Improved Treatment Options for SMA Present New Opportunities, Challenges

There are now multiple therapeutic options available for spinal muscular atrophy (SMA), a disease once considered incurable; however, there remains a need for additional treatments and better ways to predict treatment response.

There are now multiple therapeutic options available for spinal muscular atrophy (SMA), a disease once considered incurable; however, there remains a need for additional treatments and better ways to predict treatment response, according to a review published in the Journal of Clinical Medicine.

SMA is a heterogeneous hereditary neuromuscular disease that is classified into subtypes by age on disease onset and the maximum motor milestones achieved. SMA I indicates the most severe subtype, and SMA IV is the mildest. The authors evaluated the available data of SMA therapies in preclinical development, in clinical trials, and in clinical practice:

  • SMA I presents before 6 months, patients never acquire a sitting position, and life expectancy due to respiratory failure is under 2 years without drug treatment.
  • SMA II presents between 6 and 18 months, patients can sit but not walk independently, and patients develop respiratory involvement that requires noninvasive ventilation, as well as orthopedic complications.
  • SMA III and SMA IV means later onset of disease and patients achieve independent walking and variable clinical course. Patients with SMA IV usually have no life-threatening events.

SMA occurs in 1 in 11,000 live births and 1 in 40 to 67 adults is a carrier of the autosomal recessive gene. “However, the epidemiologic burden of SMA differs among the subtypes,” the authors noted. SMA III has a lower incidence compared with the other subtypes, with one review finding:

  1. SMA I occurs in 5.83 per 100,000 live births, or 60% of all SMA cases
  2. SMA II occurs in 2.66 per 100,000 live births, or 27% of all SMA cases
  3. SMA III occurs in 1.20 per 100,000 live births, or 12% of all SMA cases

The first FDA-approved drug for SMA was nusinersen (Spinraza), an antisense oligonucleotide. The FDA approved the treatment in December 2016, and the European Medicines Agency (EMA) approved it in June 2017. Phase 1 and 2 trials in children with SMA II and SMA III showed promising results, which led to ENDEAR and CHERISH, 2 phase 3, randomized, double-blind, sham-procedure controlled trials. These trials showed improvements in motor function, a prolonged time to death, and a prolonged time to needing permanent ventilation. Both trials were ended early because of their positive results.

Recently, the FDA approved risdiplam (Evrysdi) on August 7. Shortly after, the EMA accepted the marketing authorization application on August 17. There were 2 key trials: FIREFISH evaluated risdiplam in 21 patients with infantile-onset SMA aged 1 to 7 months, and SUNFISH included 180 patients between the ages of 2 and 25 who had later-onset SMA. FIREFISH showed the majority (81%) of infants were alive and did not need permanent ventilation after 23 months. SUNFISH found statistically significant improvement in motor function among children and adults as measured by a change in baseline in the Motor Function Measure - 32 items score.

Both nusinersen and risdiplam utilize a splicing modification of SMN2. However, onasemnogene abeparvovec (Zolgensma) is a SMN1 gene replacement therapy. The FDA approved the treatment in certain patients with SMA who are younger than 2 years in May 2019. The European Commission granted conditional approval in May 2020 for certain patients with SMA.

STR1VE-US, an open-label, phase 3, single-arm, single-dose, multicenter trial, showed that 91% of the patients had event-free survival at 14 months and 59% had functional sitting for ≥30 seconds at 18 months. The START trial compared 12 patients with infantile-onset SMA who received a high dose with 3 who received a low dose. The patients in the high-dose cohort did not need permanent ventilation by 24 months. The patients in the low-dose cohort did not achieve the ability to sit up without support for ≥30 seconds, but 75% of the patients in the high-dose cohort achieved this milestone.

There are more, as of yet unapproved, potential treatments in the pipeline. Reldesemtiv is a selective small-molecule troponin activator in fast skeletal muscles that has a phase 1 study confirming its safety. A phase 2 double-blind, randomized, placebo-controlled trial also shows how the compound at a higher dose increases the 6-minute walk test from baseline.

SRK-015, a monoclonal antibody, has improved muscle force in SMA mice, and a phase 1 trial confirmed the safety and tolerability. It is currently in a phase 2 study evaluating the therapy in 58 patients between the ages of 2 and 21 years who have SMA II and SMA III.

According to the authors, the studies have demonstrated that pre-symptomatic children or children with the shortest disease duration had better efficacy.

“This is a consequence of the rapid denervation process occurring in the first six months of life, and the aim of pre-symptomatic treatment is the precocious rescue of motoneurons,” they explained.

There are a variety of biomarkers currently being investigated. The availability of reliable biomarkers can help to predict the variability in treatment response among patients, the authors noted.

Although the authors consider this “an exciting era” for SMA, newborn screening is vital because it can lead to early treatment and provide optimal care.

“Each therapeutic strategy has its weaknesses and strengths, and clinicians need to know them to optimize clinical care,” they wrote. “Once these approaches will be available for all SMA types, the final choice will be based on patient’s clinical features and compliance and on the feasibility of drug administration.”


Messina S, Sframeli M. New treatments in spinal muscular atrophy: positive results and new challenges. J Clin Med. 2020;9(7):2222. doi:10.3390/jcm9072222

Related Videos
James Howard, MD
Related Content
© 2023 MJH Life Sciences
All rights reserved.