Medical Policy

Policy Num:      05.001.028
Policy Name:    Treatment for Spinal Muscular Atrophy
Policy ID:          [05.001.028]  [Ac / B / M+ / P+]  [5.01.28]

Last Review:       April 19, 2024
Next Review:      April 20, 2025
 

Related Policies: None

Treatment for Spinal Muscular Atrophy

Summary

Description

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 survival motor neuron 1 protein, the motor neurons in the spinal cord degenerate, resulting in atrophy of the voluntary muscles of the limbs and trunk. Treatments in this review include 1) Nusinersen which 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 survival motor neuron 2 protein, which is very similar to SMN1. 2) Onasemnogene abeparvovec-xioi which 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 spinal muscular atrophy. 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 survival motor neuron protein expression. 3) Risdiplam which is a once-daily self-administered oral therapy. It is a selective SMN2 splicing modifier designed to bind with specificity to SMN2 pre-mRNA to modulate SMN2 pre-mRNA splicing towards the production of full-length SMN2 mRNA.

Summary of Evidence

Presymptomatic Patients with a Genetic Diagnosis of Spinal Muscular Atrophy and a Minimum of 2 but Less Than 4 Copies of SMN2

For individuals who are presymptomatic with a genetic diagnosis of spinal muscular atrophy and a minimum of 2 but less than 4 copies of SMN2 who receive nusinersen, the evidence includes an open-label single-arm trial. Relevant outcomes are overall survival, change in disease status, morbid events, functional outcomes, quality of life, and treatment-related mortality and morbidity. After a median of 2.9 years of follow-up of 25 infants who received the first dose of nusinersen at a median age of 22 days and are now median age of 34.8 months, 100% were alive, 100% achieved the ability to sit without support, 92% achieved the ability to walk with assistance, and 88% achieved the ability to walk independently. While none required permanent ventilation or tracheostomy, 4 (16%) participants with 2 SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. Results reported with additional 2 years of follow-up (data cut-off: February 15, 2021) demonstrated durability of treatment effect, and favorable safety profile after ~5 yeas of nusinersen treatment. These results demonstrate that early treatment resulted in the achievement of motor milestones among patients who are not likely to attain them without treatment. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Infantile-Onset or Type I Spinal Muscular Atrophy

For individuals who have type I (infantile-onset) spinal muscular atrophy who receive nusinersen, the evidence includes a randomized, double-blind, controlled trial. Relevant outcomes are overall survival, change in disease status, morbid events, functional outcomes, quality of life, and treatment-related mortality and morbidity. The phase 3 confirmatory ENDEAR trial (N =121) showed clinically meaningful and statistically significant improvement in motor milestones, event-free survival, and overall survival that exceeded those seen in the control group, with an acceptable safety profile. The proportion of patients, who met the primary endpoint responder definition of achieving motor milestones, was 51% in the nusinersen arm compared with 0% in the sham-controlled arm. Further, the hazard ratio for event-free survival was 0.53 favoring nusinersen over sham-controlled. It is notable, however, that 50% of nusinersen-treated subjects did not achieve the primary endpoint motor milestone response. 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 3 points over 6 months. Given the limited data on the durability of response, long-term safety, and lack of efficacy in a substantial number of patients continued risk-benefit assessment of long-term treatment with nusinersen is necessary. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Type II and III Spinal Muscular Atrophy

For individuals who have type II or III spinal muscular atrophy who receive nusinersen, the evidence includes a double-blind, randomized controlled trial. Relevant outcomes are overall survival, change in disease status, morbid events, functional outcomes, quality of life, and treatment-related mortality and morbidity. Efficacy findings from single-arm studies of type II and III spinal muscular atrophy are difficult to interpret because these trials used a wide range of nusinersen doses and lacked control arms. The phase 3 confirmatory CHERISH trial (N =126) showed clinically meaningful and statistically significant improvement in motor milestones (measured using Hammersmith Functional Motor Scale–Expanded scores) that exceeded those seen in the control group (difference of 5.9 points favoring nusinersen over sham control, p<.001). The respective proportion of patients with clinically meaningful improvements in Hammersmith scores greater than 3 points was 57% vs 26% (p<.001). Multiple secondary endpoints also showed a consistency in treatment effect favoring nusinersen over sham control. Given the limited data on the durability of response, long-term safety, and lack of efficacy in a substantial number of patients continued risk-benefit assessment of long-term treatment with nusinersen is necessary. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Onasemnogene Abeparvovec-Xioi

Infantile-Onset or Spinal Muscular Atrophy Type I

For individuals who have spinal muscular atrophy type I (infantile-onset) who receive onasemnogene abeparvovec-xioi, the evidence includes 2 single-arm studies. Relevant outcomes are overall survival, change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. The FDA approval was based on a pooled analysis of 21 patients from the 2 single-arm studies. 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 patients with spinal muscular atrophy type I with 2 copies of SMN2. Results of the phase 3 confirmatory study (STRIVE-US) published after the FDA approval were consistent with previously available findings at the time of approval. Results of an ongoing study to assess long-term safety and durability of response in infants with SMA type 1 with a median time since dosing of 5.2 years showed that the developmental milestones achieved in the phase 1 clinical trial were maintained and new milestones gained. Thirteen of 15 original patients were included in the analysis. All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of “standing with assistance” without the use of nusinersen. However, 7 of the 13 subsequently received concomitant nusinersen. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Presymptomatic Patients with a Diagnosis of Spinal Muscular Atrophy and Less Than 4 Copies of SMN2

For individuals who are presymptomatic with a genetic diagnosis of spinal muscular atrophy and less than 4 copies of SMN2 who receive onasemnogene abeparvovec-xioi, the evidence includes one single-arm study- SPR1NT. Relevant outcomes are overall survival, change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. The SPR1NT trial included infants less than 6 weeks of age who did not display any symptoms of SMA at the time of infusion. The trial was divided into 2 cohorts based on SMN2 copy number. All patients irrespective of SMN2 copy numbers achieved their respective primary endpoint, able to sit without support for at least 30 seconds at 18 months of age for 2 copies of SMN2 or ability to stand for 3 seconds or more without assistance at 24 months for those with 3 copies of SMN2. Multiple secondary endpoints were also supportive of clinical benefit including achievement of age-appropriate gross motor milestones and functions and independence from nutritional and respiratory support. In the natural history of SMA Type 1, untreated children with 2 or 3 copies of the SMN2 backup gene would not achieve such skills. These results demonstrate that early treatment resulted in the achievement of motor milestones among patients who are not likely to attain them without treatment. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Risdiplam

Spinal Muscular Atrophy Type I

For individuals who have symptomatic SMA type I (infantile-onset) who receive risdiplam, the evidence includes 1 single-arm prospective phase 2/3 FIREFISH study. Relevant outcomes are overall survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. Results of a part 1 study (dose-finding and exploratory) in which 4 patients received low dose and 17 patients received high dose risdiplam are available. The results of the part 1 study (dose-finding and exploratory) showed 41% (7 of 17 infants) were able to sit without support for at least 5 seconds as assessed by BSID-III after 12 months of treatment. After a minimum follow-up of 12 and 23 months of treatment with risdiplam, 90% (19/21) and 81% (17/21) of patients were alive without permanent ventilation. Results of a part 2 study in which 41 patients received the FDA recommended dose reported that after 12 months of treatment, 29% were able to sit without support for at least 5 seconds, 56% achieved a CHOP-INTEND score of 40 or higher, 90% achieved an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% achieved a HINE-2 motor milestone response, and 85% survived without permanent ventilation. Results of part 2 of the study in which 41 patients received FDA recommended dose reported that after 12 and 24 months of treatment, 29% and 61% were able to sit without support for at least 5 seconds respectively, 56% and 76% achieved a CHOP-INTEND score of 40 or higher respectively and 85% and 83% survived without permanent ventilation respectively. The observed treatment effect on motor functions and event-free survival is beyond what is typical based on the known natural history of patients with SMA type I with 2 copies of SMN2. However, there is limited data to assess the long-term durability of treatment effect as well as safety-related to adverse events that are rare or have delayed onset. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Spinal Muscular Atrophy Type II and III

For individuals who have symptomatic type II or III SMA who receive risdiplam, the evidence includes a single ongoing double-blind, 2-part, placebo-controlled (SUNFISH) study. Relevant outcomes are overall survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. Pediatric or adult patients (2-25 years old) with type II or III SMA patients were enrolled in the SUNFISH study. Results of 180 patients from part 2 with 12 months follow-up reported least-square mean change in MFM-32 from baseline was greater in patients receiving risdiplam compared with placebo with a difference of 1.55 (95% CI: 0.30 to 2.81). Responder analysis (using a threshold of increase in 3 or more points in MFM-32 as being clinically meaningful) showed that 38% of those receiving risdiplam met the criteria of achieving a clinically meaningful improvement in motor function compared to 24%. Upper limb function measured by RULM showed a 1.6 point improvement in the risdiplam-treated group compared to no change in the placebo group. At month 24 of risdiplam treatment, 32% of patients demonstrated improvement (a change of ≥3) from baseline in MFM32 total score; 58% showed stabilization (a change of ≥0). Overall, gains in motor function at month 12 were maintained or improved upon at month 24. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to assess whether treatment of spinal muscular atrophy improves the net health outcome.

Policy Statements

Nusinersen

Initial Treatment

Nusinersen may be considered medically necessary if all the following conditions are met:

1. Diagnosis of spinal muscular atrophy confirmed by genetic testing demonstrating bi-allelic mutations in the survival motor neuron 1 (SMN1) gene as stated below:

   1. 1. Deletion of both copies of the SMN1 gene OR

      2. Compound heterozygous mutations of the SMN1 gene (defined below):

         1. Pathogenic variant(s) in both copies of the SMN1 gene

         2. Pathogenic variant in 1 copy and deletion of the second copy of the SMN1 gene.

2. If the individual is symptomatic, documentation of a genetic test confirms 2, 3, or 4 copies of the SMN2 gene; OR if the individual is asymptomatic, documentation of a genetic test confirms 2 or 3 copies of the SMN2 gene.

3. The individual is not on permanent ventilator dependence.

4. Medication is being administered at the United States Food and Drug Administration approved dosing by a healthcare professional (see Policy Guidelines).

5. The individual is not concurrently enrolled in a clinical trial for any experimental therapy for spinal muscular atrophy.

6. Prescribed by a neurologist with expertise in treating spinal muscular atrophy.

Initial authorization period is for 12 months.

Continuation of Treatment

Incremental reauthorization for nusinersen may be considered medically necessary if the following conditions are met:

1. The individual continues to meet initial treatment criteria cited above;

2. Documented evidence to support clinically meaningful improvement in motor milestones during the previous treatment period. Obtain a baseline motor milestone score from a validated assessment such as Hammersmith Infant Neurologic Exam (HINE), Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), etc.

Reauthorization period is for 12 months.

Nusinersen is considered investigational for all other indications.

Concurrent use of nusinersen with onasemnogene abeparvovec-xioi and/or risdiplam is considered investigational.

Use of nusinersen after administration of onasemnogene abeparvovec-xioi is considered investigational.

Onasemnogene Abeparvovec-Xioi

Onasemnogene abeparvovec-xioi may be considered medically necessary if all of the following conditions are met:

1. Diagnosis of spinal muscular atrophy confirmed by genetic testing demonstrating bi-allelic mutations in the survival motor neuron 1 (SMN1) gene as stated below:

   1. Deletion of both copies of the SMN1 gene OR

   2. Compound heterozygous mutations of the SMN1 gene (defined below):

      1. Pathogenic variant(s) in both copies of the SMN1 gene OR

      2. Pathogenic variant in 1 copy and deletion of the second copy of the SMN1 gene.

2. Documentation of a genetic test confirms no more than 3 copies of the SMN2 gene.

3. The individual is less than 2 years of age at the time of infusion of onasemnogene abeparvovec-xioi.

4. Documentation of baseline laboratory assessments such as AST, ALT, total bilirubin, and prothrombin time.

5. The individual does not have advanced spinal muscular atrophy (e.g., complete paralysis of limbs, permanent ventilator dependence).

6. Baseline anti-adeno-associated virus serotype 9 (AAV9) antibody titers < 1:50.

7. Prescribed by a neurologist with expertise in treating spinal muscular atrophy.

Repeat treatment or ante-partum use of onasemnogene abeparvovec-xioi is considered investigational.

Onasemnogene abeparvovec-xioi is considered investigational for all other indications.

Concurrent use of onasemnogene abeparvovec-xioi with nusinersen and/or risdiplam is considered investigational.

Use of nusinersen and/or risdiplam after administration of onasemnogene abeparvovec-xioi is considered investigational.

Risdiplam

Initial Treatment

Risdiplam may be considered medically necessary if all the following conditions are met:

1. Diagnosis of spinal muscular atrophy confirmed by genetic testing demonstrating bi-allelic mutations in the survival motor neuron 1 (SMN1) gene as stated below:

   1. Deletion of both copies of the SMN1 gene OR

   2. Identification of pathogenic variant(s) in both copies of the SMN1 gene.

2. If the individual is symptomatic, documentation of a genetic test confirms 2, 3, or 4 copies of the SMN2 gene; OR if the individual is asymptomatic, documentation of a genetic test confirms 2 or 3 copies of the SMN2 gene.

3. Individual age is 25 years or less.

4. The individual is not on permanent ventilator dependence.

5. Medication is being administered at the United States Food and Drug Administration-approved dosing (see Policy Guidelines).

6. The individual is not concurrently enrolled in a clinical trial for any experimental therapy for spinal muscular atrophy.

7. Prescribed by a neurologist with expertise in treating spinal muscular atrophy.

Initial authorization period is for 12 months.

Continuation of Treatment

Incremental reauthorization for risdiplam may be considered medically necessary if the following conditions are met:

1. The individual continues to meet initial treatment criteria cited above;

2. Documented evidence to support clinically meaningful stabilization or improvement in motor milestones during the previous treatment period. Obtain a baseline motor milestone score from a validated assessment such as Hammersmith Infant Neurologic Exam (HINE), Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), etc.

Reauthorization period is for 12 months.

Risdiplam is considered investigational for all other indications.

Concurrent use of risdiplam with onasemnogene abeparvovec-xioi and/or nusinersen is considered investigational.

Use of risdiplam after administration of onasemnogene abeparvovec-xioi is considered investigational.

Policy Guidelines

Nusinersen

The recommended dose of nusinersen is 12 mg (5 mL) administered intrathecally by, or under the direction of, healthcare professionals experienced in performing lumbar punctures. 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. Maintenance doses should be administered once every 4 months thereafter.

Dosing Limits

Initial: 4 loading doses
Maintenance: 1 dose every 4 months

Onasemnogene Abeparvovec-Xioi

The recommended dosage of onasemnogene abeparvovec-xioi is 1.1 × 10¹⁴ vector genomes (vg) per kg of body weight. It should be administered as an intravenous infusion over 60 minutes. Systemic corticosteroids equivalent to oral prednisolone at 1 mg/kg should be administered according to the U.S. Food and Drug Administration (FDA) approved prescribing label.

FDA has issued a black-box warning for onasemnogene abeparvovec-xioi due to the risk of acute serious liver injury and elevated aminotransferases. Individuals with pre-existing liver impairment may be at higher risk.

The FDA label states that “The safety and efficacy of ZOLGENSMA in individuals with anti-AAV9 antibody titers above 1:50 have not been evaluated.” Baseline anti-AAV9 antibody testing is performed prior to infusion using. Retesting may be performed if anti-AAV9 antibody titers are reported as >1:50.

Liver function (clinical exam, AST, ALT, total bilirubin, prothrombin time), platelet counts, and troponin-I levels should be monitored as per the prescribing label.

Where feasible, the individual's vaccination schedule should be adjusted to accommodate concomitant corticosteroid administration prior to and following onasemnogene abeparvovec-xioi infusion.

Use of onasemnogene abeparvovec-xioi in premature neonates before reaching full-term gestational age may not be recommended because concomitant treatment with corticosteroids may adversely affect neurological development.

Efficacy of onasemnogene abeparvovec-xioi in individuals with c.859G>C variant in SMN2 gene has not been evaluated.

A pre-symptomatic individual may be identified through the SMA newborn screening process and eligible for treatment. The requirements within the policy must be satisfied regardless of the SMA newborn screening.

Dosing Limits

1 injection per lifetime

Risdiplam

Risdiplam is administered orally once daily after a meal using a provided oral syringe. The recommended daily dosing of risdiplam is based on age and weight as follows:

• Less than 2 months of age: 0.15 mg/kg

• 2 months to less than 2 years of age: 0.2 mg/kg

• 2 years of age and older weighing less than 20 kg: 0.25 mg/kg

• 2 years of age and older weighing 20 kg or more: 5 mg

Risdiplam should be avoided in individuals with hepatic impairment. It is recommended that individuals who can become pregnant undergo pregnancy testing prior to initiating treatment with risdiplam.

Dosing Limits

7 bottles per 84 days

SMN2 Copy Numbers

For detail refer to Table 2 in the “Background” Section. Generally, the number of SMN2 gene copies is inversely related to the severity of spinal muscular atrophy. Higher numbers typically correlate with less severe disease. Among individuals clinically diagnosed with type I spinal muscular atrophy, 73% had 2 copies of SMN2, type II spinal muscular atrophy individuals 82% had 3 copies of SMN2, and type III spinal muscular atrophy individuals 51% had 3 and 46% had 4 copies of SMN2. Conversely, the probability that an unaffected child who has been tested after birth and has been found to carry a homozygous SMN1 deletion, the probability of developing type I spinal muscular atrophy if the child has 1 or 2 copies of SMN2 is greater than 97%. Those with 3 copies of SMN2 have an 83% probability of developing type II spinal muscular atrophy and those with 4 copies of SMN2 have an 84% probability of developing type III spinal muscular atrophy.

Nusinersen, onasemnogene abeparvovec-xioi, and risdiplam have not been evaluated in individuals with Type 0 or Type IV SMA.

Coding

See the Codes table for details.

Benefit Application

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) 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 by their medical necessity.

Background

Spinal Muscular Atrophy

Spinal muscular atrophy is a rare autosomal recessive genetic disorder caused by homozygous deletions or variants in the SMN1 gene located on chromosome 5. This gene produces the “survival of motor neuron” protein (SMN1), which is essential for motor neuron functioning. In 95% of cases of spinal muscular atrophy, there is a homozygous deletion of exon 7 in the SMN1 gene. The remaining 5% of cases are compound heterozygotes for SMN1 exon 7 deletions and small intragenic variants.^1, Due to absent or low levels of the survival motor neuron 1 protein, motor neurons in the spinal cord degenerate, resulting in atrophy of the voluntary muscles of the limbs and trunk affecting the ability to crawl, walk, sit up, and control head. In more severe cases, feeding, swallowing, and breathing are affected as well. The exact role of the survival motor neuron protein in motor neurons has not been completely elucidated, and levels of the survival motor neuron protein required for optimal functioning are unknown.^2,

There is wide phenotypic heterogeneity in spinal muscular atrophy, as summarized in Table 1. This is due to the presence of SMN2, a modifying/backup gene, also located on chromosome 5, which is 99% identical to SMN1. However, 70% to 90% of the SMN2 compensatory protein produced by this gene is defective and unstable due to the lack of exon 7.^3, The number of copies of the SMN2 gene varies widely (range, 0-6), resulting in a less severe form of spinal muscular atrophy among those with more copies of the SMN2 gene and vice-versa.^4, The relation between the SMN2 copy number and spinal muscular atrophy phenotype is summarized in Table 2. These data were generated from DNA samples of 375 patients with spinal muscular atrophy who previously had been classified as follows: 188 with spinal muscular atrophy type I, 110 with spinal muscular atrophy type II, and 77 with spinal muscular atrophy type III.^5,

Table 1. Characteristics and Subtypes of Spinal Muscular Atrophy
 

Adapted from the Muscular Dystrophy Association (n.d.),6, National Organization for Rare Disorders (2012),7,Zerres et al (1995),8, Finkel et al (2014),9, and Rudnik-Schoneborn et al (2001).10,SMA: spinal muscular atrophy.a Quantitative analysis of SMN2 copies in 375 patients showed that 80% of SMA type I carry 1 or 2 SMN2 copies, 82% with SMA type II carry 3 SMN2 copies, and 96% with SMA type III carry 3 or 4 SMN2 copies.5,Among 113 patients with SMA type I, 9 with 1 SMN2 copy lived <11 months, 88 of 94 with 2 SMN2 copies lived <21 months, and 8 of 10 with 3 SMN2 copies lived 33 to 66 months.11,

Table 2. Relation Between SMN2 Copy Numbers and Spinal Muscular Atrophy Phenotype

Adapted from Feldkotter et al (2002)5,SMA: spinal muscular atrophy.a Probability that an unaffected child who has been tested after birth and has been found to carry a homozygous SMN1 deletion will develop SMA type.

Diagnosis

Spinal muscular atrophy can be diagnosed using multiple molecular genetic testing techniques such as multiplex ligation-dependent probe amplification or quantitative polymerase chain reaction or a comprehensive next-generation sequencing-based approach. Individuals are classified as having spinal muscular atrophy if they have a homozygous deletion of the SMN1 gene or a homozygous absence of the SMN1 gene due to gene conversion (ie, SMN1 gene conversion to SMN2 gene) or a compound heterozygote variant in the SMN1 gene. Individuals are defined as carriers if they have 1 copy of the SMN1 gene on 1 chromosome and no copies on the other or 2 copies of the SMN1 gene on 1 chromosome and no copies on the other. Assessing SMN2 copy numbers as part of a diagnostic workup is important because it can provide critical information on disease progression and assist in possible clinical trial enrollment or treatment.

Because spinal muscular atrophy symptom onset may occur shortly after birth to months to years later, estimating the incidence and prevalence of spinal muscular atrophy subtypes is difficult. The incidence, as reported in the literature, is more precisely a birth prevalence rate, which is estimated between 9.1 and 10 per 100,000 live births,^12,13, which translates to 500 new spinal muscular atrophy cases annually.

Treatment

Medical management of spinal muscular atrophy patients includes respiratory, nutritional, and musculoskeletal supportive care. Respiratory management includes airway clearance, antibiotic treatment of infections, noninvasive and invasive ventilation. Nutritional management includes changing food consistency, gastrostomy tube feeding, and dietician assessment. Musculoskeletal supportive care includes a variety of interventions such as equipment for mobility, teaching self-care and function, physiotherapy, spinal surgery, posture and pain management, regular exercise, and scoliosis surgery. The type and extent of supportive care can affect survival in infant-onset disease (eg, gastrostomy feeding and noninvasive/invasive ventilation).

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 the production of full length functional SMN2 protein.^14,

Risdiplam is a SMN2 splicing modifier that increases exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and the production of full-length SMN protein in the brain.^15,

Onasemnogene abeparvovec-xioi, a 1-time gene replacement therapy is intended as an intravenous infusion for patients with spinal muscular atrophy type I and an intrathecal infusion for spinal muscular atrophy type II.

Regulatory Status

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

On May 24, 2019, onasemnogene abeparvovec-xioi (Zolgensma®; Avexis) was approved by the FDA for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy with bi-allelic mutations in the survival motor neuron 1 gene.

On August 7, 2020, risdiplam (Evrysdi™; Genentech) was approved by the FDA for the treatment of spinal muscular atrophy in patients 2 months of age and older. On May 31, 2022, FDA approved a label extension for oral risdiplam to include infants younger than 2 months old with spinal muscular atrophy.

Rationale

This evidence review was created in February 2017 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through January 8, 2024.

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, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Nusinersen

Clinical Context and Therapy Purpose

The purpose of nusinersen in pediatric and adult patients who have spinal muscular atrophy 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 following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with a genetic diagnosis of spinal muscular atrophy.

Interventions

The therapy being considered is nusinersen.

Comparators

Prior to the availability of nusinersen, there was no U.S. Food and Drug Administration (FDA) approved treatment for spinal muscular atrophy. 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 spinal muscular atrophy is a heterogeneous disease, measuring the impact of the intervention depends on the subtype of spinal muscular atrophy. For example, in infantile-onset spinal muscular atrophy (type I), comparing the achievement of motor milestones with the known natural history of spinal muscular atrophy is relevant, but the same may not be applicable for patients with late-onset spinal muscular atrophy (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 spinal muscular atrophy are summarized in Table 3.

Table 3. Health Outcome Measures Relevant to Spinal Muscular Atrophy

BSID: Bayley Scales of Infant and Toddler Development (Third Edition); CHOP INTEND: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HFMSE: Hammersmith Functional Motor Scale-Expanded; HINE: Hammersmith Infant Neurological Examination; MFM-32: Motor Function Measure (32 items); RULM: Revised Upper Limb Module; SMA: spinal muscular atrophy.

Given the heterogeneity and varying life expectancies among patients with different spinal muscular atrophy subtypes, the timing of follow-up of studies to reasonably assess whether nusinersen offers a net health benefit will differ by spinal muscular atrophy 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 spinal muscular atrophy subtypes is summarized in Table 4.

Table 4. Timing of Outcome Measures Relevant to Spinal Muscular Atrophy

SMA: spinal muscular atrophy.

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 RCTs;

• 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.

Population Reference No. 1 

Presymptomatic Patients with a Genetic Diagnosis of Spinal Muscular Atrophy and a Minimum of 2 But Less Than 4 copies of SMN2

Review of Evidence

Non-Randomized Studies

In the pivotal single arm NURTURE trial, ), 25 infants received nusinersen. Of the 25 infants, 15 had 2 copies of SMN2 (most likely to develop type 1 spinal muscular atrophy) and 10 had 3 copies of SMN2 (most likely to develop type II spinal muscular atrophy). 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). See Table 5 for study key characteristics summary.

Results are summarized in Table 6. The primary endpoint was time to death or respiratory intervention (invasive or non-invasive for ≥6 h per day continuously for ≥7 days or tracheostomy). The median (range) age at the first dose of nusinersen among enrolled infants was 22.0 (3–42) days. At the last visit, the median age was 34.8 months (range 25.7 to 45.4) which is generally considered past the expected age of symptom onset for spinal muscular atrophy Types I or II based on known natural history. All 25 children were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with 2 SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators ^31,.

The purpose of the 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

EU: European Union; FDA: U.S. Food and Drug Administration; SMA: spinal muscular atrophy. NURTURE: A Study of Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

Table 6. Summary of Results of NURTURE Study

CHOP-INTEND: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE: Hammersmith Infant Neurologic Examination; NURTURE: A Study of Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophya All are alive and none required permanent ventilation. Four (16%) infants (all with 2 SMN2 copies) utilized respiratory intervention for ≥6 h per day continuously for ≥7 days during an acute, reversible illness. At the last study day prior to data cutoff, 2 of these infants no longer utilized respiratory intervention; these infants had previously received respiratory intervention for ≥6 h per day for totals of 20 and 266 days during the course of the study. The other 2 infants continued to receive respiratory intervention for 2 and 10 h per day, respectively, at the last study day prior to data cutoff; these infants received respiratory intervention for ≥6 h per day for totals of 236 and 644 days, respectively, over the course of the study. 

Table 7. Study Relevance Limitations

NURTURE: A Study of Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular AtrophyThe 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

NURTURE: A Study of Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular AtrophyThe study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. 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 Spinal Muscular Atrophy and a Minimum of 2 But Less Than 4 Copies of SMN2

The evidence for use of nusinersen for presymptomatic type I (infantile-onset) spinal muscular atrophy consists of a single-arm study. After a median follow-up of 2.9 years of 25 infants who received the first dose of nusinersen at a median age of 22 days and are now median age of 34.8 months, 100% were alive, 100% achieved the ability to sit without support, 92% achieved the ability to walk with assistance, and 88% achieved the ability to walk independently. While none required permanent ventilation or tracheostomy, 4 (16%) participants with 2 SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. 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.

Summary of Evidence

For individuals who are presymptomatic with a genetic diagnosis of spinal muscular atrophy and a minimum of 2 but less than 4 copies of SMN2 who receive nusinersen, the evidence includes an open-label single-arm trial. Relevant outcomes are overall survival, change in disease status, morbid events, functional outcomes, quality of life, and treatment-related mortality and morbidity. After a median of 2.9 years of follow-up of 25 infants who received the first dose of nusinersen at a median age of 22 days and are now median age of 34.8 months, 100% were alive, 100% achieved the ability to sit without support, 92% achieved the ability to walk with assistance, and 88% achieved the ability to walk independently. While none required permanent ventilation or tracheostomy, 4 (16%) participants with 2 SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. 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. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2 

Type I (Infantile-Onset) Spinal Muscular Atrophy

The evidence base for infantile-onset or type I spinal muscular atrophy is summarized in Table 9. The supporting EMBRACE and CS3A studies are not reviewed in detail. EMBRACE was terminated early to roll over participants to an open label extension study after the demonstration of motor function benefit with nusinersen in ENDEAR.

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

EMBRACE: A Study to Assess the Safety and Tolerability of Nusinersen in Participants With Spinal Muscular Atrophy; ENDEAR: A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy; PK: pharmacokinetics; RCT: randomized controlled trial; a Available as abstract only.

Randomized Studies

The pivotal ENDEAR trial was a multicenter randomized, double-blind trial in which 121 infants with a documented genetic diagnosis of spinal muscular atrophy with symptom onset before 6 months of age were randomized 2:1 to nusinersen (n=80) or to sham injection (n=41).^32, Nusinersen was approved on the basis of a 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.^32, 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. 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 2 treatment groups were not balanced with respect to age at symptom onset, use of ventilatory support, and the presence of symptoms specific to spinal muscular atrophy. 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

DB-RCT; double-blind randomized controlled trial; ENDEAR: A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy; EU: European Union; FDA: U.S. Food and Drug Administration; SMA: spinal muscular atrophy. 

Table 11. Summary of Results of ENDEAR Trial

CI: confidence interval; CMAP: compound muscle action potential; HINE: Hammersmith Infant Neurologic Examination; HR: hazard ratio; ENDEAR: A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy;Adapted from Finkel et al (2017).32, 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.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 (ie, 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 (ie, 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.cA 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).dA 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. Study Relevance Limitations

ENDEAR: A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular AtrophyThe 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.

Section Summary: Type I (Infantile-Onset) Spinal Muscular Atrophy

The evidence for use of nusinersen for symptomatic type I (infantile-onset) spinal muscular atrophy consists of a double-blind RCT. The 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 3 points over 6 months. Given the limited data on the durability of response, long-term data documenting safety and efficacy are needed.

Summary of Evidence

For individuals who have type I (infantile-onset) spinal muscular atrophy who receive nusinersen, the evidence includes a randomized, double-blind, controlled trial. Relevant outcomes are overall survival, change in disease status, morbid events, functional outcomes, quality of life, and treatment-related mortality and morbidity. The phase 3 confirmatory ENDEAR trial (N =121) showed clinically meaningful and statistically significant improvement in motor milestones, event-free survival, and overall survival that exceeded those seen in the control group, with an acceptable safety profile. The proportion of patients, who met the primary endpoint responder definition of achieving motor milestones, was 51% in the nusinersen arm compared with 0% in the sham-controlled arm. Further, the hazard ratio for event-free survival was 0.53 favoring nusinersen over sham-controlled. It is notable, however, that 50% of nusinersen-treated subjects did not achieve the primary endpoint motor milestone response. 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 3 points over 6 months. Given the limited data on the durability of response, long-term safety, and lack of efficacy in a substantial number of patients continued risk-benefit assessment of long-term treatment with nusinersen is necessary. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3 

Type II or III Spinal Muscular Atrophy

The evidence base for patients with type II or III spinal muscular atrophy is summarized in Table 13. The evidence base for patients with type II and III spinal muscular atrophy consists of 4 early-phase, open-label studies and a double-blind phase 3 RCT. Of these, data from phase 1 single-arm studies are not reviewed in detail because they were early dose-finding and proof-of-concept studies.

Table 13. Summary of Key Trial Characteristics in Type II and III Spinal Muscular Atrophy Patients

CHERISH: A Study to Assess the Efficacy and Safety of Nusinersen in Participants With Later-onset Spinal Muscular Atrophy (SMA); RCT: randomized controlled trial; SMA: spinal muscular atrophy

Randomized Studies

The pivotal CHERISH trial randomized 126 nonambulatory individuals. See Table 14 for the study summary.The primary endpoint was change in Hammersmith Functional Motor Scale Expanded score compared with baseline. Results are summarized in Table 15. The trial met its primary endpoints with nusinersen showing clinically meaningful improvement in mean Hammersmith Functional Motor Scale Expanded 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<.001) had an increase from baseline to month 15 in the Hammersmith Functional Motor Scale Expanded 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. 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 5 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.

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.

Table 14. Summary of Key Characteristics of CHERISH Trial

CHERISH: A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA); DB-RCT; double-blind randomized controlled trial; EU: European Union; FDA: U.S. Food and Drug Administration; SMA: spinal muscular atrophy.

Table 15. Summary of Results of CHERISH Trial

CHERISH: A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA); CI: confidence interval; HFMSE: Hammersmith Functional Motor Scale–Expanded; LSM: least-squares mean; RULM: Revised Upper Limb Module; WHO: World Health Organization.Adapted from Mercuri et al (2018).36,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.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. Study Relevance Limitations

CHERISH: A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA); 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.

Section Summary: Type II or III Spinal Muscular Atrophy

The evidence for the use of nusinersen for patients with type II or III spinal muscular atrophy consists of a double-blind RCT. The 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.

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 spinal muscular atrophy, 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, and 2 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

For individuals who have type II or III spinal muscular atrophy who receive nusinersen, the evidence includes a double-blind, randomized controlled trial. Relevant outcomes are overall survival, change in disease status, morbid events, functional outcomes, quality of life, and treatment-related mortality and morbidity. Efficacy findings from single-arm studies of type II and III spinal muscular atrophy are difficult to interpret because these trials used a wide range of nusinersen doses and lacked control arms. The phase 3 confirmatory CHERISH trial (N =126) showed clinically meaningful and statistically significant improvement in motor milestones (measured using Hammersmith Functional Motor Scale–Expanded scores) that exceeded those seen in the control group (difference of 5.9 points favoring nusinersen over sham control, p<.001). The respective proportion of patients with clinically meaningful improvements in Hammersmith scores greater than 3 points was 57% vs 26% (p<.001). Multiple secondary endpoints also showed a consistency in treatment effect favoring nusinersen over sham control. Given the limited data on the durability of response, long-term safety, and lack of efficacy in a substantial number of patients continued risk-benefit assessment of long-term treatment with nusinersen is necessary. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4 

Onasemnogene Abeparvovec-Xioi

Clinical Context and Therapy Purpose

The purpose of onasemnogene abeparvovec-xioi in patients who have a genetic diagnosis of spinal muscular atrophy is to provide a treatment option that is an improvement on existing therapies. Potential benefits of this gene therapy^37, 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 have failed.

• Treatment reduces complexity in administration (avoidance of repeated intrathecal injections) that may significantly improve patient outcomes.

• Treatment reduces caregiver or broader family burden.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who are symptomatic infants diagnosed with type 1 spinal muscular atrophy and presymptomatic infants with a genetic diagnosis of spinal muscular atrophy.

Interventions

The therapy being considered is onasemnogene abeparvovec-xioi.

Comparators

The relevant comparators are continued medical management (respiratory, digestive, and orthopedic support) and nusinersen.

Outcomes

The general outcomes of interest are survival, functional ability, quality of life, and treatment-related mortality and morbidity. For details, see Table 4. Given the heterogeneity and varying life expectancies among patients with different spinal muscular atrophy subtypes, the timing of follow-up of studies to reasonably assess whether onasemnogene abeparvovec-xioi offers a net health benefit will differ by spinal muscular atrophy subtypes as well as by the timing of treatment initiation relative to symptom onset. For details, see Tables 3 and 4.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with preference for prospective studies.

• To assess longer 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.

Non Randomized Studies

The clinical development program for onasemnogene abeparvovec-xioi is summarized in Table 17.

Table 17. Summary of the Clinical Development Program for Onasemnogene Abeparvovec-Xioi

PIVOTAL: Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1; SPR1NT: Pre-Symptomatic Study of Intravenous Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2; START: Long-Term Follow-up Study for Patients From AVXS-101-CL-101; STRIVE EU: Single-Dose Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1; STRIVE US: Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1; STRONG: Study of Intrathecal Administration of Onasemnogene Abeparvovec-xioi for Spinal Muscular Atrophy.a Long-term, safety follow-up study of patients enrolled in NCT02122952.

Symptomatic Spinal Muscular Atrophy TYPE I (Infantile-Onset)

The clinical development program of onasemnogene abeparvovec-xioi for patients with symptomatic spinal muscular atrophy type I includes 4 prospective cohort studies and is summarized in Table 17.; ). These trials enrolled a total of 65 patients with symptomatic spinal muscular atrophy type I. The study characteristics and results are summarized in Tables 18 and 19.

The FDA approval was based on a pooled analysis of 21 patients with 2 copies of SMN2 from the pivotal phase I and STRIVE-US trial with a data analysis cut off of March 2019. Efficacy was established on the basis of survival, and achievement of developmental motor milestones such as sitting without support. Comparison of the results of the ongoing clinical trial to available natural history data of patients with infantile-onset spinal muscular atrophy was the primary evidence for the effectiveness of onasemnogene abeparvovec-xioi. The FDA analysis is summarized in Table 19. The inclusion and exclusion criteria of the phase 3 confirmatory study (STRIVE-US) were the same as the phase 1 dose-finding study.^39, The co-primary efficacy outcomes are functional independent sitting for 30 or more seconds at 18 months of age and event-free survival at 14 months of age (defined as the avoidance of either death or need for tracheostomy or ventilation ≥16 hours/day for ≥2 consecutive weeks). Secondary efficacy outcomes are the ability to thrive at 18 months of age, including not receiving nutrition through mechanical support or other nonoral methods, ability to tolerate thin liquids (formal swallowing test), and maintaining weight (>3rd percentile for age and sex) and ability to remain independent of ventilatory support at 18 months of age. Results are summarized in Tables 18 and 19.

Results of an ongoing study to assess long-term safety and durability of response in infants with SMA type 1 with a median time since dosing of 5.2 years (range 4.6 to 6.2 years) have been published^40, and summarized in Tables 18 and 19. Seven of 13 were receiving concomitant nusinersen (all 3 patients in the low-dose cohort and 4 of the 10 patients in the therapeutic-dose cohort). The primary objective is to assess safety, and the secondary objective is to determine whether developmental milestones achieved in the phase 1 clinical trial were maintained and new milestones gained. Thirteen of 15 original patients were included in the analysis; 2 patients’ families declined follow-up participation. At the data cutoff on June 11, 2020, the median age of 13 patients followed was 38.9 months. Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of “standing with assistance” without the use of nusinersen.

While the current evidence for symptomatic type I spinal muscular atrophy patients is limited to patients with 2 copies of SMN2, approximately 20% of type I spinal muscular atrophy patients may have 3 copies of SMN2.^5, Given the treatment effect observed in symptomatic patients, it is possible that patients with 3 copies of SMN2 may experience a clinically meaningful benefit. However, there is no published evidence to support such a hypothesis. Further, there is no published data that supports clinical benefit in Type I spinal muscular atrophy patients who are administered onasemnogene abeparvovec-xioi after 6 months of age.

Novartis Gene Therapies has sponsored creation of RESTORE, a prospective, multicenter, multinational observational registry. ^41, Participants will be managed according to usual clinical practice. Both newly recruited SMA treatment centers and sites involved in existing SMA registries will be eligible to participate; de novo; sites already participating in another registry may be included via consortium agreements. Participants will be enrolled over a 5-year period and followed for 15 years or until death. Assessments will include SMA history and treatment, pulmonary, nutritional, and motor milestones, healthcare resource utilization, work productivity, activity impairment, adverse events, quality of life, caregiver burden, and survival. Results for 117 participants describing real-world outcomes in individuals with SMA aged ≥6 months at the time of onasemnogene abeparvovec infusion have been presented at conferences but have not been published in a peer reviewed journal at the time of 2023 update of this review.

Table 18. Summary of Key Characteristics of Nonrandomized Trials

a Protocol was amended to lower the age to 6 months of age or younger.b c.859G>C substitution is a positive modifier and has been shown to results in a mild SMA phenotype.42,c At 6.7×1013 vg/kg. d At 2.0×1014 vg/kg.e The oldest patients is 46.2 months of age, with 40.6 months of follow-up.

Table 19. Summary of Key Results of Nonrandomized Trials

AE: adverse events; ALT: alanine aminotransferase; AST; aspartate aminotransferase; CHOP INTEND: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; NA: not applicable; NR: not reported; SAE: serious adverse event; ULN: upper limit of normal.a  In the completed clinical trial, 1 patient (the first patient infused in that study) was enrolled prior to the protocol amendment instituting administration of prednisolone before and after infusion.b  Ability to thrive was a composite endpoint defined by swallowing function (the ability to tolerate thin liquids shown by a formal clinical swallowing assessment [eg, bedside swallow exam]) AND nutritional support (feeding exclusively by mouth, defined as not receiving nutrition through a feeding tube or other non-oral methods) AND and weight maintenance (maintaining weight greater than the third percentile for the appropriate age and sex)

The purpose of the study limitations tables (see Tables 20 and 21) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table. Due to strict inclusion criteria, the patient population included in the trial was more homogeneous (eg, SMN2 copy number differences), younger, and treated earlier from the time of onset of symptoms than patients in routine clinical practice. For example, the weighted mean (standard deviation) age of symptom onset and age of confirmed genetic diagnosis in spinal muscular atrophy type I patients was 2.5 (0.6) and 6.3 (2.2) months, respectively, based on a systematic literature review of studies published between 2000 and 2014.^44, The weighted diagnostic delay in this systematic review was 3.6 months. In the onasemnogene abeparvovec-xioi phase I study, the age of symptom onset and age of confirmed genetic diagnosis were 1.4 months (range, 0-3 months) and 2 months (range, 0-4.5 months), respectively. Therefore, the benefits observed in this study setting might not translate to patients in a real-world setting. However, with increasing efforts toward newborn screening for spinal muscular atrophy, it is possible that the delay in diagnosis of spinal muscular atrophy may be shortened.

Table 20. Study Relevance Limitations

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 21. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps 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: Symptomatic Spinal Muscular Atrophy Type I (Infantile-Onset)

The evidence for use of onasemnogene abeparvovec-xioi for symptomatic spinal muscular atrophy type I (infantile-onset) consists of 2 single-arm studies. The FDA approval was based on a pooled analysis of 21 patients from the 2 single-arm studies. 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 patients with spinal muscular atrophy type I with 2 copies of SMN2. Results of the phase 3 confirmatory study (STRIVE-US) published after the FDA approval were largely consistent with previously available findings at the time of approval. Results of an ongoing study to assess long-term safety and durability of response in infants with SMA type 1 with a median time since dosing of 5.2 years showed that the developmental milestones achieved in the phase 1 clinical trial were maintained and new milestones gained. Thirteen of 15 original patients were included in the analysis. All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of “standing with assistance” without the use of nusinersen. However, 7 of the 13 subsequently received concomitant nusinersen.

Summary of Evidence

For individuals who have spinal muscular atrophy type I (infantile-onset) who receive onasemnogene abeparvovec-xioi, the evidence includes 2 single-arm studies. Relevant outcomes are overall survival, change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. The FDA approval was based on a pooled analysis of 21 patients from the 2 single-arm studies. 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 patients with spinal muscular atrophy type I with 2 copies of SMN2. Results of the phase 3 confirmatory study (STRIVE-US) published after the FDA approval were largely consistent with previously available findings at the time of approval. Results of an ongoing study to assess long-term safety and durability of response in infants with SMA type 1 with a median time since dosing of 5.2 years showed that the developmental milestones achieved in the phase 1 clinical trial were maintained and new milestones gained. Thirteen of 15 original patients were included in the analysis. All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of “standing with assistance” without the use of nusinersen. However, 7 of the 13 subsequently received concomitant nusinersen. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5 

Presymptomatic Infants with a Genetic Diagnois of Spinal Muscular Atrophy and Less Than 4 Copies of SMN2

The clinical development program of onasemnogene abeparvovec-xioi for presymptomatic infants with a genetic diagnosis of spinal muscular atrophy and less than 4 copies of SMN2 includes a single prospective cohort study called SPR1NT. The study characteristics are summarized in Table 22 and results are summarized in Table 23.The study included 2 cohorts: 14 children with 2 copies of SMN2 and 14 children with 3 copies of SMN2 expected to develop SMA type 1. Results of the cohorts were reported in 2 separate publications.^45,46, All patients with 2 copies of SMN2 reached 18-months-of-age (study end) and achieved the primary endpoint of sitting without support for at least 30 seconds.^45, Seventy-nine percent (11/14) achieved this milestone within an age-appropriate time period based on the WHO MGRS of healthy children living under conditions highly unlikely to constrain growth.^47,All patients with 3 copies of SMN2 reached 24-months-of-age (study end) and achieved the primary endpoint of standing without support up to the 24-months-of-age visit. Ninety-three percent (14/15) achieved this milestone within an age-appropriate time period.^46,In the natural history of SMA Type 1, untreated children with 2 copies of the SMN2 backup gene would not achieve such skills. Among the cohort of infants with 3 copies of SMN2 gene, 27% (4/15) stood for 3 seconds or more without assistance, 60% (9/15) stood for 10 seconds or more with assistance and 13% (2/15) walked 5 steps or more without assistance as measured by WHO-MGRS. All patients (29/29) did not need temporary breathing support and remained free of feeding support and 97% (28/29) remained within a normal weight range (3rd-97th percentile for age).

The purpose of the study limitations tables (see Tables 24 and 25) 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 22. Summary of Key Nonrandomized Trials

Table 23. Summary of Key Results of Nonrandomized Trial

BSID: Bayley-III Scales of Infant and Toddler Development; CHOP INTEND: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; ITT: Intention-to-treat; NA: not applicable; NR: not reported; SAE: serious adverse event; SD: standard deviation; TULN: upper limit of normal; WHO-MGRS: World Health Organization Multicentre Growth Reference Study.

Table 24. Study Relevance Limitations

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 25. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps 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 Infants with a Genetic Diagnosis of Spinal Muscular Atrophy and Less Than 4 Copies of SMN2

The evidence for use of onasemnogene abeparvovec-xioi for presymptomatic infants with a genetic diagnosis of SMA and less than 4 copies of SMN2 consists of a single-arm study (SPR1NT). This trial included infants less than 6 weeks of age who did not display any symptoms of SMA at the time of infusion. The trial was divided into 2 cohorts based on SMN2 copy number. All patients irrespective of SMN2 copy numbers achieved their respective primary endpoint, able to sit without support for ≥30 seconds at 18 months of age for 2 copies of SMN2 or ability to stand for 3 seconds or more without assistance at 24 months for those with 3 copies of SMN2. Multiple secondary endpoints were also supportive of clinical benefit including achievement of age-appropriate gross motor milestones and functions and independence from nutritional and respiratory support. In the natural history of SMA type 1, untreated children with 2 or 3 copies of the SMN2 backup gene would not achieve such skills. These results demonstrate that early treatment resulted in the achievement of motor milestones among patients who are not likely to attain them without treatment.

Summary of Evidence

For individuals who are presymptomatic with a genetic diagnosis of spinal muscular atrophy and less than 4 copies of SMN2 who receive onasemnogene abeparvovec-xioi, the evidence includes one single-arm study- SPR1NT. Relevant outcomes are overall survival, change in disease status, functional outcomes, quality of life, and treatment-related mortality and morbidity. The SPR1NT trial included infants less than 6 weeks of age who did not display any symptoms of SMA at the time of infusion. The trial was divided into 2 cohorts based on SMN2 copy number. All patients irrespective of SMN2 copy numbers achieved their respective primary endpoint, able to sit without support for at least 30 seconds at 18 months of age for 2 copies of SMN2 or ability to stand for 3 seconds or more without assistance at 24 months for those with 3 copies of SMN2. Multiple secondary endpoints were also supportive of clinical benefit including achievement of age-appropriate gross motor milestones and functions and independence from nutritional and respiratory support. In the natural history of SMA Type 1, untreated children with 2 or 3 copies of the SMN2 backup gene would not achieve such skills. These results demonstrate that early treatment resulted in the achievement of motor milestones among patients who are not likely to attain them without treatment. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 6 

Risdiplam

Clinical Context and Therapy Purpose

The purpose of risdiplam in patients who have spinal muscular atrophy type is to provide a treatment option that is an improvement on existing therapies. Potential benefits of this therapy may include the following:

• A novel mechanism of action or approach that may allow successful treatment of many patients for whom other available treatments have failed.

• Reduced complexity such as avoidance of repeated intrathecal injections with nusinersen which may reduce caregiver or broader family burden.

• Potential for a novel treatment option for older SMA patients (2-60 years old) or those who have been previously excluded from clinical trials such as those with severe scoliosis and low baseline function or those who have contradictions to currently FDA approved treatments.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with a genetic diagnosis of SMA. Because risdiplam is being studied in clinical trials with participants ranging from birth to 60 years of age, in both infantile-onset and later-onset SMA, a large number of patients with SMA may be potential candidates for treatment.‎

Interventions

The therapy being considered is risdiplam.

Comparators

The relevant comparators are continued medical management (respiratory, digestive, and orthopedic support), nusinersen, and onasemnogene abeparvovec-xioi.

Outcomes

The general outcomes of interest are survival, functional ability, quality of life, and treatment-related mortality and morbidity. Given the heterogeneity and varying life expectancies among patients with different spinal muscular atrophy subtypes, the timing of follow-up of studies to reasonably assess whether risdiplam offers a net health benefit will differ by spinal muscular atrophy subtypes as well as by the timing of treatment initiation relative to symptom onset. For details, see Tables 3 and 4.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with preference for prospective studies.

• To assess longer 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.

Non Randomized Studies

The clinical development program for risdiplam is summarized in Table 26.

Table 26. Summary of the Clinical Development Program for Risdiplam in Patients with SMA

NCT: national clinical trial.SMA: spinal muscular atrophya Enrollment completed with final enrollment of 174 patients (source: clinicaltrials.gov)b Target enrollment

Spinal Muscular Atrophy Type I (Infantile-Onset)

The evidence for type I spinal muscular atrophy (SMA) patients includes an open-label single-arm FIREFISH study (dose-finding phase n=21 and confirmed-dose n=41) in which infants aged between 1 to 7 months with 2 copies of SMN2 gene were treated with risdiplam. After an initial dose-finding protocol (part-1) under which multiple ascending doses of risdiplam were administered (low dose=4; recommended FDA dose=17), patients in part-2 of the study were administered the selected dose and will be followed for 24 months. Patient characteristics and results are summarized in Tables 27 and 28. The primary outcome for part 2 was defined as the percentage of infants who could sit without support at 12-months assessed by Gross Motor Scale of the Bayley Scales of Infant and Toddler Development (Third Edition) (BSID-III).

Results at 12-months and 24-months follow-up have been reported. At 12 months, 29% (12 of 41) were able to sit without support for at least 5 seconds as assessed by BSID-III and at 24 months, 61% (25 of 41) met this primary endpoint. At 12 and 24 months of treatment with risdiplam, 85% (35/41) and 83% (34/41) of trial participants were alive without permanent ventilation.^48,49, These results indicate a clinically meaningful deviation from the natural history of untreated infantile-onset SMA. As described in the natural history of untreated infantile-onset SMA, patients would not be expected to attain the ability to sit independently, and no more than 25% of these patients would be expected to survive without permanent ventilation beyond 14 months of age.^19,38,

The purpose of the limitations tables (Tables 29 and 30) is to display notable limitations identified in each study. Notable limitations include a relatively short follow-up of 1 year and a small sample size, which is inadequate to precisely assess the magnitude of treatment effect, its durability and safety (especially adverse events that are potentially rare or have delayed onset). To address the lack of evidence on long-term efficacy and safety (beyond 1 year), registries or long-term follow-up should universally enroll all patients that receive risdiplam, as optional enrollment in longer follow-up studies is prone to selection bias. In absence of direct head-to-head comparisons with other FDA-approved treatment for type I SMA such as potentially curative 1 time onasemnogene abeparvovec or lifelong chronic intrathecal nusinersen, the role of risdiplam in the treatment pathway of newly diagnosed treatment naïve type I SMA patients is unclear. It is unknown if risdiplam should be used as a first-line agent or second-line agent in such patients or as a combination treatment. Further, it is unclear, under what clinical circumstances use of risdiplam as a second-line or third-line agent will be justified.

Table 27. Summary of Pivotal Trial Characteristics of Risdiplam for Infantile-Onset SMA

EU: Europe; SMA: spinal muscular atrophy.a Measured by Item 22 of the Bayley Scales of Infant and Toddler Development – Third Edition.b Permanent ventilation defined as requiring a tracheostomy or more than 21 consecutive days of either non-invasive ventilation (≥ 16 hours per day) or intubation, in the absence of an acute reversible event.

Table 28. Summary of Results of Pivotal Trial of Risdiplam for Infantile-Onset SMA

BSID: Bayley Scales of Infant and Toddler Development (Third Edition); CHOP INTEND: Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE: Hammersmith Infant Neurologic Examination; NA: not available; SMA: spinal muscular atrophy. a In Part 1 of the study, 21 patients have been treated with risdiplam for over 12 months (4 patients received low dose [Cohort A] and 17 received FDA recommended dose of 0.2 mg/kg/day risdiplam [Cohort B].b Defined as alive with no permanent ventilation (i.e. no tracheostomy or BiPAP ≥16 hours per day continuously for >3 weeks or continuous intubation >3 weeks, in the absence of, or following the resolution of an acute reversible event).c Reached 15 months of age or olderd Reached an age of 28 months or older; median 32 months; range 28 to 45 months.e In Part 2 of the study, 41 patients were treated with risdiplam for over 12 months with FDA recommended dose of 0.2 mg/kg/day risdiplam

Table 29. Study Relevance Limitations

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 30. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps 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: Spinal Muscular Atrophy Type I (Infantile-Onset)

The evidence for use of risdiplam for symptomatic SMA type I (infantile-onset) individuals consists of a single-phase 2/3 FIREFISH study. Results of part 1 (dose-finding and exploratory) of the study in which 4 patients received low-dose and 17 patients who received FDA recommended dose were the basis for FDA approval. Results showed 41% (7 of 17 infants) were able to sit without support for at least 5 seconds as assessed by BSID-III after 12 months of treatment. After a minimum follow-up of 12 and 23 months of treatment with risdiplam, 90% (19/21) and 81% (17/21) of patients were alive without permanent ventilation. Results of part 2 of the study in which 41 patients received FDA recommended dose reported that after 12 and 24 months of treatment, 29% and 61% were able to sit without support for at least 5 seconds, respectively, 56% and 76% achieved a CHOP-INTEND score of 40 or higher, respectively and 85%, and 83% survived without permanent ventilation, respectively. The observed treatment effect on motor functions and event-free survival is beyond what is typical based on the known natural history of patients with SMA type I with 2 copies of SMN2.

Summary of Evidence

For individuals who have symptomatic SMA type I (infantile-onset) who receive risdiplam, the evidence includes 1 single-arm prospective phase 2/3 FIREFISH study. Relevant outcomes are overall survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. Results of a part 1 study (dose-finding and exploratory) in which 4 patients received low dose and 17 patients received high dose risdiplam are available. The results of the part 1 study (dose-finding and exploratory) showed 41% (7 of 17 infants) were able to sit without support for at least 5 seconds as assessed by BSID-III after 12 months of treatment. After a minimum follow-up of 12 and 23 months of treatment with risdiplam, 90% (19/21) and 81% (17/21) of patients were alive without permanent ventilation. Results of a part 2 study in which 41 patients received the FDA recommended dose reported that after 12 months of treatment, 29% were able to sit without support for at least 5 seconds, 56% achieved a CHOP-INTEND score of 40 or higher, 90% achieved an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% achieved a HINE-2 motor milestone response, and 85% survived without permanent ventilation.Results of part 2 of the study in which 41 patients received FDA recommended dose reported that after 12 and 24 months of treatment, 29% and 61% were able to sit without support for at least 5 seconds respectively, 56% and 76% achieved a CHOP-INTEND score of 40 or higher respectively and 85% and 83% survived without permanent ventilation respectively. The observed treatment effect on motor functions and event-free survival is beyond what is typical based on the known natural history of patients with SMA type I with 2 copies of SMN2. However, there is limited data to assess the long-term durability of treatment effect as well as safety-related to adverse events that are rare or have delayed onset. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 7

Spinal Muscular Atrophy Type II and III

The evidence for pediatric or adult patients (2-25 years old) with type II or III SMA patients includes the ongoing double-blind, 2-part, placebo-controlled SUNFISH study. Patient characteristics and results are summarized in Tables 31 and 32.

Part 1 was dose-finding and exploratory in 51 patients for 12 weeks. Part 2 was the randomized, double-blind, placebo-controlled in which patients received risdiplam or placebo for 12 months. After 12 months, placebo recipients were switched to risdiplam for the next 12 months while those receiving risdiplam continued to receive treatment until 24 months.^51,This trial included a patient population who previously were excluded from clinical trials, such as ages up to 25, severe scoliosis, and low baseline function. At baseline, 67% of patients had scoliosis (32% of them with severe scoliosis). Results of Part 2 are discussed next. The least-square mean change in MFM-32 from baseline was greater in patients receiving risdiplam compared with placebo with a difference of 1.55 (95% CI: 0.30 to 2.81). Responder analysis (using a threshold of increase in 3 or more points in MFM-32 as being clinically meaningful) showed that 38% of those receiving risdiplam met the criteria of achieving a clinically meaningful improvement in motor function compared to 24% in the placebo arm. Clinical benefit was also observed in the upper limb function as measured by the revised upper limb module (RULM). Risdiplam treated patients had a mean 1.6 point improvement from baseline at month 12 compared to no mean score change in the placebo group (p=.047). In general, increases on motor function tests would not be expected in the natural history of Type 2 and 3 SMA, and the differences observed between patients treated with risdiplam and those on placebo are considered clinically meaningful.^28,

Subgroup analysis of differences in MFM-32 and RULM total scores by age, SMA subtype, and SMN2 copy number are summarized in Table 33. Planned subgroup analysis of MFM-32 and RULM by age showed a trend for greater efficacy in the younger age group. This is consistent with the pathophysiology of SMA in which motor neurons are progressively lost with time.

For MFM-32, subgroup analysis based on SMA subtype showed treatment differences in favor of risdiplam versus placebo in both SMS types 2 and 3. Subgroup analysis based on SMN2 copy number showed treatment differences in favor of risdiplam versus placebo based upon point estimates in individuals with 3 and 4 copies. However, the confidence intervals were wide, and specifically for individuals with SMN2 copy number 4, the confidence interval was inclusive of negative treatment effect. There were only 4 participants with 2 SMN2 2 copy numbers and there was a negative treatment effect. All subgroup analyses were not powered to detect statistically significant differences.

For RULM subgroup analysis was similar. The subgroup analysis based on the SMA subtype also showed treatment differences in favor of risdiplam versus placebo in both types 2 and 3. Subgroup analysis based on SMN2 copy number showed treatment differences in favor of risdiplam versus placebo based upon point estimates in individuals with 3 and 4 copies. However, the confidence intervals were wide, and specifically for individuals with SMN2 copy number 4, the confidence interval was inclusive of negative treatment effect. There were only 4 participants with 2 SMN2 copy numbers and there was a negative treatment effect. All subgroup analyses were not powered to detect statistically significant differences.

The purpose of the limitations tables (Tables 34 and 35) is to display notable limitations identified in each study. Other notable limitations include a relatively short follow-up of 1 year which is inadequate to assess the durability of efficacy and safety (especially adverse events that are potentially rare or have delayed onset). To address the lack of evidence on long-term efficacy and safety (beyond 1 year), registries or long-term follow-up should universally enroll all patients that receive risdiplam as optional enrollment in longer follow-up studies is prone to selection bias.

Table 31. Summary of Pivotal Trial Characteristics of Risdiplam for SMA Type II and III

DB-RCT; double-blind randomized controlled trial; EU: Europe;MFM-32: Motor Function Measure (32 items); SMA: spinal muscular atrophy.a In Part 1 ambulant or non-ambulant patients were allowed (14% were ambulatory). In Part 2, only non-ambulant patients were allowed.b Stratified by age group (2 to 5, 6 to 11, 12 to 17, or 18 to 25 years of age).

Table 32. Summary of Results of Pivotal Trial of Risdiplam for SMA Type II and III at 12 Months

CI; Confidence Interval; CGI: Clinical Global Impression of Change Scale; FVC: Forced Vital Capacity; HFMSE: Expanded Hammersmith Functional Motor Scale; MFM-32: Motor Function Measure (32 items); RULM: Revised Upper Limb Module; SMA: Spinal Muscular Atrophy; SMAIS: Spinal Muscular Atrophy Independence Scale; SE: Standard error; SD: standard deviationa The MFM total score was calculated according to the user manual, expressed as a percentage of the maximum score possible for the scale (i.e., sum of the 32 item scores divided by 96 and multiplied by 100).b FVC was measured in participants over the age of 6 years. Exact number pf subset was not reported. c Proportion of patients rated by clinicians as “no change” or “improved”. The CGI-C is a single item measure of change in global health, using 7 response options: “Very much improved”, “Much improved”, “Minimally improved”, “No change”, “Minimally worse”, “Much worse”, “Very much worse”.

Table 33. Subgroup Analysis of the Pivotal SUNFISH Trial of Risdiplam for SMA Type II and III^28,

CI: Confidence Interval; MFM-32: Motor Function Measure (32 items); RULM: Revised Upper Limb Module; SMA: Spinal muscular atrophy.a Number reported for MFM32.b Number reported for RULM.

Table 34. Study Relevance Limitations

RULM: Revised Upper Limb Module; 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 35. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps 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: Spinal Muscular Atrophy Type II and III

The evidence for use of risdiplam for pediatric or adult patients (2-25 years old) with type II or III SMA patients includes ongoing double-blind, 2-part, placebo-controlled SUNFISH study. Results of 180 patients (confirmatory study) from part 2 with 12 months follow-up are available. The least square mean change in MFM-32 from baseline was greater in patients receiving risdiplam compared with placebo with a difference of 1.55 (95% CI: 0.30 to 2.81). Responder analysis (using a threshold of increase in 3 or more points in MFM-32 as being clinically meaningful) showed that 38% of those receiving risdiplam met the criteria of achieving a clinically meaningful improvement in motor function compared to 24%. Notable limitations include a relatively short follow-up of 1 year which is inadequate to assess durability of efficacy and safety (especially adverse events that are potentially rare or have delayed onset).

Summary of Evidence

For individuals who have symptomatic type II or III SMA who receive risdiplam, the evidence includes a single ongoing double-blind, 2-part, placebo-controlled (SUNFISH) study. Relevant outcomes are overall survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. Pediatric or adult patients (2-25 years old) with type II or III SMA patients were enrolled in the SUNFISH study. Results of 180 patients from part 2 with 12 months follow-up are available. The least-square mean change in MFM-32 from baseline was greater in patients receiving risdiplam compared with placebo with a difference of 1.55 (95% CI: 0.30 to 2.81). Responder analysis (using a threshold of increase in 3 or more points in MFM-32 as being clinically meaningful) showed that 38% of those receiving risdiplam met the criteria of achieving a clinically meaningful improvement in motor function compared to 24%. Upper limb function measured by RULM showed a 1.6 point improvement in the risdiplam-treated group compared to no change in the placebo group. However, there is limited data to assess the long-term durability of treatment effect as well as safety-related to adverse events that are rare or have delayed onset. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Institute for Health and Care Excellence

On July 24, 2019 the National Institute for Health and Care Excellence (NICE) issued technology appraisal guidance on nusinersen for treating spinal muscular atrophy. Nusinersen is recommended as an option for treating SMA only if people have pre-symptomatic SMA, or SMA types 1, 2 or 3 and the conditions laid out in the managed access agreement were followed. ^58,

On December 16, 2021, the NICE issued technology appraisal guidance on risdiplam for treating spinal muscular atrophy. Risdiplam is recommended as an option for treating 5q spinal muscular atrophy in people 2 months and older with a clinical diagnosis of SMA types 1, 2 or 3 or with pre-symptomatic SMA and 1 to 4 SMN2 copies and the conditions laid out in the managed access agreement were followed.^59,

On July 7, 2021, the NICE issued specialized technology appraisal guidance on onasemnogene abeparvovec for treating spinal muscular atrophy.^60, Recommendations are summarized below.

Onasemnogene abeparvovec is recommended as an option for treating 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of type 1 SMA in babies, only if:

• They are 6 months or younger, or they are aged 7 to 12 months, and their treatment is agreed by the national multidisciplinary team. It is only recommended for these groups if permanent ventilation for more than 16 hours per day or a tracheostomy is not needed and the company provides it according to the commercial arrangement.

• For babies aged 7 to 12 months, the national multidisciplinary team should develop auditable criteria to enable onasemnogene abeparvovec to be allocated to babies in whom treatment will give them at least a 70% chance of being able to sit independently.

• Onasemnogene abeparvovec is recommended as an option for treating presymptomatic 5q SMA with a bi-allelic mutation in the SMN1 gene and up to 3 copies of the SMN2 gene in babies. It is recommended only if the conditions in the managed access agreement are followed.

On April 19, 2023, the NICE issued a specialized technology appraisal guidance on onasemnogene abeparvovec for treating presymptomatic spinal muscular atrophy.^61, Recommendations are summarized below.

• Onasemnogene abeparvovec is recommended as an option for treating presymptomatic 5q SMA with a biallelic mutation in the SMN1 gene and up to 3 copies of the SMN2 gene in babies aged 12 months and under. It is only recommended if the company provides it according to the commercial arrangement.

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 spinal muscular atrophy on April 3, 2019, and subsequently on May 24, 2019, published an update following U.S. Food and Drug Administration (FDA) approval of onasemnogene abeparvovec-xioi.^38,

Nusinersen

Based on the lack of relevant data, the report concluded that the evidence for nusinersen was insufficient for type 0 and IV spinal muscular atrophy.

• For infantile-onset spinal muscular atrophy, 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 spinal muscular atrophy patients with more severe disease were underrepresented in the trials and may not adequately reflect the “real-world” patient population.”

• For later-onset spinal muscular atrophy, 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 spinal muscular atrophy, 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+).

Onasemnogene Abeparvovec-Xioi

The report only included and appraised the published evidence from the Phase I dose-finding study of onasemnogene abeparvovec-xioi. The authors did not rate the quality of this study because they do not conduct quality assessment of non-comparative studies.

• For type 0, later-onset (types II and III), type IV and presymptomatic spinal muscular atrophy, the Report concluded that the evidence for onasemnogene abeparvovec-xioi was insufficient due to lack of relevant data. The report also rated the evidence to be insufficient for comparison of onasemnogene abeparvovec-xioi versus nusinersen for infantile-onset spinal muscular atrophy due to lack of evidence.

• For infantile-onset spinal muscular atrophy, the report concluded with high certainty that onasemnogene abeparvovec-xioi provides a substantial net health benefit, and rate the evidence base as “superior” to standard care (A).

• In summarizing the uncertainties of the clinical evidence, the Institute for Clinical and Economic Review report noted considerable uncertainty in the generalizability of the results and in the long-term durability and tolerability of treatment. Further, the report notes additional uncertainty related to the possibility of loss of transgene expression over time and subsequent treatment pathway. The report also noted that some patients in the pivotal trial subsequently received nusinersen, but the effects of combination or sequential therapies have not been well studied.

Subsequent to the FDA approval of onasemnogene abeparvovec-xioi, the Institute for Clinical and Economic Review issued an update with a brief discussion of additional data/interim analyses from ongoing trials that were presented at the Muscular Dystrophy Association Clinical and Scientific Conference April 13-17, 2019 and American Academy of Neurology Annual Meeting May 4-10, 2019) and manufacturer press releases. In summary, the Institute for Clinical and Economic Review noted that the updated data are largely consistent with previously available findings and as the data evolves and confirm the initial findings, the evidence rating may be revised.

U.S. Preventive Services Task Force Recommendations

Not applicable

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished and ongoing trials that might influence this review are listed in Table 33.

Table 33. Summary of Key Trials

NCT: national clinical trial; SMA: spinal muscular atrophy.a Denotes industry-sponsored or cosponsored trial.

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Codes

Policy History