Nusinersen (Spinraza) is the first FDA-approved, disease-modifying therapy for the treatment of spinal muscular atrophy (SMA). Nusinersen is an antisense oligonucleotide that binds to a sequence downstream of exon 7 in the SMN2 gene. The oligonucleotide blocks the production of a less stable and partially functional protein (SMNΔ7) in favor of a highly stable and fully functional, SMN protein.

Nusinersen is administered via the intrathecal route. Treatment requires loading doses initially, followed by maintenance doses. According to the prescribing instructions, nusinersen (Spinraza) should be administered at a dose of 12 mg once every 14 days for the first three doses, followed by one 12 mg infusion 30 days later. After these loading doses, a 12 mg dose of the oligonucleotide should be administered every four months as maintenance.

FDA and EMA approval of nusinersen (Spinraza) was based largely on the results of the ENDEAR trial.1 The ENDEAR was a multi-center, double-blind, sham-controlled phase 3 clinical trial in 82 infants with SMA seven months of age or younger. The primary endpoints were motor-milestone response and event-free survival. Secondary endpoints included overall survival and event free survival stratified by the disease duration at screening. Infants in the nusinersen group did significantly better in the motor-milestone response testing than infants who received a sham infusion. Twenty-one of 51 infants receiving active treatment (41%) showed a positive response compared to zero of 27 infants in the sham group (P<0.001). The stark contrast between active and control groups prompted an early termination of the trial. At final tally, 51% of treated infants had a positive outcome compared to none in the sham group. Fewer children in the nusinersen-treated group died or required permanent ventilation assistance during the study than in the sham-treated cohort (39% vs 68%; hazard ratio 0.53; 95% CI 0.32-0.89).1

Nusinersen (Spinraza) was also trialed in older children with SMA in the CHERISH trial.2 The CHERISH trial was also structured as a multi-center, double-blind, sham controlled phase 3 trial, however it included children with SMA who had first symptom onset at six months of age or older. The primary endpoint of the trial was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment. As with ENDEAR, initial positive results from treatment prompted an early termination of the trial. In early analysis, the nusinersen-treated group had a least-squares mean increase on the HFMSE of 4.0 points compared to a decrease of 1.9 points in the sham-treated group. At the end of the trial, 57% of children in the treated group had an increase in HFSME of at least three points compared to 26% in the control group, which is considered clinically meaningful.

The anti-sense oligonucleotide was generally well tolerated, though this assessment was based on a population of children who have numerous medical challenges and complications from their disease. Notably, large percentages of children in both treatment and control groups experienced adverse events. The most common adverse events noted from treatment were respiratory tract infections and constipation. There is also an increased risk of thrombocytopenia, coagulopathy, and kidney damage. As such, a complete blood count (CBC), coagulation panel, and spot urine protein analysis should be ordered prior to starting treatment, and immediately prior to each intrathecal administration. 

As this is the first treatment of its kind for spinal muscular atrophy and greater than 50% of patients are expected to have significant clinical benefit, the cost per treatment is understandably large. According to Lexicomp, the average wholesale price of a single dose of the drug (12 mg/5 mL) is $30,000. Thus, the cost of the drug alone may approach $180,000 for the first year. When discussing disease-modifying treatment with parents of young children with SMA, it is important to explain the lack of other treatments, the possibility of modest clinical benefit, and the costs of nusinersen (Spinraza) so that they can make an informed decision about this treatment.


1. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen Versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1723-1732. doi:10.1056/NEJMoa1702752 

2. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen Versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018;378(7):625-635. doi:10.1056/NEJMoa1710504