BACKGROUND AND PURPOSE: 

• Biallelic SMN1 deletions and three SMN2 copies usually leads to the development of spinal muscular atrophy (SMA) type 2 in childhood 
• Onasemnogene abeparvovec is gene replacement therapy  
  • Delivers SMN cDNA using an adeno-associated virus-9 (AAV9) vector 
  • Single IV infusion  
• Strauss et al. (Nature Medicine, 2022) investigated the efficacy and safety of onasemnogene abeparvovec treatment for pre-symptomatic children with SMA type 2 

METHODS: 

• Open-label, single-arm, Phase III study  
  • 16 sites in 6 countries 
• Participants 
  • Infants identified with SMA through newborn screening  
  • Normal neuromuscular function who were able to swallow and breathe normally 
• Intervention 
  • Onasemnogene abeparvovec 
• Study design 
  • Single infusion over 60 minutes  
  • Multiple outpatient assessment visits through 24 months of age  
• Primary outcome 
  • Independent standing, for at least 3 seconds at any visit up to 24 months of age 
• Secondary outcome 
  • Walking independently, for at least five steps at any visit up to 24 months of age 

RESULTS: 

• 15 children | 9 female  
  • Median gestational age at birth: 39 weeks 
  • Median weight: 3.4 kg  
  • Median age at time of molecular confirmation: 8 days  
• At screening, all children had normal neuromuscular function 
• Standing independently at 24 months (P<0.0001) 
  • Treatment group: 100% (14 occurred within normal developmental window) 
  • Natural history population: 24% 
• Walking independently at 24 months (P<0.0001)  
  • Treatment group: 93% 
  • Natural history population: 21% 
• All children survived without permanent ventilation at 14 months 
• Maintained body weight (≥3rd WHO percentile) without feeding support through 24 months: 67% 
• No children required nutritional or respiratory support 
• There were no serious adverse events that were treatment-related 

CONCLUSION: 

• For asymptomatic infants with SMA type 2, onasemnogene abeparvovec was effective and safe 
• Most treated children were able to sit and walk independently at 24 months of age 
• The authors state 

Given the durability of benefit observed in the follow-up study of the Phase I START trial, and the fact that motor neurons are non-dividing cells, we are optimistic that one-time treatment with onasemnogene abeparvovec will add years of independent mobility, intact bulbar function, and good health-related quality of life for children in the three-copy cohort 

Learn More – Primary Sources: 

Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial

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