AVXS-101 Phase 1 Gene-Replacement Therapy (GRT) Clinical Trial in Spinal Muscular Atrophy Type 1 (SMA1): 24-Month Event-Free Survival and Achievement of Developmental Milestones

Objectives: SMA1 is a rapidly progressing, debilitating neurodegenerative disease caused by biallelic deletion/mutation of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron loss, muscle weakness, respiratory failure, and early death. Children with SMA1 do not sit unassisted, almost none achieve a children’s hospital of Philadelphia infant test of neuromuscular disorders (CHOP-INTEND) score ≥ 40 by 6 months, and 92% die/require permanent ventilatory support by 20 months. AVXS-101, a one-time investigational gene-replacement therapy (GRT), treats the genetic root cause of SMA, and is designed for immediate, sustained expression of SMN protein, allowing rapid onset and durable effect because it targets nondividing neurons.

Background: In the phase 1 trial (NCT02122952), symptomatic SMA1 patients received a one-time intravenous dose of AVXS-101 at low (cohort 1, n = 3) or proposed therapeutic dose (cohort 2, n = 12). Primary objective was safety, secondary objectives were survival (avoidance of death/permanent ventilatory support) and sitting unassisted. CHOP-INTEND scores and other motor milestones were recorded.

Methods: At 24 months, all patients were alive without need for permanent ventilatory support. Motor function improved in cohort 2 patients: 11/12 had CHOP-INTEND scores ≥ 40; 11/12 sat unassisted ≥ 5 seconds, 10 for ≥ 10 seconds, 9 for ≥3 0 seconds; 11/12 had head control; nine rolled over. Two patients crawled, pulled to a stand, stood, and walked independently. In the long-term follow-up study, two more patients sat unassisted ≥ 30 seconds and two stood with support; 3/4 received no medicinal treatments besides AVXS-101. No patient received nusinersen during the 24-month study period. Four patients had an asymptomatic transient rise in serum aminotransferase.

Conclusion: In contrast with natural history, AVXS-101 showed dramatic improvements in survival, motor function, and achievement of motor milestones of cohort 2 patients. No waning of effect or regression in motor function was reported.