Risdiplam Shows Promise for Infants With Type 1 Spinal Muscular Atrophy

Investigators sought to examine the safety, pharmacokinetics, and pharmacodynamics of risdiplam in infants with type 1 spinal muscular atrophy.

Infants born with type 1 spinal muscular atrophy had increased expression of functional survival of motor neuron (SMN) protein after risdiplam therapy, according to study findings published in The New England Journal of Medicine.

This was a 2 part, phase 2-3, open label study in which researchers recruited infants (N=21) aged 1 to 7 months with symptomatic, 5q-autosomal recessive spinal muscular atrophy with 2 copies of SMN2 (ClinicalTrials.gov Identifier: NCT02913482). Patients received once daily oral or feeding tube-administered 0.00106 mg/kg risdiplam.

Once daily treatment doses were escalated to 0.0106, 0.04, 0.08, 0.2, and 0.25 mg/kg over time in such a way that 2 randomized cohorts were created. One was a low-dose (700 ng•h per milliliter; n=4) and the other was a high-dose (2000 ng•h per milliliter; n=17) cohort.

Study researchers assessed children assessed for circulating functional SMN protein, ophthalmologic effects, and safety through February 2019 after a median of 14.8 months.

Among the patients, 71% were girls and 24% were on respiratory support. The median Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score was 24 (range, 10-34).

The final dosage for the low- and high-dose groups were 0.08 and 0.2 mg/kg, respectively. Among the low-dose group, 3 of the infants began to receive the high dose at age 12 months and the other infant was transferred to palliative care at day 19 due to disease progression.

A total of 24 serious adverse events included pneumonia (n=3), respiratory infection (n=2), viral respiratory infection (n=2), acute respiratory failure (n=2), and respiratory distress (n=2). During the study, 3 infants died, and another died shortly after the study’s conclusion.

Ophthalmologic assessments indicated that the infants had age-related retinal immaturity, but this resolved with time.

Among the low- and high-dose groups, functional SMN circulating protein was 1.31 (range, 0.58-4.82) and 2.54 (range, 1.10-6.40) ng/ml at baseline. At 4 weeks, SMN protein increased by 4.5 (range, 1.2-5.4) and 2.1 (range, 0.9-6.5) times baseline levels and at 12 months, 3.0 (range, 1.1-3.6) and 1.9 (range, 0.6-7.8) among low- and high-dose cohort participants, respectively.

By the study’s twelfth month, 7 infants in the high-dose group were able to sit on their own for 5 or more seconds, 9 could maintain head control at all times, and 1 could bear weight when standing. No low-dose recipients achieved these outcomes. The study researchers observed CHOP-INTEND scores of 40 or greater among 11 infants. No infants in either cohort lost their ability to swallow, and 86% of all infants in the study could feed orally.

This study may have been limited by the choice to recruit older infants than those recruited for other trials of type 1 spinal muscular atrophy therapies.

This trial found risdiplam therapy increased circulating functional SMN protein, indicating a shift toward full-length SMN2 expression with a relatively good safety profile. The second part of this trial will assess clinical endpoints.

Disclosure: This clinical trial was supported by F. Hoffmann-La Roche. Please see the original reference for a full list of authors’ disclosures.


Baranello G, Darras BT, Day JW, et al; FIREFISH Working Group. Risdiplam in type 1 spinal muscular atrophy. N Engl J Med. 2021;384(10):915-923. doi:10.1056/NEJMoa2009965