Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterized by the loss of motor neurons in the spinal cord and lower brain stem. It is caused by a mutation in, or the absence of, survival motor neuron gene 1 (SMN1) on chromosome 5, which causes a decrease in the amount of SMN protein produced. SMN protein is critical to the function of the nerves that control muscles. Another gene, survival motor neuron gene 2 (SMN2), also produces SMN protein. Because of a splicing error, most of the SMN protein produced by SMN2 lacks exon 7, which is necessary for the production of fully functional SMN protein, thereby rendering the protein produced unusable. The number of copies of SMN2 varies from person to person, and is inversely proportional to the severity of the disease. Individuals with SMA have at least one copy of the SMN2 gene.
SMA has been estimated to occur in one in 10,000 live births in the United States. SMA that is genetically diagnosed prior to the onset of symptoms by the absence of the SMN1 gene is considered to be presymptomatic. There are four primary types of 5q-SMA, which are characterized by severity and age at which symptoms begin:
Type 0 is prenatal onset SMA. At birth, individuals with SMA type 0 have severe weakness and hypotonia. These individuals never achieve any motor milestones and death occurs by 6 months, but usually by 1 month, due to respiratory failure.
Type 1, also called infantile-onset or Werdnig-Hoffmann disease, is the most severe and is the number one genetic cause of death for infants. These individuals are classified as "nonsitters." Symptoms, including progressive proximal weakness, poor head control, progressive respiratory insufficiency, hypotonia, areflexia, and tongue fasciculations, present within the first 6 months of life. The life span for these children is usually less than 2 years due to respiratory failure.
Type 2 is an intermediate form of SMA that usually presents between 6 and 24 months of age. These individuals are classified as "sitters." In addition to the symptoms displayed in type 1, individuals with type 2 also exhibit progressive scoliosis and joint contractures. The life span of these individuals varies greatly, with many individuals living into their second decade with adequate supportive care.
Type 3, also known as Kugelberg-Welander disease, usually has symptom onset after 18 months. Symptoms seen in this population include progressive proximal weakness, causing "walkers" to eventually need a wheelchair, and hand tremors. This is a more mild form of SMA, and individuals can have a lifespan comparable to those without SMA.
Type 4 is rare and usually presents in adulthood. Symptoms of weakness and mild motor impairment can begin as early as 18 but usually begin after 35, leading to mild motor impairment. These individuals generally have a normal life span.
Other forms of SMA exist that do not involve mutations in the SMN1 gene. These types are referred to as non–5q-SMA because the genes that cause them are not located in the SMN region of chromosome 5. These types of SMA include spinal and bulbar muscular atrophy, SMA distal type V, and SMA proximal adult.
Nusinersen (Spinraza) low- and high-dose regimens were approved by the US Food and Drug Administration (FDA) on December 23, 2016, and March 30, 2026, respectively, for the treatment of SMA in pediatric and adult individuals. It is an antisense oligonucleotide designed to treat SMA caused by mutations in the SMN gene located on chromosome 5q. Nusinersen (Spinraza) targets the SMN2 gene, increasing production of a complete SMN protein by enhancing exon 7 inclusion in mRNA. Antisense drugs contain synthetic genetic material that bind to RNA, and can be used to fix splicing errors in genes such as SMN2. The low dose is dosed intrathecally in a series of four loading doses (12 mg) within the first 60 days, and then maintenance doses (12 mg) every 4 months thereafter. The higher dose includes two loading doses (50 mg) followed by maintenance doses (28 mg) every 4 months.
Onasemnogene abeparvovec-xioi (Zolgensma) was approved by the FDA on May 24, 2019, for the treatment of individuals younger than 2 years of age with SMA with biallelic mutations in the SMN1 gene. Onasemnogene abeparvovec-xioi (Zolgensma) is intended as a one-time gene replacement therapy designed to deliver a functional copy of the SMN1 gene to motor neuron cells of individuals with SMA. Because motor neurons are nondividing cells, it is postulated that once the SMN1 gene is incorporated in the cells, it would be retained over time and potentially allow for long-term, sustained SMN protein expression.
Onasemnogene abeparvovec-brve (Itvisma) was approved by the FDA on November 24, 2025, for the treatment of SMA in adults and children 2 years of age or older with a confirmed mutation in the SMN1 gene. Onasemnogene abeparvovec-brve (Itvisma) is a concentrated version of onasemnogene abeparvovec-xioi (Zolgensma), and is administered as a one-time, intrathecal injection.
PEER-REVIEWED LITERATURE
NUSINERSEN (SPINRAZA)
SMA Types 1, 2, 3
The efficacy and safety of nusinersen (Spinraza) were studied in a phase 3 multicenter, randomized, double blind, sham procedure–controlled study (ENDEAR). Beginning in August 2014, ENDEAR studied 121 individuals with infant-onset (type I) SMA. Forty percent of the 82 eligible individuals in the nusinersen (Spinraza) group reached the primary endpoint at the time of interim analysis of achieving a motor milestone response. This response was evaluated according to the Hammersmith Infant Neurologic Examination (HINE). In the final analysis, 51% of individuals in the nusinersen (Spinraza) group achieved a motor milestone response (HINE), compared to 0% of individuals in the sham-controlled group. Individuals who received nusinersen (Spinraza) showed improvement from baseline in motor skills based on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), although the study was not statistically controlled for multiple comparisons at the study interim. In the final analysis, 71% of individuals in the nusinersen (Spinraza) group achieved an improvement in motor skills (CHOP-INTEND), compared to 3% of individuals in the sham-controlled group.
The safety and efficacy of nusinersen (Spinraza) in individuals who developed symptoms of SMA after 6 months of age (i.e., types 2, 3) were evaluated in the CHERISH trial, which was a multicenter, double-blind, sham-controlled phase 3 study. The 126 individuals in the study received either an intrathecal dose of nusinersen (Spinraza), 12 mg, or a sham procedure on days 1, 29, 85, and 274. The primary endpoint was the least squares mean change from baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) score at 15 months. In the final analysis, there was a least squares mean increase in the nusinersen (Spinraza) group and a least squares mean decrease in the sham-control group. These results favored the nusinersen (Spinraza) group (least squares mean difference in change, 4.9 points), showing significant improvement in motor function.
The DEVOTE study (Finkel et al., 2026) assessed
the safety and efficacy of high‑dose nusinersen (Spinraza; 50/28 mg) in diverse SMA
populations. Part B was a randomized, double‑blind phase 2/3 study of 99
treatment‑naïve individuals, including 75 infants with infantile‑onset SMA
randomly assigned 2:1 to high‑dose versus standard dosing and 24 children with later‑onset
SMA enrolled as a supportive cohort, with comparisons to matched ENDEAR and
CHERISH controls. Part C was an open‑label transition study of 40 previously
treated children and adults who switched from standard‑dose to high‑dose
nusinersen, focusing primarily on safety and exploratory motor outcomes. In
Part B, treatment‑naïve infants with SMA demonstrated a statistically
significant and clinically meaningful improvement in motor function (CHOP‑INTEND:
difference in ranks 26.06 [95% CI, 17.9–34.2; P<0.0001]; HINE-2:
least-squares mean change 26.67 [95% CI, 18.8–34.5], P<0.0001]) versus
matched sham controls at day 183. Treatment‑naïve later‑onset patients showed
numerically greater improvements in HFMSE and RULM and faster neurofilament
reduction, although analyses were exploratory and underpowered. In Part C,
previously treated patients who transitioned from standard‑dose nusinersen (Spinraza) experienced modest but meaningful motor function gains (mean HFMSE improvement,
1.8 points [standard deviation (SD), 3.99]; mean RULM improvement 1.2 [SD, 2.14]),
with neurofilament levels remaining low and no new safety concerns identified.
The evidence is sufficient to support the clinical effectiveness of the higher dose
nusinersen (Spinraza) regimen across a range of SMA populations, with extrapolation to
presymptomatic individuals considered safe and appropriate.
Safety and long-term efficacy were studied in the EMBRACE trial, a phase 2, double-blind, randomized, sham-controlled study in individuals with infant or later-onset SMA who did not qualify for the ENDEAR or CHERISH trials (Ascadi et al., 2021). Children aged 7 months to more than 6 years were randomly assigned 2:1. All had at least two but no more than three SMN2 copies. The primary and secondary endpoints were adverse events (AE) and nusinersen (Spinraza) concentration in plasma and cerebral spinal fluid (CSF). The most common AEs were deemed associated with the progression of SMA (i.e., pyrexia, upper respiratory tract infection). Vomiting was seen within 72 hours of nusinersen (Spinraza) administration, but not in the sham cohort. An exploratory efficacy analysis demonstrated improved motor milestones and reduced ventilation support; therefore, individuals in the sham cohort crossed over to the treatment group in the second phase of the trial. Combined efficacy results showed 13 of 14 participants as HINE-2 responders. The efficacy analysis is limited by its exploratory nature and by use of a scoring system intended for children aged 2 years or younger. Regardless, the EMBRACE study was able to demonstrate nusinersen (Spinraza) tolerability.
Presymptomatic Individuals, Likely to Develop SMA Types 1 or 2
Efficacy in presymptomatic individuals, those with a genetic deletion or variant causing a likelihood to develop types 1 or 2, was studied in a phase 2, open-label, uncontrolled trial of 25 individuals, called NURTURE. Individuals were ages 3 days to 42 days at the time of the first dose. Nusinersen (Spinraza) was administered during four loading doses, followed by maintenance doses every 4 months. The primary end point was time to death or respiratory intervention (invasive or noninvasive ventilation for >6 hours/day continuously for ≥7 days or tracheostomy). At 365 days of the study visit, the mean CHOP-INTEND total score was estimated as 56 and 64 in individuals with two and three copies of SMN2, respectively. Based on a natural history cohort of children with SMA with two SMN2 copies, the highest individual CHOP-INTEND score was 33 and the mean score was 19.9 over a 2-year period. At the data cutoff (July 5, 2017), all infants were alive and none required tracheostomy or permanent ventilation. Two (13%) of 15 infants with two SMN2 copies required respiratory intervention for 6 or more hours per day continuously for 7 or more days during an acute, reversible viral infection, and thus met the primary end point.
SMA Types 0, 4
Studies evaluating the use of nusinersen (Spinraza) in types 0 or 4 SMA have not been identified.
ONASEMNOGENE ABEPARVOVEC-XIOI (ZOLGENSMA)
Infantile-Onset or SMA Type 1
For individuals who have SMA type 1 (infantile-onset) who receive onasemnogene abeparvovec-xioi (Zolgensma), the evidence includes a prospective cohort of 15 individuals followed for 2 years. Relevant outcomes are overall survival, change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. In this single phase 1 study of symptomatic infants with two copies of the SMN2 gene, 12 of 15 infants received the proposed therapeutic dose while three received the minimally effective dose. At the end of the 2-year follow-up, all 15 infants survived and none of the 12 individuals who received the proposed therapeutic dose required permanent ventilation. All 12 individuals also achieved at least one motor milestone, with 92% of those achieving scores greater than 40 on the CHOP-INTEND (a score >40 is a favorable outcome). The FDA approval was based on a pooled analysis of 21 individuals from the pivotal phase 1 and ongoing confirmatory phase 3 STRIVE-US trial. The observed treatment effect on survival, event-free survival, and achievement of motor functions is beyond what is typical based on the known natural history of individuals with SMA 1 with two copies of SMN2. The available published data support a clinically meaningful durable treatment effect through 2 years. However, there are limited data to assess the long-term durability of treatment effect and safety related to adverse events that are rare or have delayed onset. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
Presymptomatic Individuals with a Diagnosis of SMA and Three or Fewer Copies of SMN2
In a phase III, single-arm trial, 15 presymptomatic children with biallelic SMN1 mutations and three copies of SMN2 were treated with onasemnogene abeparvovec (Zolgensma) in the SPR1NT trial (Strauss et al., 2022). All infants had the ability to breathe and swallow normally, and a median baseline peroneal compound muscle action potential (CMAP) of 4.10 mV suggestive of normal neuromuscular function. Treatment began at a median age of 32 days (range, 9–43 days). The primary and secondary motor milestones were independent standing for at least 3 seconds at any visit up to 24 months of age and independent walking for at least five steps at any visit up to 24 months of age.
All 15 children achieved the primary endpoint at a median age of 377 days (range, 284–549), and maintained this milestone up to the 24-month study visit. Ninety-three percent did so within the normal World Health Organization (WHO) developmental window of less than or equal to 514 days (99th percentile). Fourteen of fifteen children achieved the secondary outcome with a median age of 422 days (range, 362–563). An exploratory functional endpoint demonstrated 100% of children were free from permanent ventilation at 14 months of age. The Bayley Scales of Infant and Toddler Development (BSID) was used for diagnosing motor developmental delays. All 15 children achieved a scale score of 4 or higher (within 2 SD of reference mean) on both the gross and fine motor subsets during at least one post-baseline visit. At any post-infusion visit, the median maximum peroneal CMAP was 6.00 mV (range, 4.2–8.5), demonstrating a median increase of 1.80 mV. All children experienced a treatment-emergent adverse event (TEAE) and at least three experienced a serious TEAE.
Type 2 SMA is milder than types 0 and 1; however, individuals are affected by irreversible neuromuscular function and a short life expectancy, particularly those with two or fewer copies of the SMN2 gene; however, children with three copies of the SMN2 gene will also experience irreversible motor neuron loss and symptom presentation, although onset is highly variable. This was the first trial to study children with presymptomatic SMA—children at risk for SMA type 2—and three copies of the SMN2 gene. The majority of children achieved both the primary and secondary endpoints when treated with onasemnogene abeparvovec (Zolgensma), suggestive of delayed symptom onset. Due to limited evidence on the presymptomatic SMA population, it is difficult to determine whether onasemnogene abeparvovec (Zolgensma) contributed to significantly delayed symptom onset from those who did not receive treatment. Moreover, the absence of follow-up data beyond 2 years renders the long-term durability of the treatment uncertain. Regardless of the limitations, the evidence for onasemnogene abeparvovec (Zolgensma) was adequate to demonstrate a positive impact on functional health outcomes in children with presymptomatic SMA and three copies of the SMN2 gene.
Symptomatic Individuals with a Diagnosis of SMA and Four or Fewer Copies of SMN2
McMillan et al. (2025) investigated onasemnogene abeparvovec-xioi (Zolgensma) for the treatment of 24 pediatric individuals with SMA types 3 or less followed for 52 weeks in the SMART study. The majority of participants had three SMN2 copies (75%), while others had two (n=5) or four or more (n=1) SMN2 copy numbers. The mean age at time of treatment administration was 4.69 years (1.51–9.13). Eighty-eight percent had previously received a disease-modifying treatment (i.e., nusinersen [Spinraza] or risdiplam [Evrysdi]). The primary and secondary endpoints were adverse events and motor function scores (i.e., HFMSE, Revised Upper Limb Module [RULM]), respectively. All participants had at least one treatment-emergent adverse event (TEAE; e.g., vomiting, pyrexia) with seven experiencing serious AEs. An increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels was seen among 88% of individuals, and ALT remained greater than the upper limit of normal for the majority at 52 weeks. The median change in HFMSE score in those aged 24 months or more (n=20) at week 52 was 4.0 points (−5 to 11), with two participants whose HFMSE scores decreased (≤3 points). Of the 18 whose scores increased, 11 (61%) had a clinically meaningful increase of three or more in HFMSE total score. There was a median increase of 2.0 points (−5 to 10) in the RULM, in which the majority (16/18) saw stable or improved RULM. Forty-one percent of individuals saw a clinically meaningful increase of three or more points in the RULM score. This was a pivotal study for investigating onasemnogene abeparvovec-xioi (Zolgensma) in those who have previously received SMA disease-modifying treatment across a broad range of weights and ages. Although the long-term hepatotoxicity remains a concern, there were no cases of Hy's law, suggesting an adequate safety profile relative to other onasemnogene abeparvovec-xioi (Zolgensma) trials. The majority of individuals achieved a clinically significant motor improvement. The SMART study's results complements the real-world evidence demonstrating safety and efficacy among varying SMA types, as well as those who are treatment-naïve or those previously treated with an alternative therapy.
ONASEMNOGENE ABEPARVOVEC-BRVE (ITVISMA)
A phase I, open-label ascending-dose study (STRONG; Finkel et al., 2023) was conducted to assess the safety and efficacy of varying doses of intrathecal onasemnogene abeparvovec (Itvisma) in 32 individuals with SMA aged 6 to less than 60 months. Individuals were stratified into three dose cohorts: Low, 6.0 × 1013 vector genomes (vg) (n=3); medium, 1.2 × 1014 vg (n=25); and high, 2.4 × 1014 vg (n=12). Owing to adequate statistical power, the medium dose cohort was the only group where an efficacy analysis was performed. Additionally, they were further stratified by age (i.e., young 6 to <24 months; older 24 to <60 months). All children had three copies of the SMN2 gene without the genetic modifier (c.859G>C)—whose variant in the SMN2 gene has been associated with milder phenotypic outcomes. The mean age at time of administration was 20.3 months (range, 7–55) and mean age at symptom onset was 8 months (range, 0–11). This study was the first of its kind to include children living with SMA older than 2 years of age for gene therapy. Although high rates of adverse events were observed and efficacy was not demonstrated in the low- and high-dose groups, the medium-dose cohort of onasemnogene abeparvovec (Itvisma) showed an acceptable safety profile consistent with previously observed adverse events in onasemnogene abeparvovec (Itvisma) trials. The observed treatment effect on motor functions in the medium-dose group is beyond what is typical based on the known natural history of individuals with SMA, where all individuals in the older group achieved a clinically meaningful change in HFMSE scores. This pilot study provides initial safety evidence among those with later onset SMA (i.e., types II and III) and three copies of the SMN2 gene.
Proud et al. (STEER Trial; 2025) conducted a phase 3 randomized trial comparing treatment with intrathecal (IT) onasemnogene abeparvovec-brve (Itvisma IT) versus sham control in treatment-naïve individuals diagnosed with SMA. Participants were between 2 and 17 years of age (mean, 5.88; range, 2.1–16.6) and could sit but have never walked independently. In total, 126 participants were randomly assigned into treatment group (n=75) or sham cohort (n=51). The majority had three copies of the SMN2 gene (IT, 97.3%; Sham, 90.2%). The primary endpoint was change from baseline in HFMSE score at end of follow-up. Secondary measures include achievement of at least a three-point improvement in HFSME score, change from baseline in RULM, and various safety outcomes. The aforementioned secondary endpoints were also stratified in the age 2 to younger than 5 years of age group alone. Exploratory endpoints were change from baseline in HFMSE and RULM in those 5 to less than 18 years of age. The treatment group showed a 2.39-point improvement in HFMSE scores versus 0.51 in the sham cohort. The least squares mean (LSM) difference among groups reached statistical significance (LSM, 1.88 95% confidence interval [CI], 0.51–3.25; P=0.0074). Although secondary endpoints trended favorably in the all ages, treatment cohort compared to sham, including a greater percentage meeting a HFMSE improvement of three points or more (39.2% vs 26.0%), no secondary analyses among any of the age groups achieved statistical significance. Safety events were similar between groups with majority of AEs resulting from disease progression (e.g., upper respiratory tract infection). In the 5 to less than 18 years of age range, the LSM change from baseline in HFMSE score was 1.60 versus −0.86, favoring the treatment group (LSM difference, 2.45; CI, 0.42–4.49) and also showed greater improvement compared to the 2 to younger than 5 years of age group (LSM difference, 1.44; CI, −0.33 to 3.22). The LSM difference in RULM scores from baseline was modest (1.72; CI, 0.14–3.30). The STEER trial demonstrated a clinically meaningful benefit of IT compared with sham control in individuals living with SMA aged between 2 to less than 18 years, with effects sustained for up to 1 year. Individuals aged between 5 and 18 years appeared to show greater improvement in HFMSE and RULM scores compared with those aged between 2 and 5 years. While the authors suggest these age-related differences may be clinically significant, the exploratory nature of these analyses limits definitive conclusions regarding IT effectiveness across age strata. Overall, onasemnogene abeparvovec-brve (Itvisma) is associated with favorable motor function outcomes and represents the first gene therapy option available for individuals older than 2 years of age. Long-term follow-up is ongoing through the SPECTRUM extension study, which allows crossover from the sham cohort. The expected completion date is 2030.
In a phase IIIb, open-label, multicenter study, the STENGTH trial sought to evaluate the safety, tolerability, and efficacy of intrathecal onasemnogene abeparvovec (Itvisma IT) in individuals who have previously received an SMA therapy (i.e., nusinersen [Spinraza], risdiplam [Evrysdi]) up to 1-year (Kwon et al., 2025). The mean age was 7.4 (2 to 17) and majority presented 3 copies of the SMN2 gene (n=23/27; 2 SMN2 copies: n=4/27). Treatment with IT demonstrated an adequate safety profile similar to predecessor trials among treatment-naïve individuals (i.e., STRONG, STEER). This safety profile along with motor scores (mean change from baseline, 0.17 [range, −5.5 to 7.5]) were sustained for up to 52 weeks. Onasemnogene abeparvovec-brve (Itvisma) appears to be a safe option for those who have received prior treatment with nusinersen (Spinraza) or risdiplam (Evrysdi).
OFF-LABEL INDICATIONS
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
