How is spinal muscle atrophy (SMA) treated?

Updated: May 04, 2020
  • Author: Ashish S Ranade, MBBS, MS, MRCS; Chief Editor: Jeffrey A Goldstein, MD  more...
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Curative therapy for SMA has been elusive. The survival rate is poor among young patients. Interest has arisen in the use of inhibitors of gamma-aminobutyric acid (GABA) synthesis, with promising results. Developments in the use of antisense-based therapy have been described. [34, 35, 36, 37, 38]

In December 2016, the US Food and Drug Administration (FDA) approved nusinersen, the first drug approved for treatment of children (including newborns) and adults with SMA. Nusinersen is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Through in-vitro assays and studies in transgenic animal models of SMA, nusinersen was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein. [39]

FDA approval was based on the ENDEAR trial, a phase 3 randomized, double-blind, sham-controlled study (N = 121) in patients with infantile-onset (most likely to develop type 1) SMA. [40]  At a planned interim analysis, the rate of achieving a motor milestone response was higher in infants treated with nusinersen (40%) than in those not so treated (0%), as measured by the Hammersmith Infant Neurological Examination (HINE). Additionally, a smaller percentage of patients died in the nusinersen group (23%) than in the untreated group (43%).

Interim findings from CHERISH, another phase 3 trial, involved 126 nonambulatory patients with later-onset SMA (consistent with type 2), including those with the onset of signs and symptoms at 6 months or later and an age of 2-12 years at screening. [41]  Prespecified interim analysis demonstrated a difference of 5.9 points at 15 months between the treatment arm (n = 84) and the sham-controlled arm (n = 42), as measured by the Hammersmith Functional Motor Scale Expanded (HFMSE). From baseline to 15 months of treatment, patients in the nusinersen group achieved a mean improvement of 4.0 points in the HFMSE, whereas those in the control group showed a mean decline of 1.9 points.

A 2020 Cochrane review reported, on the basis of moderate-certainty evidence, that nusinersen improves motor function in type II SMA. [42]  Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid, and the combination of valproic acid and acetyl-L-carnitine probably have no clinically important effect on motor function in SMA types II or III (or both), on the basis of low-certainty evidence. Olesoxime and somatropin may also have little to no clinically important effect, but the evidence was of very low certainty.

A 2019 Cochrane review reported, on the basis of very limited evidence, that intrathecal nusinersen probably prolongs ventilation-free and overall survival in infants with type I SMA. [43]  It is also probable that a greater proportion of infants treated with nusinersen versus a sham procedure achieve motor milestones and can be classed as responders to treatment on clinical assessments (HINE-2 and Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND]). The proportion of children experiencing adverse events and serious adverse events is no higher with nusinersen than with a sham procedure (moderate-certainty evidence). It is uncertain whether riluzole has any effect in type I SMA.

A multicenter observational study reported that there is some evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q SMA, with clinically meaningful improvements noted in motor function. [44]

The American Academy of Neurology (AAN) has stated that evidence of efficacy is currently greatest for treatment of infantile- and childhood-onset SMA in the early and middle symptomatic phases. Whereas approved indications for nusinersen use in North America and Europe are broad, payer coverage for populations outside those in clinical trials remain variable. Evidence, availability, cost, and patient preferences all influence decision-making regarding nusinersen use. [45]


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