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#Grand Rounds

Nusinersen: A Treatment for Spinal Muscular Atrophy (SMA) has Arrived

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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

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Related ObG Topics:

Spinal Muscular Atrophy: Genetic Concepts and Carrier Screening 
ACOG Opinion on Expanded Carrier Screening
Genetic Carrier Screening in Ashkenazi Jewish Patients

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