Motor function improved in younger patients, stabilized in older ones

Oral risdiplam showed benefit on motor scores among people with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA), the phase III SUNFISH part 2 study found.

“Overall, SUNFISH part 2 showed a significant difference in motor function in a population aged 2–25 years treated with risdiplam relative to placebo, with improvement observed in younger individuals and stabilization in older individuals,” wrote Eugenio Mercuri, MD, of Catholic University in Rome, Italy, and co-authors in Lancet Neurology.

“SUNFISH part 2 is, to our knowledge, the first randomized, double-blind, placebo-controlled clinical study of an oral treatment for spinal muscular atrophy to report such a result in a patient population with a broad range of ages and functional status, including individuals with advanced disease and comorbidities,” the researchers noted.

“SUNFISH part 2 is ongoing and will provide additional evidence regarding the long-term safety and efficacy of risdiplam,” they added.

Risdiplam is an oral small molecule approved in 2020 for use in type 2 and type 3 SMA. It modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN, the protein deficient in SMA.

Mercuri and colleagues studied 180 patients with 5q autosomal recessive type 2 or type 3 SMA who were non-ambulant (unable to walk unassisted for ≥ 10 m) but could sit independently. Participants were randomized between October 2017 and September 2018 to either daily weight-based oral risdiplam (n=120) or placebo (n=60), with a primary endpoint of change from baseline in the Motor Function Measure total score at 12 months (range 0-96; higher scores imply better motor function). Participants who received at least one dose of either risdiplam or placebo were included in the safety analysis.

SMA type was type 2 in 70% of the risdiplam and 73% of the placebo group. Adult patients (age 17-25) made up 12-13% of the study cohort overall. Mean age at symptoms onset was 14.1 months in the risdiplam group and 18.5 months in the placebo group. Scoliosis was present in 63% of the risdiplam and 73% of the placebo group.

For the primary outcome efficacy analysis, the least squares mean change from baseline to 12 months on the Motor Function Measure was 1.36 (95% CI 0.61-2.11) in the risdiplam group versus –0.19 (95% CI –1.22 to 0.84) in the placebo group, with a treatment difference of 1.55 (95% CI 0.30-2.81, P=0.016).

“Our exploratory subgroup analyses showed that motor function was generally improved in younger individuals and stabilized in older individuals, which requires confirmation in further studies,” Mercuri and colleagues wrote.

Adverse events that were reported more frequently in patients who received risdiplam compared with placebo included pyrexia (21% versus 17%), diarrhea (17% versus 8%), rash (17% versus 2%), mouth and aphthous ulcers (7% versus 0%), urinary tract infection (7% versus 0%), and arthralgias (5% versus 0%).

Serious adverse events occurred with similar frequency (20% for risdiplam versus 18% for placebo), though pneumonia was more frequent for risdiplam (8% versus 2%). The finding for pneumonia was due to “an unexpectedly low incidence of serious pneumonia in the placebo group, which did not increase after these patients switched to risdiplam in the open-label period, indicating that occurrences of serious pneumonia were due to underlying disease rather than a risdiplam-induced adverse event,” Mercuri and co-authors noted.

“Risdiplam treatment was not associated with any drug related safety findings leading to withdrawal,” they added. “Intensive ophthalmological monitoring did not show any clinically significant findings. Non-clinical findings of bone marrow depression and epithelial effects associated with risdiplam were not observed.”

“These promising results, along with the robust safety profile and the absence of retinal toxicity (which was a limitation in preclinical studies) provide a new opportunity in the care pathway for patients with spinal muscular atrophy,” observed Valeria Sansone, MD, of the University of Milan in Italy, in an accompanying editorial.

“However, these results require in-depth consideration before they can be used to guide treatment choices,” Sansone wrote. “Improvement in motor function was seen in the younger age groups, especially in children 2-5 years of age, but not in the small number of people 18-25 years of age in the risdiplam group (n=14).”

“Considering the decline in motor function that is usually observed around adolescence in patients with spinal muscular atrophy type 2 or type 3, the improvements in motor function in the older children included in this study (i.e., aged 6–11 years and 12–17 years), although smaller than those in the younger children (i.e., aged 2–5 years), are perhaps more clinically meaningful when considering the usual course of the disease,” she pointed out.

“Risdiplam clearly represents a potential new treatment opportunity for young children with spinal muscular atrophy,” Sansone added. “The data in adults, although encouraging, need to be confirmed in larger cohorts and over longer periods than in this study. Clinicians should discuss risdiplam with patients and families as a new treatment opportunity with a good tolerability and safety profile, but emphasize that unanswered questions exist for use in adults with spinal muscular atrophy when considering efficacy and long-term expectations.”

Several SMA treatments have been approved in recent years. Nusinersen, the first approved drug for SMA, is an anti-sense oligonucleotide that promotes the inclusion of exon 7 in the SMN2 transcript so that it can be translated into functional, full-length SMN protein, which promotes motor neuron survival. Onasemnogene abeparvovec is given as a single intravenous infusion in a lifetime and acts on SMN1.

Safety profiles and easier routes of administration for risdiplam (taken orally once daily, acting on SMN2) and onasemnogene abeparvovec (given as a single intravenous infusion in a lifetime, acting on SMN1) are especially appealing, Sansone noted.

Limitations of the present study include stratification only by age in the analysis. “The absence of other stratification led to an imbalance in baseline characteristics: Baseline motor scale total scores were higher in the placebo group than in the risdiplam group, whereas the risdiplam group had a lower proportion of patients with four SMN2 copies and severe scoliosis,” Mercuri and colleagues wrote. In addition, more patients in the placebo group were receiving baseline pulmonary care.

  1. Oral risdiplam showed benefit on motor scores among people with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA), the phase III SUNFISH part 2 study found.

  2. Risdiplam showed a significant difference in motor function in a population 2–25 years old relative to placebo, with improvement seen in younger individuals and stabilization in older individuals.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was funded by F Hoffmann-La Roche.

Mercuri has received fees for serving on scientific advisory boards; speaker fees from F Hoffmann-La Roche, Biogen, AveXis/Novartis, Scholar Rock, and Cytokinetics; and grants from Biogen during the conduct of the study.

Sansone served on advisory boards for Roche, Biogen, and Novartis, but did not take part in any of the risdiplam trials.

Cat ID: 130

Topic ID: 82,130,730,130,192,925