Risdiplam shows promise for infants with type 1 spinal muscular atrophy

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

This was a two-part, open-label Phase 2-3 study in which researchers recruited infants (N = 21) 1 to 7 months of age with symptomatic, 5q-autosomal recessive spinal muscular atrophy with 2 copies of SMN2 ( Identifier : NCT02913482). Patients received Risdiplam 0.00106 mg / kg administered orally or by gavage once daily.

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

The study’s researchers rated children who were assessed for circulating functional SMN protein, ophthalmic effects, and safety after a median of 14.8 months through February 2019.

Among the patients, 71% were girls and 24% received breathing assistance. The mean Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP) INTEND was 24 (range, 10-34).

The final dose for the low and high dose groups was 0.08 and 0.2 mg / kg, respectively. In the low dose group, 3 of the infants received the high dose at 12 months of age and the other child was transferred to palliative care on 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 dyspnoea (n = 2). 3 infants died during the study and another died shortly after the study was completed.

Ophthalmic examinations showed that the infants had age-related retinal immaturity, but this improved over time.

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

By the twelfth month of the study, 7 infants in the high-dose group could sit alone for 5 or more seconds, 9 could maintain head control at all times, and 1 could carry weight while standing. No low-dose recipients achieved these results. The study researchers observed CHOP-INTEND scores of 40 or greater in 11 infants. No infant in any of the cohorts lost their ability to swallow, and 86% of all infants in the study were able to eat orally.

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

This study found that risdiplam therapy increased circulating functional SMN protein, suggesting a shift towards full-length SMN2 expression with a relatively good safety profile. In the second part of this study, clinical endpoints will be assessed.

Disclosure: This clinical study was supported by F. Hoffmann-La Roche. See the original reference for a full list of what the authors said.


Baranello G., Darras BT, Day JW, et al .; FIREFISH working group. Risdiplam for type 1 muscular atrophy of the spine. N Engl J Med. 2021; 384 (10): 915- 923. doi: 10.1056 / NEJMoa2009965

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