HFMSE) and the Revised Upper Limb Module (RULM).

Among treatment-naïve populations, MAIC analyses suggested similar motor function outcomes between OAV101 IT and risdiplam. The estimated mean difference for HFMSE change from baseline was 1.93 points (95% CI, −0.25 to 4.10), while the difference for RULM change was −1.46 points (95% CI, −3.38 to 0.46).

Comparisons with nusinersen also suggested comparable outcomes, with mean differences of −0.13 points (95% CI, −2.93 to 2.66) for HFMSE and −1.15 points (95% CI, −3.32 to 1.01) for RULM.

Results from multilevel network meta-regression showed numerical favorability for OAV101 IT versus risdiplam in RULM change, although the credible interval crossed zero (mean difference, 0.04; 95% credible interval, −2.47 to 2.52).

Among patients previously treated with other disease-modifying therapies, unanchored MAIC analyses suggested similar improvements between OAV101 IT and continued treatment with nusinersen or risdiplam. Estimated differences included 2.16 points (95% CI, −0.06 to 4.38) for HFMSE and −0.26 points (95% CI, −1.64 to 1.12) for RULM.

Context: Gene Replacement Therapy for SMA

Intrathecal onasemnogene abeparvovec is a gene replacement therapy designed to deliver a functional copy of the SMN1 gene using an adeno-associated virus 9 (AAV9) vector, enabling sustained SMN protein production. The therapy represents an intrathecal formulation of onasemnogene abeparvovec, the gene therapy originally approved in 2019 as an intravenous infusion for pediatric SMA.

In November 2025, the FDA approved the intrathecal formulation, marketed as Itvisma, making it the first intrathecally administered gene therapy for SMA and expanding gene therapy access to a broader patient population.²

The approval was primarily supported by results from the phase 3 STEER trial (NCT05089656), a 52-week randomized study of treatment-naïve patients with SMA type 2. In that trial, patients receiving intrathecal onasemnogene abeparvovec demonstrated a 2.39-point improvement in HFMSE compared with 0.51 points in the sham-treated group (P = .0074).³

Supportive findings also came from the phase 3b STRENGTH study (NCT05386680), which evaluated the therapy in patients previously treated with nusinersen or risdiplam. Over 52 weeks, patients demonstrated stabilization of motor function, with a least-squares mean HFMSE increase of 1.05 points.

Clinical Perspective

Although the MDA analyses suggest broadly comparable motor outcomes between OAV101 IT and existing SMA therapies, indirect comparisons rely on cross-trial adjustments and cannot fully replace randomized head-to-head studies.

Still, these findings may provide useful context for comparative effectiveness assessments as clinicians and policymakers evaluate how gene replacement therapy fits alongside antisense and small-molecule approaches in the treatment of SMA.

REFERENCES
1. Riley N, Ballarini N, Marx A, et al. LB: Indirect Treatment Comparisons of OAV101 IT vs Risdiplam and Nusinersen in SMA patients. Presented at: 2026 MDA Clinical & Scientific Conference; March 8-11; Orlando, FL. Abstract 499 LBM.
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 March 11, 2026. 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
3. New Novartis Phase III data demonstrate meaningful efficacy and safety results of intrathecal onasemnogene abeparvovec in broad patient population with SMA. News release. Novartis. March 19, 2025. Accessed March 11, 2026. https://www.novartis.com/news/media-releases/new-novartis-phase-iii-data-demonstrate-meaningful-efficacy-and-safety-results-intrathecal-onasemnogene-abeparvovec-broad-patient-population-sma