Zolgensma—Gene Replacement Therapy—for Treatment of Spinal Muscular Atrophy

Results from multiple trials of SMN1gene-replacement therapy (Zolgensma; Avexis, Bannockburn, IL) show promise for single-dose treatment of spinal muscular atrophy (SMA). 

In the STRIVE phase 3 study for treatment of spinal muscular atrophy, 22 infants under age 6 months, diagnosed genetically (biallelic SMN1 mutations/deletions, 2 SMN2 copies), were treated. Of the 15 babies treated more than 13.6 months or who discontinued the study before then, 13 (87%) survived without needing permanent ventilation, in contrast to the 25-50% survival rate for children with SMA when untreated. Of those who reached age 10.5 months or discontinued the study before then, 95% (19/20) survived without ventilation. Over half the children have survived to age 14.4 months, and 11 are able to sit without support for at least 30 seconds, a milestone achieved at average age 11.9 months (mean 8.2 months posttreatment). 

In the SPR1NT trial, children age 6 weeks or less who were asymptomatic and had 2 or 3 copies of SMN2 were treated. All treated children have survived to a median age of 6.1 months, and 4 are able to sit unsupported for at least 30 seconds, with 1 able to stand with assistance. Among the children with 2 copies of SMN2 (n = 8), all have achieved a CHOP-INTEND score of 50 points, with 6 achieving 60 points and 3 reaching the maximum score of 64 points.

Children with 2 copies of SMN2, age 6 to 60 months, who could sit but not walk were treated in the strong trial and all 30 have survived over a mean follow-up period of 6.5 months. For both the 12 children who were age 24 to 60 months at the time of treatment and the 7 who were age 6-23 months had a mean 4.2-point increase on the Hammersmith Functional Motor Scale-Expanded (HFMSE) at their most recent study visit (5-12 months post-treatment). The ability to stand independently has been gained by 2 children, 1 of who has also learned to walk independently. 

"Patients treated with Zolgensma before the onset of symptoms are achieving age-appropriate motor milestones in line with normal development. These SPR1NT data reinforce the potential Zolgensma has as a foundational treatment for patients with SMA. With just a single, one-time dose, we are seeing Zolgensma provide prolonged survival, rapid motor function improvement and milestone achievements that patients never experience if their disease is left untreated," said David Lennon, President of AveXis. 

Adverse events observed include elevated transaminases, platelet count decrease and thrombocytopenia, elevated blood creatine phosphokinase, elevated troponin, croup, lethargy, and hypercalcemia. In STRIVE, 1 participant died of respiratory failure that was classified as unrelated to treatment after having had gains in motor milestone development. A single enrollee in SPR1NT was found to have 4 copies of SMN2, and thus included only in the safety and not efficacy analysis.

These data were presented at the American Academy of Neurology annual meeting May 4-10, Philadelphia, PA.