Risdiplam in Type 1 Spinal Muscular Atrophy

N Engl J Med. 2021 Mar 11;384(10):915-923. doi: 10.1056/NEJMoa2009965. Epub 2021 Feb 24.

Abstract

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein.

Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds.

Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study.

Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Azo Compounds / administration & dosage*
  • Azo Compounds / adverse effects
  • Azo Compounds / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Infant
  • Male
  • Neuromuscular Agents / administration & dosage*
  • Neuromuscular Agents / adverse effects
  • Neuromuscular Agents / pharmacokinetics
  • Progression-Free Survival
  • Pyrimidines / administration & dosage*
  • Pyrimidines / adverse effects
  • Pyrimidines / pharmacokinetics
  • RNA Splicing
  • Respiratory Insufficiency / etiology
  • Respiratory Tract Infections / etiology
  • Spinal Muscular Atrophies of Childhood / complications
  • Spinal Muscular Atrophies of Childhood / drug therapy*
  • Spinal Muscular Atrophies of Childhood / mortality
  • Survival of Motor Neuron 1 Protein / blood*
  • Survival of Motor Neuron 1 Protein / genetics

Substances

  • Azo Compounds
  • Neuromuscular Agents
  • Pyrimidines
  • Survival of Motor Neuron 1 Protein
  • Risdiplam

Associated data

  • ClinicalTrials.gov/NCT02913482