The use of once-daily risdiplamin in type 2 and non-ambulant type 3 spinal muscular atrophy (SMA) patients leads to a significant improvement in motor function when compared to placebo. This is according to the latest data from the SUNFISH clinical trial, the findings of which were published by Eugenio Mercuri (Catholic University, Rome, Italy) et al in The Lancet: Neurology.
An exploratory subgroup analyses also indicated that motor function was generally improved in younger patients and stabilised in older patients, although this “requires confirmation in further studies”, note the researchers.
The phase three, double-blind, randomised, placebo-controlled trial is designed to investigate the safety and efficacy of the drug risdiplam in these patients. Risdiplam modifies pre-mRNA splicing of the Survival of Motor Neuron 2 (SMN2) gene in order to increase production of functional SMN.
Patients aged between two and 25 years with confirmed 5q autosomal recessive type 2 or type 3 SMA were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least two in entry item A of the Revised Upper Limb Module assessment.
Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5mg (for individuals weighing ≥20kg) or 0.25 mg/kg (for individuals weighing <20kg), or daily oral placebo—which was matched to risdiplam in both colour and taste.
The primary endpoint was change from baseline in 32-item Motor Function Measure total score at 12 months. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the pre-specified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis.
Between October 2017 and September 2018, a total of 180 patients were randomly assigned to receive either risdiplam (n=120) or placebo (n=60). For analysis of the primary endpoint, 115 patients from the risdiplam group and 59 patients from the placebo group were included.
Findings showed that at 12 months, the least squares mean change from baseline in 32-item Motor Function Measure was 1.36 (95% confidence interval [CI] 0.61 to 2.11) in the risdiplam group and –0.19 (–1.22 to 0.84) in the placebo group, with a treatment difference of 1.55 (0.30 to 2.81; p=0·016) in favour of risdiplam.
In addition, 120 patients who received risdiplam and 60 who received placebo were included in the safety analyses. Adverse events that were reported in at least 5% more patients who received risdiplam than those who received placebo were pyrexia (25 [21%] of 120 patients who received risdiplam vs. 10 [17%] of 60 patients who received placebo), diarrhoea (20 [17%] vs. five [8%]), rash (20 [17%] vs. one [2%]), mouth and aphthous ulcers (eight [7%] vs. 0), urinary tract infection (eight [7%] vs. 0), and arthralgias (six [5%] vs. 0).
The incidence of serious adverse events was similar between treatment groups (24 [20%] of 120 patients in the risdiplam group; 11 [18%] of 60 patients in the placebo group), with the exception of pneumonia (nine [8%] in the risdiplam group; one [2%] in the placebo group).
SUNFISH part 2 is currently ongoing and is expected to provide additional evidence regarding the long-term safety and efficacy of risdiplam.