Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is primarily caused by reduced levels of survival of motor neuron (SMN) protein due to homozygous deletions or loss-of-function mutations in the SMN1 gene.
The deficiency in SMN protein results in the manifestation of SMA symptoms. A homologous gene, SMN2, attempts to compensate by producing low levels of functional SMN protein through alternative splicing of its pre-mRNA, excluding exon 7 from the majority of its transcripts.
However, SMN2 is unable to fully compensate for the loss of SMN1. Patients with type 2 SMA typically exhibit symptoms between 6 and 18 months of age. While they may achieve the ability to sit independently, occasional standing or taking a few steps with support, independent walking remains unattainable.
On the other hand, those with type 3 SMA experience symptom onset after 18 months of age and may achieve the ability to walk independently, though this ability may be lost over time. The type 2 and 3 SMA patient population spans a broad range, including children, teenagers, and adults with diverse functional statuses, contractures, and scoliosis.
The SUNFISH (NCT02908685) study, an ongoing Phase 2/3 trial, focuses on the evaluation of risdiplam’s efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics in a diverse patient population aged 2–25 years with type 2 or type 3 SMA. Unlike some studies that exclude patients with more advanced disease hallmarks, such as severe scoliosis, contractures, and impaired bulbar function, SUNFISH aims to include a broad spectrum of patients with varying baseline motor function.
The study consists of two parts, with Part 1 being a dose-finding study in patients with type 2 or type 3 SMA to determine the appropriate dose for Part 2. In the initial phase, risdiplam treatment resulted in a sustained increase in SMN protein in the blood, and exploratory efficacy analyses suggested improvements or stabilization in motor function.
Part 2, the confirmatory phase, investigated the efficacy of risdiplam in individuals with type 2 or non-ambulant type 3 SMA. The results from SUNFISH Part 2 revealed a statistically significant difference in motor function improvement between patients treated with risdiplam and those on placebo at the 12-month mark. This report delves into the longer-term exploratory efficacy and safety results after 24 months of risdiplam treatment in SUNFISH Part 2.
The study also explores the efficacy and safety of 1 year of risdiplam treatment in patients who initially received placebo up to month 12. The trial, conducted in accordance with Good Clinical Practice guidelines and the World Medical Association Declaration of Helsinki, involved patients aged 2–25 years with genetically confirmed 5q-autosomal recessive SMA, excluding those who had received specific SMN2-targeting treatments.
During the 24-month exploratory period, the study assessed various outcomes, including motor function measured by the Motor Function Measure-32 (MFM32), Hammersmith Functional Motor Scale—Expanded (HFMSE), and Revised Upper Limb Module (RULM). Respiratory function was evaluated through multiple parameters, and patient- and caregiver-reported independence was measured using the SMA Independence Scale-Upper Limb Module (SMAIS-ULM). Safety and tolerability were continuously monitored throughout the study.
The results showcased that risdiplam treatment in a clinically diverse patient population with later-onset SMA led to sustained and clinically relevant gains in motor function. These gains were demonstrated by improvements in MFM32 total scores, with 32% of patients showing improvement and 58% maintaining stabilization at the 24-month mark.
Additional measures, such as RULM and caregiver-reported SMAIS-ULM, confirmed these positive outcomes. Notably, the benefits observed after 12 months of risdiplam treatment were either maintained or further improved after 24 months, emphasizing the long-term efficacy of risdiplam in treating SMA.
The safety profile after 24 months remained consistent with the previously observed profile after 12 months of treatment, reinforcing risdiplam’s positive benefit–risk profile for the treatment of children, teenagers, and adults with later-onset SMA. Furthermore, the study’s open-label extension phase, which spans three years of further treatment, aims to provide additional insights into the long-term effects and safety of risdiplam.
The SUNFISH Part 2 study, evaluating risdiplam in a diverse SMA patient population, demonstrates promising and sustained improvements in motor function over 24 months. These findings contribute valuable information to the growing body of research on SMA treatments and underscore the potential of risdiplam in improving the lives of individuals with SMA.
Journal Reference
Oskoui M, Day JW, et al., SUNFISH Working Group. Two-year efficacy and safety of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy (SMA). J Neurol. 2023 May;270(5):2531-2546. doi: 10.1007/s00415-023-11560-1.
