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.).