Improved Motor Function With Risdiplam in Infants With Type 1 SMA

Field: Medicine (Health Sciences)

Source: Darras BT, Masson R, Mazurkiewicz-Bełdzińska M, et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021;385(5):427–435; doi:10.1056/NEJMoa2102047Investigators from multiple institutions conducted a prospective open-label study on the effectiveness of risdiplam for treatment of infants with type 1 spinal muscular atrophy (SMA). Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional survival of motor neuron protein in blood. Study participants were infants 1–7 months old with type 1 SMA who were enrolled at 14 centers in 10 countries. Eligibility criteria included a genetic diagnosis of 5q SMA, onset of symptoms between 28 days and 3 months of age, and 2 copies of SMN2. Study children ≥5 months old received oral risdiplam, 0.2 mg/kg daily; younger patients were begun at a dose of 0.04 or 0.08 mg/kg/day and adjusted upward.The primary outcome was the ability to sit without support for ≥5 seconds after 12 months of treatment. Secondary endpoints included a score of ≥40 on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), ≥4-point improvement in CHOP-INTEND scores from baseline, a motor milestone response, defined as more improvement than worsening with respect to motor milestones, as measured with the Hammersmith Infant Neurologic Examination (HINE-2), and no permanent ventilator support after 12 months of treatment. For the primary outcome of sitting without support, the investigators chose a performance criterion of 5% based on clinical experience. For the secondary outcomes, the performance criteria were based on the upper limits of 90% confidence intervals for each outcome based on data from a historical control group of 16 children with type 1 SMA and 24 with type 1B SMA. Data on serious adverse events also were collected.A total of 41 infants with a median age of 5.3 months at baseline were enrolled; 95% of study children were able to swallow, and 71% were not receiving pulmonary care. After 12 months of treatment, 29% of patients were able to sit without support for ≥5 seconds (P <0.001 compared to performance criterion). Among the secondary outcomes, 56% of participants had a CHOP-INTEND score ≥40 (performance criterion, 17%; P <0.001), 90% had an increase of ≥4 points in their score since baseline (performance criterion, 17%; P <0.001), 78% had a HINE-2 motor milestone response (performance criterion, 12%; P <0.001), and 85% were not on permanent ventilation (performance criterion, 42%; P <0.001). There were 48 serious adverse events, including pneumonia (13 infants), bronchiolitis, hypotonia, and respiratory failure in 2 infants each; 3 children died.The authors conclude that use of risdiplam was associated with a higher percentage of infants with type 1 SMA meeting motor milestones compared to historic controls.Dr Candee has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.SMA is an autosomal recessive neurodegenerative disorder resulting from lack of motor neuron preservation in the setting of a SMN1 gene mutation and ensuing SMN protein deficiency.1 Infants with type 1 SMA exhibit early hypotonia, weakness, and dysphagia, typically within the first few months of life. They usually do not achieve independent sitting and, without feeding and ventilatory support, do not survive beyond 2 years of age.1Risdiplam is the latest of 3 available treatment options for mitigating the anticipated progression of neuromuscular decline seen in infants, children, and adults with SMA.2 While its predecessors are given intrathecally at predetermined intervals or intravenously once, risdiplam is the only daily, orally administered option.2The current open-label study confirms the medication’s safety and efficacy in achieving more advanced motor developmental milestones, most notably sitting, when compared to historical controls. The achievement of significantly higher percentages across not only the primary endpoint, but across all of the 4 well-chosen secondary endpoints (including survival without permanent ventilation and event-free survival) after 12 months of therapy, emphasizes treatment superiority.The most common adverse events were those typically seen in infants with the progressive neuromuscular weakness that occurs in the setting of SMA. Although retinal toxicity was noted in monkey trials using risdiplam, the absence of any ophthalmologic adverse events in this study is consistent with larger-scale trials and validates that ophthalmologic monitoring is not indicated.3An inherent study weakness, albeit an unavoidable one when treatment is highly likely to be beneficial to the participant, is the use of historical controls (versus concurrently randomized participants). Longer term head-to-head trials of risdiplam versus 1 or more of the other available SMA treatment options are ongoing.Risdiplam is a safe and effective therapeutic option for infants with type 1 SMA. Treatment results in significantly improved motor development when compared to historical controls.Anyone who has provided health care to an infant with type 1 SMA and shared the parents’ despair over the bleak prognosis is heartened by the results of this study. The gains from treatment were relatively modest, but, hopefully, this is just the beginning of new and effective therapies for this terrible disease.