P.358The value of AVXS-101 gene-replacement therapy (GRT) for spinal muscular atrophy type 1 (SMA1): improved survival, pulmonary and nutritional support, and motor function with decreased hospitalization

Abstract

SMA1 is a progressive neurologic disease that causes loss of motor muscle function and death/permanent ventilation by 2 years of age. The GRT onasemnogene abeparvovec (AVXS-101) treats the genetic root cause of SMA, biallelic mutation/deletion of survival motor neuron 1 (SMN1) gene. In a phase 1/2a study, 12 SMA1 patients (enrolled: 12/2014—12/2015) were treated with a one-time intravenous infusion of AVXS-101 (CL-101; NCT02122952; proposed therapeutic dose). Event-free survival (absence of death/permanent ventilation), pulmonary/nutritional interventions, swallowing, hospitalization, CHOP INTEND scores, and safety were assessed for 2 years. By study end, all patients (therapeutic dose) survived event-free; 7 did not need daily noninvasive ventilation; 11 had stable/improved swallowing (i.e., fed orally, 6 exclusively by mouth); 11 spoke. Participants experienced a mean (range) 1.4 (0—4.8) respiratory hospitalizations/year. Mean (range) proportion of time hospitalized, hospitalization rate/year, and length of stay were 4.4% (0—18.3%) 2.1 (0—7.6), and 6.7 (3.0—12.1) days, respectively. CHOP INTEND increased 9.8 (standard deviation [SD]=3.9) and 15.4 (SD=6.4) points at 1- and 3-months post-dose from baseline. Patients who received AVXS-101 (therapeutic dose) have maintained motor milestones at long-term follow-up (NCT03421977), supporting long-term treatment durability. Adverse events included elevated serum aminotransferase levels, attenuated by prednisolone. AVXS-101 resulted in rapid, sustained improvements in CHOP INTEND scores, dramatic survival, and motor function improvements at long-term follow-up, viewed as a clinical demonstration of continuous SMN expression. The reduced healthcare utilization in treated infants could decrease cost; alleviate patient, caregiver, and societal burden; and improve quality of life.