John Day, MD, PhDJohn Day, MD, PhD
Interim data from the phase 3 STR1VE study demonstrate positive benefits, including longer survival rate and motor function improvements in patients with spinal muscular atrophy (SMA) Type 1 who received onasemnogene abeparvovec-xioi (Zolgensma; AveXis), as known as AVXS-101, compared to the general population.  
 
Of the 19 patients who reached age 13.6 months at data cutoff, 17 (89.5%) were surviving without permanent ventilation compared with 25% survival in untreated natural history.  
 
Data was presented by John Day, MD, PhD, professor of neurology, University of Stanford, during the virtual Clinical Trials Session of the 2020 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference on March 24, 2020.  
 
Onasemnogene abeparvovec-xioi, at the time of its approval, was the only gene therapy FDA-approved for SMA to include patients who are presymptomatic. Zolgensma was approved in May 2019 for the treatment of SMA in pediatric patients <2 years of age with mutations in the SMN1 gene.  
 
STR1VE is a phase 3, open-label, single-arm, single-dose gene replacement therapy clinical trial (NCT03306277) for patients with SMA Type 1 with 1 or 2 survival motor neuron 2 (SMN2) copies. Inclusion criteria for those in the study had biallelic SMN1 mutations, no tracheostomy or current use for non-invasive ventilatory support averaging >6 hours a day, and showed no signs of aspiration on a formal swallowing test and ability to tolerate non-thickened liquids based on a formal swallowing test.  
 
The trial included 22 patients, who received a 1-time intravenous (IV) administration of onasemnogene abeparvovec at the therapeutic dose. Patients included in the study were aged <6 months at time of dosing.  
 
READ MORE: Intrathecal Zolgensma Shows Early Efficacy in SMA
 
Researchers used achievement of independent sitting for at least 30 seconds (time frame: 18 months of age visit) and event-free survival (time frame: 14 months of age visit) as primary outcome measures. Event-free survival was defined by the avoidance of combined endpoint of either death or permanent ventilation.  
 
Permanent ventilation was defined as tracheostomy or the requirement of ≥ 16 hours of respiratory assistance per day for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative ventilation. Researchers viewed permanent ventilation as a surrogate for death.  
 
Secondary end points of the study included ability to thrive and ventilatory support independence through 18 months. Unanticipated treatment-related toxicity of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher were among the safety outcomes measured.  
 
Of the 22 patients included in the study, 13 (59.1%) achieved developmental milestone of functional independent sitting for >30 seconds at the 18 months of age study visit (P <.0001 vs Pediatric Neuromuscular Clinical Research network). Additionally, a fourteenth patient achieved the milestone of sitting independently for 30 seconds at 16 months of age, but this milestone was not confirmed at the Month 18 visit.  
 
At 18 months of age, 20 of 22 (90.9%) were surviving free of permanent ventilation. Prior to data cutoff at 13.6 months of age, 1 patient died at age 7.8 months due to respiratory failure that was not considered related to onasemnogene abeparvovec treatment. Additionally, 1 patient withdrew consent at 11.9 months of age. That patient also required permanent ventilation at 11 months.  
 
The absence of non-invasive ventilatory support at any point during the study occurred in 15 of 22 patients (68.2%). At 18 months of age, 18 of the 22 patients (81.8%) did not use ventilatory support (as assessed by Trilogy Bilevel Positive Airway Pressure data alone). Of the 22 patients included in the study, 9 (40.9%) achieved the co-secondary end point of the ability to thrive at 18 months of age (97.5% CI, 18.6–66.4; P <.0001).  
 
Each patient recorded at least adverse event (AE), while AEs related to onasemnogene abeparvovec were found in 12 patients (54.5%). Serious AEs were recorded in 10 of the 22 patients (45.5%). As previously stated, one patient died due to respiratory arrest, unrelated to onasemnogene abeparvovec.  
REFERENCE:  
Day J, Chirboga C, Crawford T, et al. Onasemnogene abeparvovec-xioi gene therapy for spinal muscular atrophy type 1 (SMA1): phase 3 US study (STR1VE) update. Presented at: 2020 MDA Clinical & Scientific Conference. Abstract 40