Early Diagnosis and Speed to Effect in Spinal Muscular Atrophy Type 1 (SMA-1)

Objectives: Spinal muscular atrophy type 1SMA-1 is a rapidly progressing disease resulting in death or need for permanent ventilation by 2 years of age; early intervention with disease modifying treatment is critical. In the pivotal phase 3 nusinersen study (ENDEAR; NCT02193074), approximately 10% of patients died/required permanent ventilation within 2 months after initiation of therapy (time required for four loading doses); 39% of patients died/required permanent ventilation by 6 months from dosing. This may reflect a nonimmediate therapeutic impact related to the loading dose schedule. This study explored rapidity of therapeutic effect of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy (CL-101 phase 1 study; NCT02122952), as measured by early changes in children’s hospital of Philadelphia infant test of neuromuscular disorders (CHOP-INTEND) score, compared with the response to nusinersen in ENDEAR (≤ 5-point increase at 2 months postdosing).

Methods: Symptomatic SMA-1 infants were treated with a one-time AVXS-101 intravenous injection (cohort 2; n = 12; 24 months follow-up). Outcomes of interest were event-free survival (EFS; CL-101: death or ≥ 16 hours ventilation/day for > 2 weeks; ENDEAR: death, tracheostomy, or ≥ 16 hours ventilation/day for > 21 days) and motor function improvements from baseline using CHOP-INTEND. All 12 AVXS-101-treated patients showed EFS at study end, versus 49/80 (61%) nusinersen patients. At 1, 3, and roughly 10 months post-AVXS-101 treatment, CHOP-INTEND increased 9.8, 15.4, and 27 points, respectively. At 2 and roughly 10 months postnusinersen initiation, CHOP-INTEND increased ≤ 5 and approximately 10 points, respectively. By 6 months, 11/12 (92%) AVXS-101-treated patients achieved CHOP-INTEND scores ≥ 40 versus 30/78 (38.5%) nusinersen-treated patients at last interim data-cut (day 183–394).

Conclusion: AVXS-101 appears to improve survival and induce more rapid motor function improvements compared with nusinersen. Advances in understanding SMA underscores the need for early diagnosis and treatments with a near-immediate onset of action to maximize clinical improvements.