Among infants with type 1 spinal muscular atrophy (SMA), treatment with risdiplam was associated with improvements in motor function and meeting developmental motor milestones, according to study results published in The New England Journal of Medicine.
Children with SMA may not be able to sit without support, walk, or hold their heads up, possibly because of variations in their survival of motor neuron (SMN) genes SMN1 and SMN2, resulting in reduced production of the functional SMN protein. Risdiplam, an orally administered small-molecule that increases the expression of SMN2 messenger RNA and levels of SMN protein, was approved for the treatment of patients with SMA aged 2 months and older.
The objective of the current trial (FIREFISH; ClinicalTrials.gov Identifier: NCT02913482) was to determine the efficacy and safety of risdiplam in infants with type 1 SMA aged between 1 and 7 months at enrollment.
The open-label study included 41 infants (median age, 5.3 months; 22 girls) who received treatment at 14 centers in 10 countries. All participants had genetic and clinical diagnosis of type 1 SMA with 2 copies of SMN2.
The primary study outcome was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary endpoints were better motor function, defined as a score of 40 or higher on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), an increase of 4 or more points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by section 2 of the Hammersmith Infant Neurological Examination-2, and survival without permanent ventilation.
After 12 months of treatment with risdiplam, 12 of the 41 infants (29%) were able to sit without support for 5 or more seconds; this rate was significantly higher than the performance criterion rate of 5% from natural history data (P <.001).
Compared with those in the historical cohorts, infants who received treatment with risdiplam showed an improvement in motor function; 56% had a CHOP-INTEND score of 40 or greater, a significantly higher percentage than the performance criterion rate of 17% in the historical cohorts (P <.001). An increase of 4 or more points from baseline was also more common among patients who received risdiplam treatment compared with the historical cohorts (90% vs 17%, respectively; P <.001).
Motor milestone response, according to Hammersmith Infant Neurological Examination-2, was reported in 78% of patients who received risdiplam treatment for 12 months compared with 12% of those in the historical cohorts (P <.001).
Survival without permanent ventilation was also higher among patients who received risdiplam treatment compared with those in the historical cohorts (85% vs 42%, respectively; P <.001).
Overall, 254 adverse events were reported, 48 of which were serious. Serious adverse events included pneumonia (32%), bronchiolitis (5%), hypotonia (5%), and respiratory failure (5%). Fatal respiratory complications were reported in 3 infants.
The study had several potential limitations, including the small sample size of the historical cohorts and the use of historical control participants, which did not allow for comparisons to be made to study outcomes with the same confidence as comparisons in a randomized trial. Another study limitation was the open-label design.
“Oral risdiplam treatment over a period of 12 months in patients with type 1 SMA resulted in higher percentages of infants who met motor milestones, survived without need for ventilation, and showed improvements in motor function than the percentages in natural-history cohorts,” the researchers concluded.
Disclosure: This research was supported by F. Hoffmann-La Roche. Please see the original reference for a full list of disclosures.
Darras BT, Masson R, Mazurkiewicz-Bełdzińska M, et al, for the FIREFISH Working Group. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021;385(5):427-435. doi:10.1056/NEJMoa2102047