SMA is a genetic, progressive neuromuscular disease that affects a broad age range and disease severity is highly variable. SMA is caused by deletions and/or mutations of the survival of motor neuron 1 (SMN1) gene and is characterized by motor neuron loss, leading to muscle weakness and atrophy. Typically, a greater number of copies of SMN2, a paralogous gene, correlates with less severe disease. Risdiplam (EVRYSDI®), an orally administered SMN2 pre-mRNA splicing modifier, is approved by the FDA for the treatment of pediatric and adult patients with SMA.
This Phase 4, multicenter, prospective, long-term follow-up study (LTFU; NCT05232929) was designed to investigate the long-term safety and effectiveness of risdiplam in pediatric and adult patients with all SMA types.
Patients with a genetically confirmed diagnosis of 5q–autosomal recessive SMA who received risdiplam after FDA approval based on the prescriber’s clinical judgment, per the risdiplam US prescribing information, are eligible to enroll in the study. Exclusion criteria include hypersensitivity to risdiplam or participation in a registrational trial of risdiplam (FIREFISH [NCT02913482], SUNFISH [NCT02908685], JEWELFISH [NCT03032172] or RAINBOWFISH [NCT03779334]).
Enrollment of ≈500 patients is planned. Patients will be followed for up to 5 years from enrollment or until withdrawal of consent, loss to follow-up or death. Primary outcomes are the rate of AEs, AEs of special interest and serious AEs. Secondary outcomes include the percentage of participants considered improved on the CGI-C Scale. Exploratory outcomes include the change in motor function measured by scales such as the CHOP-INTEND, RULM, 6-Minute Walk Test, HFMSE and HINE-2 and attainment of the six WHO gross motor milestones. Other exploratory outcomes include changes in respiratory function as assessed by spirometry, time to permanent ventilation, changes in bulbar function (e.g. feeding and swallowing status), number and length of hospitalizations, survival in infants aged <2 years with Type 1 SMA over time and patient- and caregiver-reported outcomes using the SMAIS–ULM and the PEDI-CAT. Conclusions The LTFU study is actively recruiting participants at multiple sites across the US. The study is expected to provide data on the real-world use, safety and effectiveness of risdiplam in various SMA patient populations.