Risdiplam Leads to Greater Production of Vital SMN, SMA Study Says

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The results also showed that the infants achieved certain milestones in motor development, pulmonary function, and survival.

Detailed results from a 2-part, phase 2/3, open-label study of risdiplam in infants 1 to 7 months of age with type 1 spinal muscular atrophy (SMA) found that treatment led to a greater expression of increased levels of survival motor neuron (SMN) protein, which is critical for maintaining nerve and muscle function.

Risdiplam, approved by the FDA in August 2020, is designed to treat SMA by increasing and sustaining the production of the SMN protein. It is sold under the name Evrysdi by Genentech, part of study funder Hoffmann-La Roche. Results were published this week in The New England Journal of Medicine.

The trial, FIREFISH, evaluated the drug’s safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics in infants with type 1 SMA, with the first part being a dose-escalation study and to determine the dose for part 2. Data from the trial were used to support the drug’s approval last year.

Type 1 SMA is the most severe form of this rare, progressive, recessive neuromuscular disease, which is marked by an inability to sit, weakness, respiratory failure, and reduced life expectancy. SMA is caused by deletions or loss-of-function mutations in the SMN1 gene, which results in reduced levels of functional SMN protein.

A total of 21 infants were enrolled, with 4 infants in the low-dose cohort and 17 in the high-dose cohort.

The median duration of treatment was 14.8 months at the time of analysis. The median age at enrollment was 6.7 months and symptom onset between the ages of 28 days and 3 months. The authors said the patients in this study were older and had a longer duration of disease than infants in other type 1 SMA studies.

In the low-dose grouping:

  • The final dose was 0.08 mg/kg/day at month 12
  • Baseline median SMN protein concentrations in the blood were 1.31 ng/mL, increasing to 3.05 ng/mL, or 3.0 times the baseline value

In the high-dose group:

  • The final dose was 0.2 mg/kg/day at month 12
  • Baseline median SMN protein concentrations in blood were 2.54 ng/mL, increasing to 5.66 ng/mL, or 1.9 times the baseline value

The higher dose was selected for part 2 of the study, which is continuing.

In addition, the published results included exploratory efficacy data analyzed post hoc. Although the authors cautioned that the results can only be compared with what is known about the disease, and can only be qualitatively compared with populations from earlier studies, the results showed that the infants achieved certain milestones in motor development, pulmonary function, and survival.

In the high-dose group, 7 infants (41%) were able to sit without support for at least 5 seconds, while 9 infants (53%) achieved upright head control and 11 (6%) were able to stand.

The authors said the ability to sit without support is not expected in type 1 SMA.

Infants in both the low- and high-dose groups also had improved pulmonary function, with 86% (18/21) able to feed orally, either exclusively or in combination with a feeding tube. In addition, 90% (19/21) of infants were alive without permanent ventilation

Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure; at the time of publication, 4 infants had died of respiratory complications.


Baranello G, Darras BT, Deconinck N, et al. Risdiplam in type 1 spinal muscular atrophy. N Engl J Med. Published online February 24, 2021. doi:10.1056/NEJMoa2009965