By Dr Isabella Colonna
For February we have selected Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomized, placebo-controlled trial. Lancet Neurol 2022; Jan 1 2022. doi: 10.1016/S1474-4422(21)00367-7
Our research paper of February is a phase 3, randomised, double-blind, placebo-controlled study, aiming to investigate the safety and the efficacy of risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SMA). Risdiplam is an oral drug which modifies survival motor neuron (SMN)2 pre-mRNA splicing in order to increase the production of functional SMN protein.
This paper reports the results of the second part of SUNFISH, a two-part study investigating risdiplam in patients aged 2-25 years with confirmed 5q autosomal type 2 and non-ambulant type 3 SMA. This trial was conducted at 42 hospitals in 14 different countries across Europe, North and South America, and Asia.
Study participants were considered eligible if they were non-ambulant, could sit independently, and presented a score of at least 2 in entry item A of the Revised Upper Limb Module (RULM) scale, which assesses the upper limb motor function. After considering inclusion and exclusion criteria, all individuals were randomly assigned (2:1) to receive either risdiplam or placebo and were stratified for ages (2–5 years, 6–11 years, 12–17 years, and 18–25 years). The dose of Risdiplam was 5mg daily for individuals weighing more than 20kg or 0.25mg/kg daily for individuals weighing less than 20kg, as determined in the first part of SUNFISH. In this study population, 128 patients were affected by type 2 SMA and 52 individuals were diagnosed with non-ambulant type 3 SMA with two, three or four SMN2 copies. After randomisation, 115 and 59 patients received risdiplam and placebo, respectively.
The authors found that, after a follow-up time of 12 months, study participants who were treated with risdiplam presented a higher score on the 32-item Motor Function Measure (MFM32) scale than the placebo group, reflecting an improvement in motor function ability and resulting in a statistically significant treatment difference of 1.55 (95% CI 0·30 – 2·81; p=0.016). A greater number of individuals who improved in MFM32 total score of ≥3 points was observed among the patients treated with risdiplam than in the placebo group (unadjusted and adjusted p=0.047). This improvement in MFM32 was more pronounced in the youngest patients (2-5 years), while no MFM32 change was seen in the oldest group (18-25 years). On the contrary, stabilisation or improvement (change of ≥0 points) in MFM32 total score was reported across all age groups, indicating a benefit of risdiplam also in more advanced stages of the disease. A significant treatment difference was reported in the change from baseline in RULM total score between the two groups (unadjusted p=0·0028, adjusted p=0·047).
Adverse events were more frequently observed in the patients treated with risdiplam, while the incidence of serious of adverse events was similar between the two groups, with the exception of pneumonia which occurred in nine and one patients in the risdiplam and placebo group, respectively. However, no adverse events led to a modification of risdiplam dose and resolved with ongoing treatment. In conclusion, the authors of this study found a significant treatment effect of risdiplam, in comparison to placebo, on motor function in a SMA patient population with a wide range of ages and functional status, showing an improvement in younger patients and stabilisation in older individuals.
