Updates on three treatments of spinal muscular atrophy

Apart from already available nusinersen, follow-up data of two experimental treatments of spinal muscular atrophy (SMA) were presented: risdiplam and zolgensma (AVXS-101).

Motor function and event-free survival continued to improve in infants who initiated nusinersen in the ENDEAR study; and motor function stabilised or improved in those who initiated nusinersen in the SHINE study [1]. After nearly 3 years of treatment, the average Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) score increased by 16.8 points in participants who received nusinersen in ENDEAR and SHINE (n=65), and by 8.2 points in those who had received sham-control in ENDEAR and nusinersen in SHINE (n=24). Patients also continued to achieve motor milestones during SHINE. Median survival without need for permanent ventilation was 75.0 weeks.

Risdiplam was well-tolerated and lead to sustained increases in SMN protein in patients with Type 2 and 3 SMA. This was concluded from an update on the SUNFISH part 1 dose-finding study, and from exploratory efficacy data [2]. This study is not designed and powered to detect efficacy, but it was noted that patients on risdiplam experienced improvement over 12 months on the Motor Function Measure (MFM) compared to natural history data. In FIREFISH part 1 study, risdiplam also improved motor function in babies with Type 1 SMA [3]. Of 14 babies, 13 (93%) had ≥4-point improvement in CHOP INTEND total score from baseline at 8 months (median change of 16 points). From baseline to 8 months the number of babies meeting the following Hammersmith Infant Neurological Examination (HINE)-2 motor milestones increased:

• full head control (6/14: 43%);
• horizontal or upward kicking (7/14: 50%);
• rolling to side or from prone to supine (4/14: 29%);
• sitting with or without support (6/14: 43%).

Patients treated with a one-time dose of nasemnogene abeparvovec (AVXS-101, now known as zolgensma) in SMA Type 1 continued to gain strength, develop, and achieve new milestones, demonstrating a long-term, durable response [4]. Among 12 patients receiving the proposed therapeutic dose of this gene-replacement therapy in the START study, 11 patients could hold their head erect for ≥3 seconds and sit without support for ≥5 seconds; 10 patients could sit without support for ≥10 seconds, 9 could sit without support for ≥30 seconds, 2 were able to stand alone and walk with assistance, and 2 could walk alone. The mean time since treatment was 3.7 years.

Results from the STR1VE study were also updated [5]. In this study, participants with SMA Type 1 with one or two copies of the SMN2 backup gene and bi-allelic SMN1 gene deletion or point mutations received zolgensma gene therapy at <6 months of age. CHOP INTEND scores increased by an average of 6.9 points 1 month after gene transfer, 11.7 points 3 months after gene transfer, and 14.3 points 5 months after gene transfer. Of 22 patients, 21 achieved a CHOP INTEND score of ≥40. Patients continued to gain motor milestones, including 1 patient who could crawl, 1 patient who could pull to a stand, and 11 patients who could sit without support for at least 30 seconds.

1. Finkel RS, et al. AAN 2019, S25.004.
2. Mercuri E, et al. AAN 2019, S25.007.
3. Baranello G, et al. AAN 2019, S25.003.
4. Mendell JR, et al. AAN 2019, S25.006.
5. Day JW, et al. AAN 2019, P1.6-058.



Posted on 30 July, 201923 April, 2024