Description
Spinal muscular atrophy (SMA) is an inherited disorder caused by homozygous deletions or variants in the SMN1 gene. As a consequence of absent or low levels of SMN1 protein, the motor neurons in the spinal cord degenerate, resulting in atrophy of the voluntary muscles of the limbs and trunk. Nusinersen is a synthetic antisense oligonucleotide designed to bind to a specific sequence in exon 7 of the SMN2 transcript, causing the inclusion of exon 7 in the SMN2 transcript, leading to production of full length functional SMN2 protein, which is very similar to SMN1.

Infantile-Onset or Type I SMA
For individuals who have type I (infantile-onset) SMA (symptomatic or presymptomatic) who receive nusinersen, the evidence includes 2 randomized, double-blind, controlled trials (results not yet reported for one) and 1 single-arm open-label study. Relevant outcomes are overall survival, change in disease status, morbid events, functional outcomes, health status measures, quality of life and treatment-related mortality and morbidity. Trial results in symptomatic patients have shown clinically meaningful improvement in motor milestones, as well as event-free survival, which exceeded those seen in the control group, with an acceptable safety profile. The proportion of patients who met the primary end point responder definition of achieving motor milestones was 40% in the nusinersen arm, compared to 0 in the sham-controlled arm. Further, the hazard ratio for event-free survival was 0.53 in favor of nusinersen versus sham controlled. It is notable, however, that most nusinersen-treated subjects did not achieve the primary end point motor milestone response. Given the limited data on durability of response, long-term safety and lack of efficacy in substantial number of patients, continued risk-benefit assessment of long-term treatment with nusinersen is necessary. The open-label uncontrolled trial in presymptomatic infantile-onset SMA patients found a benefit of early treatment with nusinersen. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Type II and III SMA
For individuals who have type I or II SMA who receive nusinersen, the evidence includes 4 single-arm studies and 1 double-blind, randomized controlled trial. Relevant outcomes are overall survival, change in disease status, morbid events, functional outcomes, health status measures, quality of life and treatment-related mortality and morbidity. Efficacy findings from single-arm studies of type II and III SMA are difficult to interpret, because these trials used a wide range of nusinersen doses and lacked control arms. Results of the confirmatory phase 3 CHERISH trial are not yet available. The evidence is insufficient to determine the effects of the technology on health outcomes.

Type 0 or IV SMA
For individuals who have type 0 SMA or type IV SMA who receive nusinersen, no studies were identified. Relevant outcomes are change in disease status, morbid events, functional outcomes, health status measures, quality of life and treatment-related mortality and morbidity. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background  
SPINAL MUSCULAR ATROPHY
Spinal muscular atrophy (SMA) is a rare autosomal recessive genetic disorder caused by homozygous deletions or variants in the SMN1 gene in chromosome 5. This gene is responsible for producing the "survival of motor neuron" protein (SMN1). As a consequence of absent or low levels of SMN1, the motoneurons in the spinal cord degenerate, resulting in atrophy of the voluntary muscles of the limbs and trunk. During early development, these muscles are necessary for crawling, walking, sitting up and head control. The more severe types of SMA can also affect muscles involved in feeding, swallowing and breathing. The exact role of the SMN protein in motoneurons has not been completely elucidated, and levels of the SMN protein required for optimal functioning are unknown.1 SMN2 is a nearly identical modifying gene capable of producing nearly identical compensatory SMN2 protein. However, 70% to 90% of the transcripts produced from the SMN2 gene produce a truncated protein that is defective and unstable due to lack of exon 7.² Further, humans exhibit variability (range, 0 – 6) in the number of copies of the SMN2 gene, and copy number is inversely proportional to severity of disease.³ These factors in tandem lead to wide variability in disease severity.

SMA is classified into 4 main categories (with additional subcategories) based on the age at the onset of symptoms.^4,5 Generally, early onset of disease directly correlates to severity of symptoms and rate of disease progression. There is no exact marker to classify these categories, and they are not well-distinguished by ICD-10-CM code.

• Type 0: The most severe form of SMA, symptoms can often be seen in the later stages of pregnancy. Fetal movements are less than expected and, after birth, the infant will have little ability to move and may not be able to breathe and swallow independently. Death occurs before the age of 6 months.
• Type I (also called infantile SMA or Werdnig-Hoffman disease, and subcategorized as IA, IB and IC): Onset within 6 months of birth, and symptoms progress rapidly, and most infants die before 1 year of age from respiratory failure. About 60% of patients with SMA suffer from this phenotype.^6,7
• Type II (also called intermediate SMA or Dubowitz disease): Onset within 6 to 18 months, with a less severe progression. Typically, a child can sit independently if positioned, but is unable to walk. More than 70% of patients live beyond 25 years of age with adequate supportive care.
• Type III (also called Kugelberg-Welander disease and subcategorized as IIIA and IIIB): Onset after 18 months of age. Lifespan is not affected, with wide-ranging reduction in muscle strength with a chronic course. The outcome depends primarily on the severity of muscle weakness at presentation, rather than age of onset, but earlier onset tends to correlate with greater weakness.⁸
• Type IV (also called adult-onset SMA): Usually presents in the third decade of life and is otherwise similar to SMA type III.

The prevalence of SMA is estimated to be between 9.1 and 10 per 100,000 live births.9,10 In 95% of cases, both copies of the SMN1 exon 7 are absent. The remaining 5% of cases are compound heterozygotes for SMN1 exon 7 deletion and small intragenic variants. The molecular diagnosis of SMA consists of the detection of the absence of exons 7 of the SMN1 gene in the majority of cases.¹¹ 

Treatment
Nusinersen is a modified antisense oligonucleotide (a synthetic genetic material) that binds to a specific sequence in the intron downstream of exon 7 of the SMN2 transcript; nusinersen causes the inclusion of exon 7 in the SMN2 transcript, leading to production of full length functional SMN2 protein.¹² Prior to approval of nusinersen, there were no treatments approved by the Food and Drug Administration for SMA. Medical management of SMA patients includes respiratory, digestive and musculoskeletal supportive care.

Regulatory Status  
In Dec. 23, 2016, Spinraza^™ (nusinersen; Biogen) was approved by the U.S. Food and Drug Administration (FDA) for treatment of pediatric and adult patients with spinal muscular atrophy.

Policy  
Nusinersen may be considered MEDICALLY NECESSARY for patients who meet all of the following criteria:

Diagnosis of spinal muscular atrophy type I, II, or III

1. Submission of medical records (e.g., chart notes, laboratory values) confirming both of the following:
   • The mutation or deletion of genes in chromosome 5q resulting in one of the following:
     • Homozygous gene deletion or mutation (e.g., homozygous deletion of exon 7 at locus 5q) OR
     • Compound heterozygous mutation (e.g., deletion of SMN1 exon 7 [allele 1] and mutation of SMN1 [allele 2])
   • Patient has at least 2 copies of SMN2; 
2. Patient is not dependent on either of the following:
   • Invasive ventilation or tracheostomy OR
   • Use of non-invasive ventilation beyond use for naps and nighttime sleep;
3. Submission of medical records (e.g., chart notes, laboratory values) of the baseline exam of at least one of the following exams (based on patient age and motor ability) to establish baseline motor ability:
   • Hammersmith Infant Neurological Exam Part 2 (HINE-2) (infant to early childhood)
   • Hammersmith Functional Motor Scale Expanded (HFMSE)
   • Upper Limb Module (ULM) Test (Non ambulatory)
   • Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)
4. Patient is 16 years or younger at initiation of therapy (age based off clinical trial demographics)
5. Spinraza is prescribed by, or in consultation with, a neurologist with expertise in the treatment of SMA
6. One of the following:
   • Patient has not previously received gene replacement therapy (Zolgensma) for the treatment of SMA; OR
   • Patient is not to receive gene therapy (Zolgensma) within 4 months
7. Spinraza is to be administered intrathecally by, or under the direction of, healthcare professionals experienced in performing lumbar punctures

Continuation of Nusinersen may be considered MEDICALLY NECESSARY for patients who meet the following criteria is met:

1. Patient meets ALL initial criteria
2. Submission of medical records (e.g., chart notes, laboratory values) with the most recent results (< 1 month prior to request) documenting a positive clinical response from pretreatment baseline status to Spinraza therapy as demonstrated by at least one of the following exams:
   • HINE-2 milestones of ene of the following:
     • Improvement or maintenance of previous improvement of at least 2 point (or maximal score) increase in ability to kick
     • Improvement or maintenance of previous improvement of at least 1 point increase in any other HINE-2 milestone (e.g., head control, rolling, sitting, crawling, etc.), excluding voluntary grasp; AND

One of the following:

1. • • The patient exhibited improvement or maintenance of previous improvement in more HINE motor milestones than worsening, from pretreatment baseline (net positive improvement)
     • Achieved and maintained any new motor milestones when they would otherwise be unexpected to do so (e.g., sit unassisted, stand, walk); OR
   • HFMSE: One of the following:
     • Improvement or maintenance of previous improvement of at least a 3-point increase in score from pretreatment baseline
     • Patient has achieved and maintained any new motor milestone from pretreatment baseline when they would otherwise be unexpected to do so; OR

• •  ULM: One of the following:
    • Improvement or maintenance of previous improvement of at least a 2-point increase in score from pretreatment baseline
    • Patient has achieved and maintained any new motor milestone from pretreatment baseline when they would otherwise be unexpected to do so; OR
  • CHOP INTEND: One of the following:
    • Improvement or maintenance of previous improvement of at least a 4-point increase in score from pretreatment baseline
    • Patient has achieved and maintained any new motor milestone from pretreatment baseline when they would otherwise be unexpected to do so

Nusinersen is considered investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for patients with type 0 and IV spinal muscular atrophy. Spinraza is not proven or medically necessary for SMA without chromosome 5q mutations or deletions. Spinraza is not proven or medically necessary for routine concomitant treatment of SMA in patients who have previously received gene replacement therapy.

Policy Guidelines  
The recommended dosage is 12 mg (5 mL) administered intrathecally. Treatment is initiated with 4 loading doses; the first 3 loading doses should be administered at 14-day intervals, while the fourth loading dose is administered 30 days after the third loading dose. Subsequent maintenance doses should be administered once every 4 months thereafter.

Benefit Application  
BLUECARD/NATIONAL ACCOUNT ISSUES
State or federal mandates (e.g., FEP) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs or biologics may not be considered investigational and, thus, these devices may be assessed only on the basis of their medical necessity. 

Rationale  
This evidence review was created in February 2017 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through May 24, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function — including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms. 

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, non-randomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. 

Nusinersen
Clinical Context and Therapy Purpose
The purpose of nusinersen in pediatric and adult patients who have spinal muscular atrophy (SMA) is to provide a treatment option that is an improvement on existing therapies. Potential benefits of this therapy may include the following:

Treatment offers a novel mechanism of action or approach that may allow successful treatment of many patients for whom other available treatments are not available.

The question addressed in this evidence review is: Does treatment with nusinersen improve the net health outcome in pediatric and adult patients with a genetic diagnosis of SMA?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest are individuals who are presymptomatic with a genetic diagnosis of spinal muscular atrophy and a minimum of 2 but less than 4 copies of SMN2. 

Interventions
The therapy being considered is nusinersen.

Comparators
Prior to the availability of nusinersen, there was no Food and Drug Administration (FDA) approved treatment for SMA. Medical management includes respiratory, nutritional, and musculoskeletal supportive care.

Outcomes
The general outcomes of interest are survival, functional ability, quality of life, and treatment-related mortality and morbidity. Because SMA is a heterogeneous disease, measuring the impact of the intervention depends on the subtype of SMA. For example, in infantileonset SMA (type I), comparing the achievement of motor milestones with the known natural history of SMA is relevant but the same may not be applicable for patients with late-onset SMA (type III) in whom normal motor milestones may be delayed but nevertheless achieved or achieved but lost later. Age- and ability-appropriate motor function scales as they relate to the natural progression of SMA are summarized in Table 3.

Table 3. Health Outcome Measures Relevant to SMA

Outcome	Description	Relevance
HINE Section 2	Motor milestones includes 8 items scored on a 5-point scale with 0 as the absence of activity, and a maximum score of 4 points	Appropriate for infants 2 – 24 mo Infants with the most severe symptoms of SMA (early onset) may show a score of 0 on all 8 items of the HINE Section 219,
CHOP INTEND	Motor skills includes 16 items scored on a scale of 0 (no response) to 4 (complete response) and total score ranges from 0 to 6420,21	Appropriate for 3.8 mo to > 4 y Score > 40 rare in SMA type I with 2 SMN2 gene copies22 Mean CHOP INTEND score in healthy infants (n = 14; age, 3.3 mo) was 501.1 vs 20.2 in SMA type I (n = 16; age, 3.7 mo)
HFMSE	Motor function includes 33 items from the Gross Motor Function Measure related to lying/rolling, crawling, crawling/kneeling, standing, and walking/running/jumping that are scored on a scale of 0 to 2, with a total score that ranges from 0 to 66, where lower scores indicate poorer motor function. On average, it can be conducted in 12 min.	Appropriate for individuals with SMA types II and III23, Multiple studies have shown that HFMSE scores decline progressively in patients with SMA type II or III. However, there is conflicting data on whether such declines are linear.24,25
Natural history with and without SMA	Infants without SMA at 1 y26: 90% able to maintain head control, turn in sitting position (pivot), form a pincer grasp, play with feet, roll from prone to supine (and back), crawl on hands and knees 79% able to stand unaided 51% able to walk At 18 mo: 90% stand/walk unaided Event-free survival rates in infants with SMA type I9,27: 50% by 8 – 10.5 mo 25% by 13.6 mo 8% by 20 mo	With the availability of nusinersen, conducting placebo-controlled trials in patients with SMA type I who face near-term mortality would be unethical. Therefore, good quality natural history data from SMA and non-SMA populations using validated cohorts are essential to assess relative health benefit over short- and long-term.

CHOP INTEND: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HFMSE: Expanded Hammersmith Functional Motor Scale; HINE: Hammersmith Infant Neurological Examination; SMA: spinal muscular atrophy.

Timing
Given the heterogeneity and varying life expectancies among patients with different SMA subtypes, the timing of follow-up of studies to reasonably assess whether nusinersen offers a net health benefit will differ by SMA subtypes as well as by the timing of treatment initiation relative to symptom onset. Given the significant uncertainty about the durability of the long-term benefits and safety of therapies, long-term data in an observational setting are also a requirement. The timing of outcomes measures relevant to SMA subtypes is summarized in Table 4.

Table 4. Timing of Outcome Measures Relevant to SMA

SMA Subtype	Purpose	Timing
Presymptomatic with a genetic diagnosis of SMA and less than 3 copies of SMN 2	To assess short-term benefit (efficacy & safety)	6 mo to 1 y may be sufficient
Types I to III	To assess short-term benefit (efficacy & safety)	1 – 2 y may be sufficient
Types I to III	To assess durability of benefit and delayed/rare adverse events	10 – 15 y (survival, comparative development milestones vs natural history of SMA and non-SMA patients, safety)

SMA: spinal muscular atrophy.

Setting
Nusinersen is given as an intrathecal injection in an outpatient hospital setting by specialized trained staff.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for randomized controlled trials.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Presymptomatic Patients with a Genetic Diagnosis of SMA and 2 But Less Than 4 copies of SMN2 
Non-Randomized Studies
In a multicenter, single-arm, open-label trial, Multiple Doses of Nusinersen Delivered to Infants with Genetically Diagnosed and Presymptomatic SMA (NURTURE; NCT02386553), 25 infants documented to have 5q SMA homozygous gene deletion, homozygous variant or compound heterozygote variant, and deemed likely to develop type I or II spinal muscular atrophy (SMA; based on number of SMN2 copies) received nusinersen. Of the 25 infants, 15 had 2 copies of SMN2 (most likely to develop type 1 SMA) and 10 had 3 copies of SMN2 (most likely to develop type II SMA). Infants’ age at first dose ranged from 8 to 41 days (≤ 14 days, n = 9; > 14 to ≤ 28 days, n = 12; > 28 days, n = 4). Patients will be followed through January 2022 to evaluate the primary outcome of time to death or respiratory intervention (invasive or noninvasive ventilation for > 6 h/d continuously over for ≥ 7 days or tracheostomy). Multiple secondary endpoints related to motor improvement, growth, survival, need for ventilation, and electrophysiology were also assessed. See Table 5 for study key characteristics summary. 

Results are summarized in Table 6. Data reported from July 2017 assessed whether children developed any protocol-defined symptoms of SMA by 13 months of age.²² Of the 17 children with analyzable data, 67% (8/12) and 20% (1/5) with two and three SMN2 copies, respectively, developed one or more SMA symptoms. None of these nine children achieved hands and knees crawling (average age of attainment: 8.5 months). Five of 12 (42%) children with two SMN2 copies were unable to stand with assistance (average age of attainment: 9.2 months). By the May 2018 interim analysis, caregivers reported all 25 (100%) children had achieved sitting without support, 22/25 (88%) of children had achieved walking with assistance, and 17/25 (68%) had achieved walking alone.²⁸ Four children each achieved sitting unsupported and walking alone later than expected in healthy children, and seven children were able to walk with assistance later than expected. At the most recent study visit, the mean (range) CHOP INTEND scores for children with two and three copies were similar and reflected near maximal motor function (two copies: 61.0 (46 to 64); three copies: 62.6 (8 to 64)). All 25 children were alive at the May 2018 interim analysis and 16% (4/25) children met the primary outcome of required respiratory intervention; all 4 children had 2 SMN2 copies. All of these infants received respiratory intervention during an acute, reversible illness, and none required permanent ventilation or tracheostomy.²⁸ While the FDA label has not been updated, the FDA agreed with sponsor findings that the open-label uncontrolled trials such as NURTURE were consistent with the results of the pivotal RCT and the FDA supported the efficacy of nusinersen in infantile SMA, including when given to presymptomatic patients. The prescribing label states: “some patients achieved milestones such as ability to sit unassisted, stand, or walk when they would otherwise be unexpected to do so, maintained milestones at ages when they would be expected to be lost, and survived to ages unexpected considering the number of SMN2 gene copies of patients enrolled in the studies.”¹⁴

The purpose of study limitations tables (see Tables 7 and 8) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table. Notable study limitations include a relatively short follow-up, which is inadequate to assess the durability of the treatment effect or safety, especially those that are potentially rare or have delayed onset.

Table 5. Key Characteristics Summary of NURTURE Study

Study	Study Type	Country	Sites	Dates	Dates	Interventions		Follow-Up
						Active	Comparator
Nusinersen
De Vivo et al. (2018); NURTURE28	Single arm cohort	U.S., EU, Asia	15	2015 –ongoing	Presymptomatic infants (n = 25) likely to develop SMA type I (n = 15) or II (n = 10)	Nusinersen at FDA approved dose	Historical cohort9	Analysis May 2018: median age 26.0 months (range: 14.0 to 34.3), and median time on treatment 27.1 months (15.1 to 35.5).

EU: European Union; FDA: Food and Drug Administration; SMA: spinal muscular atrophy.

Table 6. Summary of Results of NURTURE Study

Study	Independent Sitting	Walking with Assistance	Walking Alone
De Vivo et al. (2018); NURTURE29
N	17	17	17
Nusinersen (July 2017) 2 SMN2 copies 3 SMN2 copies	93% (14) 80% (8)	33% (5) 70% (7)	20% (3) 50% (5)
Swoboda et al. (2018); NURTURE28
N	25	25	25
Nusinersen (May 2018) 2 SMN2 copies 3 SMN2 copies	100% (15) 100% (10)	80% (12) 100% (10)	53% (8) 90% (9)
Expected Age Range of Attainment in Healthy Children (months)	3.8 to 9.2	5.9 to 13.7	8.2 to 17.6

Adapted from ICER Report on SMA (2018)

Range defined by 1st – 99th percentile for the windows of milestone achievement 

Table 7. Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
De Vivo et al. (2018); NURTURE29					Not sufficient duration for benefit Not sufficient duration for harms

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 8. Study Design and Conduct Limitations

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
De Vivo et al (2018); NURTURE29,	Participants not randomly allocated Allocation not concealed Allocation concealment unclear	Outcome assessed by treating physician

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: Presymptomatic Patients with a Genetic Diagnosis of SMA and a Minimum of 2 But Less Than 4 Copies of SMN2
The evidence for use of nusinersen for presymptomatic type I (infantile-onset) SMA consists of interim reporting on a single-arm study. After a median follow-up of 27.1 months, early initiation of nusinersen in 25 presymptomatic infantile SMA patients who were 14 months or older at the time of the analysis, 100% were alive, 100% achieved sitting without support, 88% achieved walking with assistance, and 68% achieved walking alone. All of these infants received respiratory intervention during an acute, reversible illness, and none required permanent ventilation or tracheostomy. These results demonstrate that early treatment resulted in the achievement of motor milestones among patients who are not likely to attain them without treatment. However, the data is limited for the durability of response and long-term data documenting safety and efficacy are needed.

TYPE I (Infantile-Onset) SMA
The evidence base for infantile-onset or type I SMA is summarized in Table 9. This evidence base consists of two RCTs and an early-phase open-labeled study. Results of a phase 2 RCT trial, Assess the Safety and Tolerability of Nusinersen in Participants with SMA (EMBRACE) are not available and not discussed further.

Table 9. Summary of Key Clinical Trial in Infantile-Onset or Type I SMA Patients

Study (Trial)	Trial Name	Design	Dates	Patients (N)	Outcome
Finkel et al. (2017)30 (NCT02193074)	ENDEAR	RCT	Aug 2014	Symptomatic (82)	Efficacy, safety
Unpublisheda (NCT02462759)	EMBRACE	RCT	Aug 2015	Symptomatic (21)	Safety, tolerability
Finkel et al. (2016)22 (NCT01839656)	CS3A	1 arm	May 2013	Symptomatic (20)	Safety, PK

PK: pharmacokinetics; RCT: randomized controlled trial; SMA: spinal muscular atrophy.
^a Available as abstract only.

Randomized Studies
The pivotal trial was a multicenter randomized, double-blind trial, Assess the Efficacy and Safety of Nusinersen in Infants with SMA(ENDEAR; NCT02193074) in which 121 infants with a documented genetic diagnosis of SMA with symptom onset before 6 months of age were randomized 2:1 to nusinersen (n = 80) or to sham injection (n = 41).³⁰ Nusinersen was approved on the basis of planned interim analysis of 82 patients who completed at least 183 days of treatment or died or withdrew. Patients’ demographics at baseline were 44% male, and 87% white, with a median length of treatment of 261 days (range, 6 – 442 days). The primary endpoint was the proportion of motor milestone responders. See Table 10 for the study summary.

Results are summarized in Table 11.³⁰ The trial met its coprimary endpoints, with nusinersen showing clinically meaningful improvement in motor milestones and probability of surviving or receiving permanent-assisted ventilation compared with sham control. The median time to death or the use of permanent-assisted ventilation was 22.6 weeks in the control group and was not reached in the nusinersen group. Multiple secondary endpoints showed a consistency in treatment effect favoring nusinersen over sham control. It is notable that half of the nusinersen-treated subjects did not achieve the primary endpoint, motor milestone response. The FDA (based on interim analysis) reported “although the response was clearly important, perhaps life-changing in few cases (6% of patients gained the ability to sit without assistance, a feat that almost never occurs in individuals with only 2 copies of the SMN2 gene), the majority of patients had a modest response or no response at all.” Further, the FDA noted that 94% of patients were not able to sit, no patient was able to stand unassisted, and no patient progressed to walking. On the motor response rate (using the HINE), the FDA concluded that, on average, mean motor milestone scores in nusinersen-treated patients improved from approximately 1 point (before treatment) to approximately 4 points at 12 months — a difference of 3 points over 6 months. At 12 months, a healthy baby would achieve a motor milestone score of 22. Thus, nusinersen is a disease-modifying treatment and not a cure. While no irreversible harms were observed in the preliminary clinical data analyzed by the FDA before drug approval, the FDA noted that such harms could not be ruled out based on animal toxicity data (potential of neurotoxicity) and class effects of antisense oligonucleotides (coagulation abnormalities, thrombocytopenia, renal toxicity). Given the limited data on the durability of response, long-term data documenting safety and efficacy is needed.

The purpose of the study limitations table (see Table 12) is to display notable limitations identified in a study. This information is synthesized as a summary of the body of evidence following each table. No study design and conduct gaps were identified. Notable study limitations include a relatively short follow-up, which is inadequate to assess the durability of the treatment effect or safety, especially those that are potentially rare or have delayed onset. In addition to the gaps identified in the tables, the two treatment groups were not balanced with respect to age at symptom onset, use of ventilatory support, and the presence of symptoms specific to SMA. These were higher in the nusinersen group than the control group. None of these differences were tested for statistical significance.

Table 10. Summary of Key ENDEAR Trial

Study	Study Type	Country	Sites	Dates	Participants	Interventions		Follow-Up
						Active	Comparator
Nusinersen
Finkel et al. (2017); ENDEAR30	DB-RCT	U.S., EU, Asia	31	2014 –2016	SMA type I with symptom onset before 6 mo (n = 121)	Nusinersen at FDA- approved dose (n = 80)	Placebo (n = 41)	Median length of treatment of 261 days (range, 6 – 442 days); trial terminated early

DB-RCT; double-blind randomized controlled trial; EU: European Union; FDA: Food and Drug Administration; SMA: spinal muscular atrophy.

Table 11. Summary of Results of ENDEAR Trial

Study	Percent motor milestone response (HINE section 2)a	No death or use of permanent-assisted ventilationb	≥ 4-point improvement in CHOP INTEND scorec	No death	No use of permanent-assisted ventilationb	CMAP responsed
Finkel et al. (2017); ENDEAR30
N	121	121	121	121	121	121
Nusinersen	37/73 (51)	49/80 (61)	52/73 (71)	67/80 (84)	62/80 (78)	26/73 (36)
Sham	0/37 (0)	13/41 (32)	1/37 (3)	25/41 (61)	28/41 (68)	2/37 (5)
HR (95% CI)	-	0.53 (0.32 to 0.89)	-	0.37 (0.18 to 0.77)	0.66 (0.32 to 1.37)	-
P value	< 0.001	0.005	< 0.001	0.004	0.13	-

Adapted from Finkel et al. (2017).³⁰ Values are percent or n (%) or as otherwise indicated. Final analysis conducted on November 21, 2016 included 121 data from infants who had undergone randomization and the assigned procedure at least once.
CI: confidence interval; CMAP: compound muscle action potential; CHOP INTEND: Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE: Hammersmith Infant Neurologic Exam; HR: hazard ratio.
^a Motor milestone response was defined according to scores on the HINE-2, which assesses the development of motor function through the achievement of motor milestones; in this trial, the scores accounted for 7 of the 8 motor milestone categories, excluding voluntary grasp. Infants were considered to have a motor milestone response if they met the following 2 criteria: improvement in at least 1 category (i.e., an increase in the score for head control, rolling, sitting, crawling, standing, or walking of ≥ 1 point, an increase in the score for kicking of ≥ 2 points, or achievement of the maximal score for kicking) and more categories with improvement than categories with worsening (i.e., a decrease in the score for head control, rolling, sitting, crawling, standing, or walking of ≥ 1 point or a decrease in the score for kicking of ≥ 2 points).
^b Permanent-assisted ventilation was defined as tracheostomy or ventilatory support for at least 16 h/d for more than 21 continuous days in the absence of an acute reversible event, as determined by an independent endpoint adjudication committee.
^c A CHOP INTEND response was defined as an increase of at least 4 points from baseline in CHOP INTEND score at the end-of-trial visit (day 183, 302, or 394).
^d A CMAP response was defined as an increase in the peroneal CMAP amplitude to at least 1 mV (or maintenance of an amplitude of ≥ 1 mV) at the end-of-trial visit (day 183, 302, or 394).

Table 12. Relevance Study Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Finkel et al. (2017); ENDEAR30					Not sufficient duration for benefit Not sufficient duration for harms

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Non-Randomized Studies
Supportive evidence also includes a published phase 2, open-labeled proof-of-concept study (NCT01839656) in which 20 patients with type I SMA with the onset of symptoms before 6 months of age were randomized to 2 doses of nusinersen (6 mg [n = 4], 12 mg [n = 16]). The study was completed in 2017 and the results of the interim analysis done in January 2016 were published.²² Incremental improvements in motor milestones on the HINE-2 were observed in 84% (16/19) of patients at the last visit compared with baseline. Improvements of 2 points or more per motor milestone category for at least 1 category were observed in 68% (13/19) of patients. Mean increase in CHOP INTEND scores was 11. 5 points from baseline to the last visit, with 78% (14/18) showing an improvement. Additional data from this study were suggestive of improvement in survival, permanent ventilation independence, and neuromuscular electrophysiology. Small sample size, short follow-up (2 – 32 months), and lack of a control group limit the interpretation of study results. Nevertheless, the data are indicative of the potential benefit of nusinersen in type I SMA.

Section Summary: Type I (Infantile-Onset) SMA
The evidence for use of nusinersen for symptomatic type I (infantile-onset) SMA consists of two double-blind RCTs and a single-arm study. The largest phase 3 confirmatory ENDEAR trial (n = 121) showed clinically meaningful and statistically significant improvement in motor milestones and event-free survival that exceeded those seen in the control group. However, most patients had a modest response or no response, and only a small proportion of patients (6%) gained the ability to sit without assistance. On average, the mean motor milestone score in nusinersen-treated patients improved by three points over six months. Given the limited data on the durability of response, long-term data documenting safety and efficacy are needed.

Type II or III SMA
The evidence base for patients with type II or III SMA is summarized in Table 13.

Table 13. Summary of Key Trial Characteristics in Type II and III SMA Patients

Study (Trial)	Trial Name	Design	Dates	N	Outcomes
Chiriboga et al. (2016)31 (NCT01494701)	CS1	1 arm	Nov 2011	28	Safety and tolerability
Chiriboga et al. (2016)31 (NCT01780246)	CS10	1 arm	Jan 2013	18	Safety and tolerability
Unpublished (NCT01703988)	CS2	1 arm	Oct 2012	34	Safety and tolerability
Unpublished (NCT02052791)	CS12	1 arm	Jan 2014	47	Safety and tolerability
Mercuri et al. (2018)32 (NCT02292537)	CHERISH	RCT	July 2014	126	Efficacy and safety

RCT: randomized controlled trial; SMA: spinal muscular atrophy.

The evidence base for patients with type II and III SMA consists of four early-phase, open-labeled studies and a double-blind phase 3 RCT. Of these, results of two early-phase 1 studies and one double-blind phase 3 RCT³² have been published.³¹ However, data from phase 1 studies are not reviewed because they were early dose-finding and proof-of-concept studies. The remaining 2 studies — CS2 and CS12 — have not been published yet but data were sourced from the Academy of Managed Care Pharmacy dossier supplied by Biogen (2016) and only summarized at the end of this section.³³

Randomized Studies
Similar to ENDEAR, Assess Clinical Efficacy and Safety of Nusinersen in Participants with Later-onset SMA (CHERISH)³² was also designed as a multicenter, randomized, double-blind trial that evaluated 126 nonambulatory patients with genetic documentation of 5q SMA (a homozygous deletion, variant, or compound heterozygote in SMN1) with the onset of signs and symptoms at more than 6 months and between ages 2 and 12 years at screening as well as the presence of the following features at screening: the ability to sit independently, no history of the ability to walk independently (defined as the ability to walk ≥ 15 feet unaided), and a Hammersmith Functional Motor Scale-Expanded (HFMSE) score between 10 and 54. Children were excluded if they had a severe contracture, evidence of severe scoliosis on radiography, respiratory insufficiency, or a gastric tube placed to provide adequate nutrition. Because of the strict inclusion and exclusion criteria to enroll a homogenous and younger patient population (median age from four to three years in treatment and control group, respectively), the results from this trial have limited generalizability to type II and III SMA patients generally seen in clinical practice. See Table 14 for study summary.

The primary endpoint was change in HFMSE score compared with baseline. HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Results are summarized in Table 15. The trial met its primary endpoints with nusinersen showing clinically meaningful improvement in mean HFMSE scores compared with sham control. In terms of responder analysis, a higher percentage of children in the nusinersen group (57%) than in the control group (26%; p < 0.001) had an increase from baseline to month 15 in the HFMSE score of at least 3 points, which was considered meaningful. Multiple secondary endpoints summarized in Table 15 showed a consistency in treatment effect favoring nusinersen compared with sham control. Approximately a quarter of placebo patients reported clinically meaningful improvements in HFMSE scores at 15 months, which is most likely a combination of the placebo effect, the learning curve for the assessment of the HFMSE and Revised Upper Limb Module (RULM) scores, and initial developmental gains, particularly in younger children. Mean HFMSE score plotted over time (data not shown) show that the initial improvement in HFMSE scores in the placebo arm was short-lived and showed a declining trend starting at 6 months and continuing to the end of the trial (i.e., 15 months). Analyses of the magnitude of change in the HFMSE score stratified by age and disease duration (data not shown) revealed greater, improvements in younger children and in those who received treatment earlier in their disease course, respectively. The overall incidences of adverse events and moderate and serious adverse events were similar for the nusinersen group and the control group (93% and 100% vs 46% and 55%, respectively). Adverse events with an incidence of five or more percentage points higher in the nusinersen group than in the control group were pyrexia, headache, vomiting, back pain, and epistaxis. Given the limited data on the durability of response, long-term data documenting safety and efficacy are needed.

Similar to ENDEAR trial, the confirmatory phase 3 CHERISH trial was terminated early because the results of a preplanned interim analysis met the primary endpoint of efficacy.³³ However, in the prespecified interim analysis, data for the 15-month time-point for HFMSE score were missing in 58% (49/84) and 55% (23/42) patients in the nusinersen and control group, respectively, and was imputed using the use of a multiple imputation method to conduct an intention-to-treat analysis. The missing data were largely due to patients who had not completed their 15-month visit at the time of analysis. In the final analysis, the proportions of missing data for HFMSE and RULM scores were imputed for 21% (18/84) and 19% (8/42) patients in the nusinersen and control group, respectively, and imputed using multiple imputation method to conduct an intention-to-treat analysis. For all other outcomes, only the observed data were included. The authors conducted multiple sensitivity analyses including (1) multiple imputations using mixed-effects model for repeated measures, (2) only completers (per protocol), (3) last observation carried forward approach, and (4) for children who had a missing 15-month assessment and discontinued due to treatment failure or death, the worst of the last observed value or the baseline value was imputed. The intergroup difference between the least-squares mean change from baseline to month 15 remained statistically significant in favor of nusinersen in all 4 scenarios with highest treatment effect (change, 5.2) in the “completers only analysis.”

The purpose of the study limitations table (see Table 16) is to display notable limitations identified in a study. This information is synthesized as a summary of the body of evidence following each table. No study design and conduct gaps were identified. Notable limitations include a relatively short follow-up, which is inadequate to assess the durability of the treatment effect or safety, especially those that are potentially rare or have delayed onset. In addition, survival, ventilation, and event-free survival were not evaluated in CHERISH.

Table 14. Summary of Key Characteristics of CHERISH Trial

Study	Study Type	Country	Sites	Dates	Participants	Interventions		Follow-Up
						Active	Comparator
Nusinersen
Mercuri et al. (2018); CHERISH32	DB-RCT	U.S., EU, Asia	24	2014 –2017	SMA type II with symptom onset after 6 mo (n = 126)	Nusinersen at FDA- approved dose (n = 84)	Placebo (n = 42)	Prespecified interim analysis when all children followed for minimum of six months and 39 or more children had completed 15-month evaluations

DB-RCT; double-blind randomized controlled trial; EU: European Union; FDA: Food and Drug Administration; SMA: spinal muscular atrophy.

Table 15. Summary of Results of CHERISH Trial

Study	Din HFMSE score from baseline, LSM (95% CI)a	Patients with Din HFMSE score ≥ 3 points Percent (95% CI)	Patients who achieved ≥ 1 new WHO motor milestone Percent (95% CI)	Dfrom baseline in no. of WHO motor milestones achieved, LSM (95% CI)a	Drom baseline in RULM score, LSM (95% CI)a	Patients who achieved ability to stand alone Percent (95% CI)	Patients who achieved ability to walk with assistance Percent (95% CI)
Mercuri et al. (2018); CHERISH32
N	126	126	126	126	126	126	126
Nusinersen	3.9 (3.0 to 4.9)	57 (46 to 68)	20 (11 to 31)	0.2 (0.1 to 0.3)	4.2 (3.4 to 5.0)	2 (0 to 8)	2 (0 to 8)
Sham	-1.0 (-2.5 to 0.5)	26 (12 to 40)	6 (1 to 20)	-0.2 (-0.4 to 0)	0.5 (-0.6 to 1.6)	3 (0 to 15)	0 (0 to 10)
Difference (95% CI)	4.9 (3.1 to 6.7)	30.5 (12.7 to 48.3)	14 (-7 to 34)	0.4 (0.2 to 0.7)	3.7 (2.3 to 5.0)	-1 (-22 to 19)	2 (-19 to 22)
Odds ratio (95% CI)b	-	6 (2 to 15)	-	-	-	-	-
P value	< 0.001c	< 0.001	-	-	-	-	-

Adapted fromMercuri et al. (2018).³²
Outcomes assessed at 15 Months. In the final analysis, the multiple imputation method was used for missing data to assess changes from baseline in the HFMSE score, percentage of children with a change in HFMSE score of at least 3 points, and change from baseline in the RULM score. The proportion of missing data for 15-month time-point for HFMSE score were 21% (18/84) and 19% (8/42) in the nusinersen and control group, respectively, and imputed using a multiple imputation method to conduct an intention-to-treat analysis.
CI: confidence interval; HFMSE: Hammersmith Functional Motor Scale-Expanded; LSM: least-squares mean; RULM: Revised Upper Limb Module; WHO: World Health Organization.
^a LSM change and LSM difference in change between groups were based on analysis of covariance with group assignment as a fixed effect and with adjustment for each child’s age at screening and the value at baseline.
^b This value is an odds ratio rather than a difference. The odds ratio for nusinersen vs control was based on logistic regression, with group assignment as a fixed effect and with adjustment for each child’s age at screening and the HFMSE score at baseline.
^c Because the p-value for the primary endpoint was significant in the interim analysis, this endpoint was not formally tested for significance in the final analysis.

Table 16. Relevance Study Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Mercuri et al. (2018); CHERISH32				Key health outcomes not addressed;	Not sufficient duration for benefit Not sufficient duration for harms

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Non-Randomized Studies
CS2 is phase 1/2, single-arm study that was completed in January 2015.³³ It included 34 patients between the ages of 2 and 15 with a documented genetic diagnosis of 5q SMA and clinical signs and symptoms attributed to SMA. Patients received various doses of nusinersen, ranging from 3 to 12 mg, with an average 8-month follow-up. The primary endpoint was safety, and the secondary endpoint was pharmacokinetic parameters. Multiple exploratory endpoints related to motor function were assessed including a change in HFMSE score. CS12 was a long-term extension study that included patients from CS2 and other studies. In the 6 patients with type II SMA, the mean change in HFMSE score after 1050 days of treatment was 12.3. In the 7 patients with type III SMA, the mean change in HFMSE score after 1050 days of treatment was 1.6.

Section Summary: Type II or III SMA
The evidence for the use of nusinersen for patients with type II or III SMA consists of four single-arm studies and a double-blind RCT. The small single-arm studies employed multiple doses of nusinersen, ranging from 6 to 12 mg in patients with type II and III SMA. The available results did not stratify outcomes by dose or type of SMA, and therefore it is difficult to interpret the data from these studies. The largest phase 3 confirmatory CHERISH trial (126 patients) showed clinically meaningful and statistically significant improvement in motor milestones that exceeded those seen in the control group. Multiple secondary endpoints showed a consistency in treatment effect favoring nusinersen over sham control. The treatment effect was greater in younger children and in those who received treatment earlier in their disease course. Given the limited data on the durability of response, long-term data documenting safety and efficacy are needed.

Type 0 or IV SMA
There are currently no studies assessing the efficacy and safety of nusinersen in patients with type 0 or IV SMA.

Safety: Nusinersen
As per the prescribing label, thrombocytopenia (including acute, severe thrombocytopenia) and renal toxicity (including potentially fatal glomerulonephritis) have been observed with antisense oligonucleotides.¹⁴ In the controlled ENDEAR trial, the most common adverse events that occurred in at least 20% of nusinersen-treated patients and occurred at least 5% more frequently than in sham-controlled patients were a lower respiratory infection, upper respiratory infection, and constipation. Atelectasis (a serious adverse event) was more frequent in nusinersen-treated patients (14%) than in sham control (5%). Adverse events reported verbally were not assessable in the sham-controlled trial because patients were infants. In the open-labeled studies of patients with type II or III SMA, the most common adverse events were a headache (50%), back pain (41%), and post-lumbar puncture syndrome (41%), which occurred within 5 days of lumbar puncture. Other adverse events in these patients were consistent with reactions observed in the controlled study. Also, 1 case of severe hyponatremia in an infant that required salt supplementation for 14 months and 2 cases of rash were reported. Both patients with rash continued to receive nusinersen and had a spontaneous rash resolution.

Development of anti-nusinersen antibodies was assessed in 126 patients of whom 5 (4%) developed treatment-emergent antidrug antibodies, of which 3 were transient, and2 were persistent. There are insufficient data to evaluate the effect of antidrug antibodies on clinical response, adverse events, or the pharmacokinetic profile of nusinersen.¹⁴

Summary of Evidence
Spinal muscular atrophy is an inherited disorder caused by homozygous deletions or variants in the SMN1 gene. As a consequence of absent or low levels of SMN1 protein, the motor neurons in spinal cord degenerate, resulting in atrophy of the voluntary muscles of the limbs and trunk. Nusinersen is a synthetic antisense oligonucleotide designed to bind to a specific sequence in exon 7 of the SMN2 transcript causing the inclusion of exon 7 in the SMN2 transcript, leading to the production of full length functional SMN2 protein, which is very similar to SMN1. Onasemnogene abeparvovec-xioi is intended as a one-time gene replacement therapy designed to deliver a functional copy of the SMN1 gene to motor neuron cells of patients 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.

Practice Guidelines and Position Statements
National Institute for Health and Care Excellence
The National Institute for Health and Care Excellence (2018) issued a provisional recommendation against the use of nusinersen for the treatment for spinal muscular atrophy (SMA) due to the lack of long-term evidence, and the subsequent uncertainty surrounding long-term benefits. Additionally, the National Institute for Health Care and Excellence also concluded that there were uncertainties in the economic evidence and it was not deemed cost effective. The Institute was expected to release the Report in November 2018 but a final Report has not been released at the time of the last update of this Medical Policy.

Institute for Clinical and Economic Review
The Institute for Clinical and Economic Review published a final Report on comparative effectiveness and value of nusinersen and onasemnogene abeparvovec-xioi for SMA on April 3, 2019 and subsequently on May 24, 2019 published an update following FDA approval of onasemnogene abeparvovec-xioi.³⁴

Nusinersen
Based on the lack of relevant data, the Report concluded that the evidence for nusinersen was insufficient for type 0 and IV SMA.

For infantile-onset SMA, the Report concluded with high certainty that nusinersen provides a substantial net health benefit, and rate the evidence base as “superior” to standard care (A). Limitations included potentially limited generalizability, as Type I SMA patients with more severe disease were underrepresented in the trials and may not adequately reflect the “real-world” "patient population.”

For later-onset SMA, the Report concluded with moderate certainty that nusinersen provides a small or substantial net health benefit with a high certainty of at least a small net health benefit and rate the evidence as “incremental or better” (B+). Limitations included potentially limited generalizability (trial population may not reflect the true patient population) lack of data on survival, ventilation, and event-free survival and long-term safety and durability of clinical benefit.

For presymptomatic SMA, the Report concluded with moderate certainty of a small or substantial net health benefit with a high certainty of at least a small net health benefit and rate the evidence as “incremental or better” (B+).

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 23.

Table 23. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing (Nusinersen)
NCT02594124a	An Open-Label Study (SHINE) for Patients With Spinal Muscular Atrophy (SMA) Who Participated in Studies With IONIS-SMNRx	271	Feb 2020
Ongoing (Onasemnogene abeparvovec)
NCT03381729 (STRONG)a	Study of Intrathecal Administration of AVXS-101 for SMA	27	Aug 2019
NCT03306277 (STR1VE US)a	Gene Replacement Therapy Clinical Trial for Patients With SMA Type 1	20	Mar 2020
NCT03461289 (STR1VE EU)a	Single-Dose Gene Replacement Therapy Clinical Trial for Patients With SMA Type 1	30	Nov 2020
NCT03505099 (SPRINT)a	Pre-Symptomatic Study of Intravenous AVXS-101 in SMA for Patients With Multiple Copies of SMN2	44	Apr 2023
NCT03421977 (START)a,b	Long-Term Follow-up Study for Patients From AVXS-101-CL-101	15	Dec 2033
REACH (yet to register)a	Information not available	Information not available	Information not available

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

References  

1. Prior TW, Snyder PJ, Rink BD, et al. Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet A. Jul 2010;152A(7):1608-1616. PMID 20578137
2. Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. Aug 2007;22(8):1027-1049. PMID 17761659
3. Lorson CL, Hahnen E, Androphy EJ, et al. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A. May 25 1999;96(11):6307-6311. PMID 10339583
4. Lefebvre S, Burlet P, Liu Q, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. Jul 1997;16(3):265-269. PMID 9207792
5. Feldkotter M, Schwarzer V, Wirth R, et al. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet. Feb 2002;70(2):358-368. PMID 11791208
6. Muscular Dystrophy Association. Spinal Muscular Atrophy. n.d.; https://www.mda.org/disease/spinal-muscular-atrophy. Accessed January 16, 2018.
7. National Organization for Rare Disorders, Russman B. Spinal Muscular Atrophy. 2012; https://rarediseases.org/rare-diseases/spinal-muscular-atrophy/. Accessed January 16, 2018.
8. Zerres K, Rudnik-Schoneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol. May 1995;52(5):518-523. PMID 7733848
9. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. Aug 26 2014;83(9):810-817. PMID 25080519
10. Rudnik-Schoneborn S, Hausmanowa-Petrusewicz I, Borkowska J, et al. The predictive value of achieved motor milestones assessed in 441 patients with infantile spinal muscular atrophy types II and III. Eur Neurol. 2001;45(3):174-181. PMID 11306862
11. Farrar MA, Vucic S, Johnston HM, et al. Pathophysiological insights derived by natural history and motor function of spinal muscular atrophy. J Pediatr. Jan 2013;162(1):155-159. PMID 22809660
12. Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med. Mar 2010;12(3):145-152. PMID 20057317
13. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. Jan 2012;20(1):27-32. PMID 21811307
14. Biogen Inc. Highlights of Prescribing Information: Spinraza (nusinersen) injection, for intrathecal use: Prescribing label. 2016; https://www.spinraza.com/content/dam/commercial/specialty/spinraza/caregiver/en_us/pdf/spinraza-prescribing-information.pdf. Accessed May 28, 2019.
15. Dominguez E, Marais T, Chatauret N, et al. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum Mol Genet. Feb 15 2011;20(4):681-693. PMID 21118896
16. Foust KD, Nurre E, Montgomery CL, et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. Jan 2009;27(1):59-65. PMID 19098898
17. Foust KD, Wang X, McGovern VL, et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. Mar 2010;28(3):271-274. PMID 20190738
18. Valori CF, Ning K, Wyles M, et al. Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci Transl Med. Jun 9 2010;2(35):35ra42. PMID 20538619
19. De Sanctis R, Coratti G, Pasternak A, et al. Developmental milestones in type I spinal muscular atrophy. Neuromuscul Disord. Nov 2016;26(11):754-759. PMID 27769560
20. Glanzman AM, Mazzone E, Main M, et al. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord. Mar 2010;20(3):155-161. PMID 20074952
21. Glanzman AM, McDermott MP, Montes J, et al. Validation of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther. Winter 2011;23(4):322-326. PMID 22090068
22. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. Dec 17 2016;388(10063):3017-3026. PMID 27939059
23. Glanzman AM, O'Hagen JM, McDermott MP, et al. Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III. J Child Neurol. Dec 2011;26(12):1499-1507. PMID 21940700
24. Mercuri E, Finkel R, Montes J, et al. Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials. Neuromuscul Disord. Feb 2016;26(2):126-131. PMID 26776503
25. Kaufmann P, McDermott MP, Darras BT, et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. Oct 30 2012;79(18):1889-1897. PMID 23077013
26. Haataja L, Mercuri E, Regev R, et al. Optimality score for the neurologic examination of the infant at 12 and 18 months of age. J Pediatr. Aug 1999;135(2 Pt 1):153-161. PMID 10431108
27. Kolb SJ, Coffey CS, Yankey JW, et al. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. Dec 2017;82(6):883-891. PMID 29149772
28. Swoboda KJ, De Vivo DC, Bertini E, et al. Nusinersen in Infants Who Initiate Treatment in a Presymptomatic Stage of Spinal Muscular Atrophy (SMA): Interim Efficacy and Safety Results From the Phase 2 NURTURE Study. Paper presented at: 23rd International Annual Congress of the World Muscle Society, 2018; October 2-6, 2018; Mendoza, Argentina.
29. De Vivo DC, Bertini E, Hwu W-L, et al. Nusinersen in Infants Who Initiate Treatment in a Presymptomatic Stage of Spinal Muscular Atrophy (SMA): Interim Efficacy and Safety Results From the Phase 2 NURTURE Study. Paper presented at: Muscular Dystrophy Association Clinical Conference 2018; March 11-14, 2018; Arlington, VA.
30. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. Nov 2 2017;377(18):1723-1732. PMID 29091570
31. Chiriboga CA, Swoboda KJ, Darras BT, et al. Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy. Neurology. Mar 08 2016;86(10):890-897. PMID 26865511
32. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med. Feb 15 2018;378(7):625-635. PMID 29443664
33. Biogen, RTI Health Solutions. Formulary Submission Dossier: Spinraza (Nusinersen) for Spinal Muscular Atrophy (NS-US-0199). Cambridge, MA: Biogen; 2016 December.
34. Institute for Clinical and Evidence Review. Spinraza® and Zolgensma® for Spinal Muscular Atrophy: Effectiveness and Value (Final Evidence Report April 3, 2019; Updated May 24, 2019). 2019; https://icer-review.org/wp-content/uploads/2018/07/ICER_SMA_Final_Evidence_Report_052419.pdf. Accessed May 28, 2019.
35. Schultz M, Swoboda KJ, Wells C, et al. AVXS-101 Gene-Replacement Therapy (GRT) Clinical Trial in Presymptomatic Spinal Muscular Atrophy (SMA): Phase 3 Study Design and Initial Baseline Demographics. The 23rd International Annual Congress of the World Muscle Society; October 2-6, 2018; Mendoza, Argentina.
36. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. Nov 2 2017;377(18):1713-1722. PMID 29091557
37. Mendell JR, Al-Zaidy S, Shell R, et al. AVXS-101 Phase 1 Gene-Replacement Therapy Clinical Trial in SMA Type 1: 24-Month Event-Free Survival and Achievement of Developmental Milestones (P.177). The 23rd International Annual Congress of the World Muscle Society; October 2-6, 2018; Mendoza, Argentina.
38. Day JW, Feltner DE, Ogrinc F, et al. AVXS-101, Gene-Replacement Therapy for Spinal Muscular Atrophy Type 1 (SMA1): Pivotal Study (STR1VE) Update (P.181). The 23rd International Annual Congress of the World Muscle Society; October 2-6, 2018; Mendoza, Argentina.
39. Lin CW, Kalb SJ, Yeh WS. Delay in diagnosis of spinal muscular atrophy: a systematic literature review. Pediatr Neurol. Oct 2015;53(4):293-300. PMID 26260993
40. Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. Sep 2009;85(3):408-413. PMID 19716110
41. Inc. A. Highlights of Prescribing Information: Zolgensma (onasemnogene abeparvovec-xioi) suspension for intravenous infusion: Prescribing label. 2019; https://www.fda.gov/media/126109/download. Accessed May 27, 2019.
42. Dodick DW, Turkel CC, DeGryse RE, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. Jun 2010;50(6):921-936. PMID 20487038
43. Aurora SK, Winner P, Freeman MC, et al. OnabotulinumtoxinA for treatment of chronic migraine: pooled analyses of the 56-week PREEMPT clinical program. Headache. Oct 2011;51(9):1358-1373. PMID 21883197
44. Cure SMA. AveXis Files for FDA Approval of Gene Therapy for Spinal Muscular Atrophy Type I. 2018; http://www.curesma.org/news/avexis-fda-approval-type-i.html. Accessed November 15, 2018.

Coding Section 

Codes	Number	Description
CPT	96450	Chemotherapy administration, into CNS (e.g., intrathecal), requiring and including spinal puncture
HCPCS		No specific code at this time. An unlisted code such as J3490 would be used.
	C9489 (effective 7/1/2017)	Injection, Nusinersen, 0.1 mg
	J2326 (effective 1/1/2018)	Injection, Nusinersen, 0.1 mg
	J3399 (effective 7/1/2020)	Injection, onasemnogene abeparvovec-xioi, per treatment, up to 5x10¹⁵ vector genomes
ICD-10-CM	G12.0	Infantile spinal muscular atrophy, type I [Werdnig-Hoffman]
ICD-10-PCS		ICD-10-PCS codes are only used for inpatient services.
	3E0R3GC	Administration, physiological systems and anatomical regions, introduction, spinal canal, percutaneous, other therapeutic substance
Type of Service
Place of Service

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2017 Forward     

03/15/2023	Annual review, no change to policy intent
03/16/2022	Annual review, no change to policy intent. Updating policy number.
03/17/2021	Annual review, no change to policy intent.
06/17/2020	Updated coding. Added Code J3399 to be effective 7/1/2020. No other changes.
03/12/2020	Annual review, rewriting policy verbiage for specificity and clarity. Also updating rationale and references.
03/04/2019	Annual review, no change to policy intent. Updating rationale and references.
03/07/2018	Annual review, no change to policy intent.
11/28/2017	Updating with 2018 coding. No other changes.
05/22/2017	Interim Review. Updated coding section.
03/01/2017	New Policy