BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder causing progressive muscle atrophy and motor decline. Intrathecal onasemnogene abeparvovec (OAV101 IT) is a one‑time gene‑replacement therapy approved by the Food and Drug Administration undergoing Joint Clinical Assessment (JCA), necessitating comparative effectiveness data. As no head‑to‑head trials compare OAV101 IT with disease‑modifying therapies (DMTs), indirect treatment comparisons (ITCs) are needed for JCA.
METHODS: SMA trials in DMT‑naïve and DMT‑experienced patients were identified via systematic review. Pivotal studies were assessed for heterogeneity in design and outcomes. DMT‑naïve ITCs used anchored matching‑adjusted indirect comparisons (MAICs) and multilevel network meta-regression (ML-NMR) leveraging individual patient data (IPD) from STEER (NCT05089656; OAV101 IT) and summary data from SUNFISH Part 2 (NCT02908685; risdiplam) and CHERISH (NCT02292537; nusinersen). DMT‑experienced unanchored MAICs used IPD from STRENGTH (NCT05386680; OAV101 IT) and summary data from the SAPPHIRE placebo arm (NCT05156320; prior and concurrent nusinersen/risdiplam). Relative efficacy was assessed using change from baseline (CFB) in Hammersmith Functional Motor Scale–Expanded (HFMSE) and Revised Upper Limb Module (RULM).
RESULTS: In DMT‑naïve MAICs versus risdiplam, OAV101 IT had comparable improvements in HFMSE CFB (mean difference [MD]:1.93; 95% confidence interval [CI]: -0.25,4.10), and RULM CFB (MD:-1.46; 95% CI: -3.38,0.46). Versus nusinersen, MAICs indicated comparable improvements in HFMSE CFB (MD:-0.13; 95% CI: -2.93,2.66) and RULM CFB (MD:-1.15; 95% CI: -3.32,1.01). ML-NMR results showed numerical favourability for OAV101 IT versus risdiplam in RULM CFB (MD:0.04; 95% credible interval:-2.47,2.52). DMT‑experienced MAICs showed OAV101 IT and nusinersen/risdiplam had comparable improvements in HFMSE CFB (MD:2.16; 95% CI: -0.06,4.38) and RULM CFB (MD:-0.26; 95% CI: -1.64,1.12).
CONCLUSIONS: These ITC results showed consistent efficacy improvements for OAV101 IT across key motor outcomes versus nursinersen and risdiplam. These results support the potential of OAV101 IT as a gene replacement therapy option for patients with SMA.