Spinal muscular atrophy (SMA) is a progressive and debilitating severe neurodegenerative disease with an incidence of approximately 1 in 10,000 live births [1,2,3,4]. It is a monogenic disorder characterized by mutations in the survival motor neuron 1 (SMN1) gene and insufficient production of functional SMN protein causing degeneration and loss of motor neurons resulting in muscle weakness and atrophy and paralysis, as SMN protein is ubiquitously expressed and plays a role in muscle functioning [3, 5,6,7].
SMA is clinically classified into four subtypes (SMA types 1–4) based on the severity of symptoms and the age of onset [1, 3, 8, 9]. The number of copies of the survival motor neuron 2 (SMN2) gene, a modifier gene nearly identical to SMN1 that produces a small, insufficient fraction of SMN protein, is a major determinant of this variability in the clinical phenotype . The most common and most severe form of SMA is type 1 (SMA type 1), also known as infantile onset, accounting for approximately 60% of cases [1, 8, 11, 12]. Infants with SMA type 1 most often become symptomatic within the 1st months of life by failing to reach basic developmental motor milestones, such as the ability to sit without support, and often face a decline in motor function as assessed by standardized methods, such as the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) [12,13,14].
Rapidly progressive muscle weakness in SMA type 1 can impede bodily functions, particularly respiratory and swallowing functions, further requiring mechanical nutritional and respiratory (e.g., permanent assisted ventilation) support. Even with proactive nutritional and respiratory support, infants with SMA type 1 typically face a decline in motor function and have a severely shortened life expectancy, rarely surviving beyond infancy [1, 8, 13]. An observational study of SMA type 1 by Finkel and colleagues  reported that infants with SMA type 1 (and 2 copies of SMN2) had a median survival of 10.5 months without death or respiratory support (defined as ≥ 16 hours per day of non-invasive ventilatory support or tracheostomy) with only 8% surviving to 20 months free of such respiratory support (see also [15,16,17]).
There has been substantial progress in the development of effective therapies for SMA [3, 8]. Nusinersen, an antisense oligonucleotide drug designed to enhance the production of SMN protein by modifying pre-messenger RNA splicing of SMN2, was the first drug to be approved by the Food and Drug Administration (FDA) to treat SMA, in December 2016 . Nusinersen has demonstrated significant efficacy in improving event-free survival, motor function, and motor milestones in infants with SMA type 1 . However, given that nusinersen does not cross the blood-brain barrier when delivered systemically and has a median half-life of 163 days, it requires direct delivery into the central nervous system through lifetime repeated intrathecal injections .
Recently, a phase 1, open-label, single-infusion, ascending dose, single-center clinical trial assessing gene-replacement therapy with onasemnogene abeparvovec (AVXS-101) in SMA type 1 infants was completed (AVXS-101-CL-101; NCT02122952). AVXS-101 uses a non-replicating adeno-associated virus capsid to deliver a functional copy of the SMN gene to motor neuron cells in SMA patients as a one-time intravenous injection. A key difference of AVXS-101 is that it can cross the blood-brain barrier allowing for effective central nervous system delivery in a single intravenous injection of the drug to target motor neurons in the central nervous system .
Despite some differences in clinical trial design and study outcomes, clinical trials of AVXS-101 and nusinersen in symptomatic infants with SMA type 1 both assessed event-free survival (i.e., time until death or the need for permanent ventilator assistance), motor function using CHOP-INTEND scores, and motor milestone achievements. Although clinical trials of AVXS-101 and nusinersen both demonstrated efficacy of the respective drugs in improving event-free survival, motor function, and motor milestone achievements, there is limited information on the comparative efficacy of the two treatments as there have been no head-to-head clinical trials. In the absence of a head-to-head trial, a between-trial comparison of the reported results of the two trials is currently the only method of comparison of relative treatment effects of nusinersen and AVXS-101.
The objective of this study was to compare AVXS-101 with nusinersen for the treatment of patients with SMA type 1 in terms of overall survival, the need to use permanent assisted ventilation, improvement in motor function, and motor milestone achievement based upon the results of two clinical trials in symptomatic infants with SMA type 1.