Risdiplam Effective in Sustained Motor Function Improvement in SMA Types 2 and 3

Maryam Oskoui, MD, MSc, FRCPC, FAAN

PTC Therapeutics has announced 2-year data from part 2 of the multicenter, randomized, placebo-controlled, double-blind SUNFISH trial (NCT02908685) evaluating risdiplam (Evrysdi) in children and adults with spinal muscular atrophy (SMA) type 2 or type 3.¹ 

Data from the trial suggest that patients treated with risdiplam experienced sustained or improved motor function after 24 months of treatment. Improvements were also reported in ability to function independently and complete daily tasks.

"We're encouraged by the long-term results from the SUNFISH trial, which reinforce the sustained clinical benefit that Evrysdi offers to a very broad population of patients with SMA, many of whom experience difficulty performing daily functions," said Stuart W. Peltz, PhD, chief executive officer, PTC Therapeutics, in a statement. "These data further support the strong US launch and the need for an at home oral treatment option for the SMA community."

The results were presented at the Muscular Dystrophy Association’s (MDA) Clinical and Scientific Conference, March 15-18, by Maryam Oskoui, MD, MSc, FRCPC, FAAN, attending staff pediatric neurologist and director, pediatric neurology, Montreal Children's Hospital.²

“Risdiplam is a centrally and peripherally distributed oral SMN2 pre-messenger RNA splicing modifier. It increases levels of functional SMN protein that are needed. It has been approved by the FDA under the trade name of Evrysdi in adults as well as children over 2 months of age with spinal muscular atrophy. I believe that lower age cutoff was chosen as the youngest patient enrolled in FIREFISH [NCT02913482],” Oskoui said in her presentation.

Part 1 of SUNFISH assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels in 51 patients with SMA types 2 or 3, ambulant and non-ambulant. Part 2 assessed the efficacy and safety of the Part 1-selected dose of risdiplam versus placebo in patients with SMA type 2 and non-ambulant SMA type 3.

Oskoui and colleagues analyzed data from a total of 180 patients, 120 treated with risdiplam and 60 treated with placebo for the first 12 months and then risdiplam until month 24. At Month 24, patients were offered the opportunity to enter the open-label extension phase. The mean age at symptom onset was 15.5 months (standard deviation [SD], 14.1). A total of 120 (66.7%) patients had scoliosis at baseline; 57 (31.7%) had severe scoliosis with greater than 40-degree curvature.

READ MORE: Risdiplam Efficacious in Infants with Spinal Muscular Atrophy Type 1

Oskoui and colleagues found a statistically significant difference in the change from baseline in 32-item Motor Function Measure (MFM32) total score at month 12 between patients treated with risdiplam and placebo. Difference from placebo on the Hammersmith Functional Motor Scale Expanded (HFMSE) became significant between 12 and 24 months, with patients reaching a clinically important difference of 2.15 points from baseline at 24 months.

The researchers also found improvement on the SMA Independence Scale (SMAIS) at 12 months compared to deterioration in the placebo group. This trend continued up to the 24-month mark. In patients first treated with placebo and then risdiplam after 12 months, motor scores were stable through the 12- to 24-month period and a slight improvement on SMAIS was seen.

The adverse event (AE) profile was favorable, with no treatment-related AEs leading to study withdrawal or treatment discontinuation. Common AEs included respiratory tract infection, nasopharyngitis, pyrexia, headache, diarrhea, vomiting, and cough. The incidence of AEs decreased during the 12- to 24-month period.

“Many items on the Hammersmith require patients to be on the floor on a mat. A great majority of these patients had significant hip contractures and even if there was an improvement in motor strength, they wouldn't have been able to overcome that to show an increase in the Hammersmith. The natural history as well of the Hammersmith in older patients generally shows a decline. It tends to be a little bit more stable over a 1-year period, with more decline over a 2-year period,” Oskoui said in response to a question concerning the jump in improvement on HFMSE scores from months 0-12 and months 12-24. 

“So, I was personally looking forward to see how these patients did over a 24-month period, knowing that in this population stability is a big difference compared to the natural history, and was curious if we could see increase in these skills,” she continued.

For more coverage of MDA 2021, click here.

REFERENCES

1. Results from the second year of Evrysdi™ (risdiplam) treatment demonstrated sustained improvement of motor function in a broad range of SMA patients. News release. PTC Therapeutics. Published online March 16, 2021. https://www.prnewswire.com/news-releases/results-from-the-second-year-of-evrysdi-risdiplam-treatment-demonstrated-sustained-improvement-of-motor-function-in-a-broad-range-of-sma-patients-301247815.html
2. Oskoui M, Day JW, Deconinck N, et al. SUNFISH part 2: 24-month efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA). Presented at MDA Clinical and Scientific Conference 2021; March 15-18. Poster 80