Real-world multidisciplinary outcomes of onasemnogene abeparvovec monotherapy in patients with spinal muscular atrophy type 1: experience of the French cohort in the first three years of treatment

Abstract

Background: Spinal muscular atrophy type 1 (SMA1) is the most severe and early form of SMA, a genetic disease with motor neuron degeneration. Onasemnogene abeparvovec gene transfer therapy (GT) has changed the natural history of SMA1, but real-world data are scarce.

Methods: A French national expert committee identified 95 newly diagnosed treatment-naive SMA1 patients between June 2019 and June 2022. We prospectively report on children treated with GT as the first and only therapy who had more than one-year of follow-up.

Results: Forty-six SMA1 patients received GT. Twelve patients received other treatments. Patients with respiratory insufficiency were oriented toward palliative care after discussion with families. Twenty-nine of the treated patients with more than 12 months of follow-up were included in the follow-up analysis. Among them, 17 had 24 months of follow-up. The mean age at treatment was 7.5 (2.1-12.5) months. Twenty-two patients had two SMN2 copies, and seven had three copies. One infant died in the month following GT due to severe thrombotic microangiopathy, and another died due to respiratory distress. Among the 17 patients with 24 months of follow-up, 90% required spinal bracing (15/17), three patients required nocturnal noninvasive ventilation, and two needed gastrostomy. Concerning motor milestones at the 24-month follow-up, all patients held their head, 15/17 sat for 30 s unassisted, and 12/17 stood with aid. Motor scores (CHOPINTEND and HINE-2) and thoracic circumference significantly improved in all patients.

Conclusions: Our study shows favorable motor outcomes and preserved respiratory and feeding functions in treatment-naive SMA1 infants treated by GT as the first and only therapy before respiratory and bulbar dysfunctions occurred. Nevertheless, almost all patients developed spinal deformities.

Keywords: Gene transfer therapy; Real-world outcome; Spinal muscular atrophy.

Fig. 1

Flow chart detailing SMA patients diagnosed between June 2019 and June 2022 who were eligible for gene transfer therapy. Non-SMA1 patients were excluded from this study, and all SMA1 patients were evaluated by discussion with the FILNEMUS national expert committee. The different treatment options for SMA1 patients discussed by the expert committee are shown, and SMA1 patients with more than 12 months of follow-up were included in the follow-up analysis

Fig. 2

CHOPINTEND scores (left diagram), HINE-2 scores (middle) and TC/HC ratio (right) as a function of age for the 27 SMA patients (2 deceased patients excluded). TC: thoracic circumference, HC: head circumference. Red lines represent SMA patients with two copies of SMN2, and blue lines represent SMA patients with three copies of SMN2. For comparative purposes, the CHOPINTEND score, HINE-2 score and TC/HC ratio of the two presymptomatic patients with more than 12 months of follow-up in June 2022 are shown as black lines in the figure

Fig. 3

Mean CHOPINTEND scores (left diagram), HINE-2 scores (middle) and TC/HC ratio (right) A at M0, M6 and M12 for all patients with 12 months of follow-up [n = 27] (2 deceased patients excluded) and B at M0, M6, M12 and M24 for patients with 24 months of follow-up [n = 17] (2 deceased patients excluded). TC: thoracic circumference, HC: head circumference. * indicates a significant difference (i.e., p value < 0.05 paired Student’s t test) between baseline and M12 (top 3 diagrams) or between baseline and M24 (bottom 3 diagrams)