BACKGROUND AND PURPOSE: 

• Spinal Muscular Atrophy (SMA) is a serious autosomal recessive disorder 
• ACOG recommends offering SMA screening to all pregnant women or those considering pregnancy 
• SMA is caused by deletions or loss-of-function mutations in the SMN1 gene, causing insufficient expression of the SMN protein.  
• Another gene, SMN2 that is structurally very similar to SMN1, also produces SMN protein, but at only 5 to 10% of the SMN1 levels due to a splice-site variant excludes exon 7  
• A medication called nusinersen can alter RNA splicing of SMN2, potentially improving levels and function of the SMN protein  
• Mercuri et al. (NEJM, 2018) presents results from the phase 3 trial on the use of nusinersen in children with SMA  

METHODS: 

• Multicenter, double-blind, randomized sham-controlled trial  
• Participants: Children with SMA who had symptom onset after 6 months of age 
• Children were assigned at a 2:1 ratio to 
  • Intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) 
  • Sham procedure (control group) 
• Treatment was administered on days 1, 29, 85, and 274 
• Primary outcome: Least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment 
  • HFMSE scores range from 0 to 66 with higher scores meaning better motor function 
• Secondary outcomes  
  • Percentage of children with a clinically meaningful increase from baseline in the HFMSE score, indicating an improvement in at least two motor skills 

RESULTS:

• When comparing the HFMSE score at month 15 
  • There was a least-squares mean increase of 4.0 points from baseline compared to a decrease of 1.9 points in the control group 
• There was a significant between-group difference favoring nusinersen  
  • Least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1 (P<0.001) 
• 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001) 
• The trial was terminated early due to significant improvement in the treatment arm  
• The overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively) 

CONCLUSION: 

• Nusineren lead to clinically meaningful improvement in children with later-onset SMA 

Learn More – Primary Sources: 

Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy

Related ObG Topics:

Spinal Muscular Atrophy: Genetic Concepts and Carrier Screening 

ACOG Opinion on Expanded Carrier Screening

Genetic Carrier Screening in Ashkenazi Jewish Patients