The main clinical-effectiveness evidence for risdiplam came from 2 clinical studies SUNFISH and FIREFISH. SUNFISH, which is a randomised, double-blind, multicentre (excluding UK sites), phase 2, placebo-controlled trial for the first 12 months of treatment. After 12 months, people in the placebo arm could switch to the risdiplam arm. It included 180 people aged 2 to 25 years with types 2 or 3 SMA. Part 2 of SUNFISH excluded patients who had any previous treatment, and also those with type 3 SMA who were able to walk. FIREFISH, which is a single-arm study of 41 patients aged 1 month to 7 months with type 1 SMA and two SMN2 copies. It excluded patients who had previous treatment and those having chronic ventilation. There are also 2 ongoing studies. RAINBOWFISH is a phase 2, single-arm study of babies 6 weeks or younger who had been genetically diagnosed with SMA but did not have symptoms. JEWELFISH is an open-label, single-arm study for SMA types 1, 2 and 3 in people of 6 months to 60 years who had previously enrolled in the MOONFISH study or who had previously had nusinersen, onasemnogene abeparvovec or olesoxime. The 12 month results from SUNFISH, adjusted for multiple testing, showed risdiplam improved motor function scores (measured by the MFM 32) in patients with type 2 or 3 SMA, compared with placebo. The results from FIREFISH were compared against pre-defined performance criteria based on natural history data for patients with type 1 SMA. The 12 month results suggest that more patients who had risdiplam (29%) were able to sit without support for at least 5 seconds than would be expected for patients with type 1 SMA (5%). After consultation, the company submitted 24 month follow-up data from both SUNFISH and FIREFISH. The committee noted that this longer-term data generally showed improvements or stable disease but recognised that the data was not comparative. The committee agreed that the clinical evidence showed improved motor function with risdiplam but noted that overall-survival data was only available for type 1 SMA. After consultation the company reported interim results from JEWELFISH for 174 patients, of whom 76 had previously had nusinersen. The 12 month interim data showed low rates of discontinuation of risdiplam for patients who previously had nusinersen, with rapid, sustained increase in SMN protein levels and stable motor function. The committee concluded that risdiplam may be effective after previous treatments such as nusinersen and agreed to take this into account when making its recommendations. After consultation, the company also reported interim results from RAINBOWFISH for 5 patients with pre-symptomatic SMA who had risdiplam for at least 12 months. This 12 month interim data showed 80% of patients reached the maximum score on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Infant Neurological Examination Module 2 (HINE 2) scales, which measure motor function. The committee was encouraged by early results for the pre-symptomatic SMA population and agreed to take this into account when making its recommendations. After consultation, the company's base-case incremental cost-effectiveness ratios (ICERs) for risdiplam compared with best supportive care were below £30,000 per quality-adjusted life year (QALY) gained for SMA types 2 and 3 but were above £50,000 per QALY gained for SMA type 1 (the company considers the exact ICERs to be confidential so they cannot be reported here). The committee noted that, using its preferred assumptions, the most plausible ICER for type 1 SMA is likely to be much higher than £50,000 per QALY gained. For types 2 and 3, the ICER was much higher than £30,000 per QALY gained. The committee also recalled that after consultation the company's model structure led to implausible predictions for the best supportive care arm and did not allow clinically appropriate stopping rules based on consecutive worsening to be implemented. Also, it affected how caregiver utility values were included. The committee concluded that the ICERs for risdiplam are likely to be above £50,000 per QALY gained but that changes to the model structure are needed to robustly capture all the costs and benefits associated with risdiplam. The committee acknowledged that the cost-effectiveness estimates were above the range NICE normally considers cost effective. So risdiplam cannot be recommended for routine use in the NHS. But because of the unmet need for effective treatments for SMA, risdiplam is recommended as an option for treating pre-symptomatic SMA and SMA types 1, 2 and 3, through a managed access agreement while more data is collected to address the uncertainties in the evidence. This is only if the company provides risdiplam with the confidential commercial terms agreed with NHS England. It reiterated that an updated model structure should be provided when the guidance is reviewed as part of the agreed managed access agreement.