Objective:

Evaluate long-term safety and efficacy of onasemnogene abeparvovec in patients with spinal muscular atrophy type 1 (SMA1; biallelic SMN1 mutations/deletions and two SMN2 copies) who enrolled into the LT-001 study (NCT03421977).

Background:

In the Phase I trial (START; NCT02122952), SMA1 patients who received the proposed therapeutic dose of onasemnogene abeparvovec (n=12) demonstrated substantially improved outcomes versus natural history.

Design/Methods:

The primary objective was to evaluate long-term safety assessed by medical history/record review, physical examination, laboratory evaluation, and pulmonary assessments. Efficacy was evaluated by assessing developmental milestones.

Results:

As of May 23, 2022, 13 patients (low-dose, n=3; therapeutic dose, n=10) were enrolled and followed for a mean of 95.1 (low-dose) and 83.5 (therapeutic dose) months. The oldest patient was 8.5 years of age (8.0 years post-dosing). In five patients, respiratory events and dehydration were reported. No deaths, serious treatment-emergent adverse events related to treatment, or any late-onset treatment events were reported. All patients who received the therapeutic dose survived, were free of permanent ventilation (mean [range] age at last data cut, 7.1 [6.6–7.9] years), and have maintained achieved developmental milestones. Three have achieved a new developmental milestone of standing with assistance (two without add-on therapy and one with nusinersen add-on). One patient in the low-dose cohort also achieved new developmental milestones (head control, sitting with support). Only three of 10 patients receiving the therapeutic dose required respiratory support, a decrease from five of 10 in December 2019. Four of 10 patients did not require any non-mechanical feeding support; all 10 fed orally. Four of 10 patients receiving the therapeutic dose never received add-on therapy. Of the six remaining, two started risdiplam, three switched from nusinersen to risdiplam, and one discontinued nusinersen.

Conclusions:

Onasemnogene abeparvovec continues to demonstrate a favorable risk-benefit profile and durable efficacy up to 8 years post-dosing.