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. Due to 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. Individuals with type 1 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. Individuals with type 2 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)
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.
PEER-REVIEWED LITERATURE
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: A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy (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 Exam (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 age 6 months (i.e., types 2 and 3) were evaluated in the CHERISH trial (Mercuri et al. 2018), 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 individuals showed numerically greater improvements in HFMSE and RULM and faster neurofilament reduction, although analyses were exploratory and underpowered. In Part C, previously treated individuals 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 found to be 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, likely to develop 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 (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. At the time of interim analysis (May 2018), all infants were alive and none required tracheostomy or permanent ventilation. Four (16%) of 25 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 illness. At 540 days of the study visit, the mean CHOP-INTEND total score was estimated as 61 and 62.6 in individuals with two and three copies of SMN2, respectively.
SMA Types 0, 4
Studies evaluating the use of nusinersen (Spinraza) in types 0 or 4 SMA have not been identified.
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.
