(317) Use of European rare disease registries to describe the natural history and disease progression of Spinal Muscular Atrophy (SMA) over time

Background: Spinal muscular atrophy (SMA), a rare neurodegenerative disorder with an estimated incidence of 1 in 6,000 to 10,000 live births, is the leading genetic cause of mortality in infants and children. Since the approval of new disease modifying treatments (DMTs; Spinraza in 2017, Zolgensma in 2020 and Evrysdi in 2021), studies have reported modified disease trajectories compared to the known SMA natural history.

Objectives: To describe the natural history of SMA and its progression during the use of DMTs in real-world settings, using multiple SMA European registries.

Methods: This was a non-interventional, retrospective cohort study of patients with SMA (EUPAS 50476) using 6 registries from 9 European countries (3 clinician-based registries: Belgium, Czech Republic & Slovakia, Sweden and 3 patient-based registries: Germany & Austria, Spain, UK & Ireland) federated in the TREAT-NMD network comprising data from April 2008 to May 2023. The study population included 2,188l SMA patients with genetically confirmed 5q SMA. Patients were classified as ‘treated’ if exposed to any DMT at any point in their recorded data, otherwise as ‘never treated’. To describe SMA natural history and disease progression after DMT, the following outcomes were described: motor function, skeletal deformities, respiratory function, nutritional function, any cause of hospitalisation and death.

Results: Overall, more patients had SMA type 2 (n=914, 41.8%) than type 3 (n=779, 35.6%) and type 1 (n=432, 19.7%). 847 patients (38.7%) were classified as never treated, and 1,321 (60.3%) were treated with Spinraza (n=1003, 75,9%), Evrysdi (n=403, 30.5%) or Zolgensma (n=101, 7.6%).
Functional status and motor milestones were not or rarely reported in never treated patients. Among treated patients, 101 SMA type 1 patients (36.6%) achieved “sitter” status and 33 (12%) achieved “walker” status. 75 patients (27.2%) achieved “sitting without support” and 51 (18.5%) achieved “rolling onto their side” as their best motor milestone. In SMA 2 treated patients, 329 (60.9%) achieved “sitter” status and 133 (24.6%) achieved “walker” status. In SMA 3 treated patients, 418 (87.8%) achieved “walker” status and 302 (63.4%) were able to “climb stairs” as their best motor milestone.

Conclusions: Results from this large, and first of its kind, pan-European study were generally consistent with existing studies and indicate clinically relevant gains in motor function in SMA types 1, 2 and 3 patients treated with DMTs. Areas of improvement for registry data quality have been identified to reduce data missingness and increase standardization. This would enhance their ability for regulatory decision making.