SPINRAZA, Nusinersen Form

Nusinersen (Spinraza®) is a survival motor neuron-2 (SMN2)-directed antisense oligonucleotide. FDA Approved Indication(s) Spinraza is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
All requests reviewed under this policy require medical director review It is the policy of health plans affiliated with Centene Corporation® that Spinraza is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Spinal Muscular Atrophy (must meet all):

1. Diagnosis of SMA;
   
   2. Genetic testing confirms the presence of one of the following (a, b, or c): a. Homozygous deletions of SMN1 gene (e.g., absence of the SMN1 gene); b. Homozygous mutation in the SMN1 gene (e.g., biallelic mutations of exon 7); c. Compound heterozygous mutation in the SMN1 gene (e.g., deletion of SMN1 exon 7 (allele 1) and mutation of SMN1 (allele 2));
2. Prescribed by or in consultation with a neurologist;
   
   4. Documentation of genetic testing quantifying number of copies of SMN2 gene and one of the following (a or b): a. One, two, or three copies of SMN2 gene; b. Four copies of SMN2 gene, and documentation indicates presence of SMA symptoms (e.g., weakness, tremors, loss of functionality);

3. Documentation of one of the following baseline scores (see Appendix D) (a or b): a. For age < 2 years: Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorder (CHOP-INTEND) score or Hammersmith Infant Neurological Examination (HINE) Section 2 motor milestone score; b. For age ≥ 2 years: Hammersmith functional motor scale expanded (HFMSE) score, Revised Hammersmith Scale (RHS), Upper Limb Module (ULM), Revised Upper Limb Module (RULM), or 6-Minute Walk Test (6MWT); Page 1 of 9

   CLINICAL POLICY Nusinersen

4. Member does not require tracheostomy or invasive or noninvasive ventilation for ≥ 16 hours/day continuously for > 21 days;
5. Failure of a trial of Evrysdi®, unless contraindicated or clinically significant adverse effects are experienced; Failure will be defined as decline in motor function test score(s) from baseline
   8. Spinraza is not prescribed concurrently with Evrysdi or Zolgensma®;
   9. If the member is currently on Evrysdi, documentation of prescriber attestation of Evrysdi discontinuation upon initiation of Spinraza;
6. If the member has a history of treatment with Zolgensma, must meet the following
   (a and b): a. Provider must submit evidence of poor response to Zolgensma (e.g., sustained decrease in CHOP-INTEND score over a period 6 months); b. Documentation of provider attestation of clinical deterioration;
7. Total dose does not exceed 4 doses of 12 mg, prescribed for intrathecal use.
   Approval duration: 12 months (up to 4 doses) B. Other diagnoses/indications (must meet 1 or 2):
8. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
9. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Spinal Muscular Atrophy (must meet all):
10. Currently receiving medication for SMA with 1 to 4 copies of the SMN2 gene, or member has previously met initial approval criteria;
11. Member does not require tracheostomy or invasive or noninvasive ventilation for ≥ 16 hours/day continuously for > 21 days;

12. Member is responding positively to therapy, as evidenced by one of the following (a, b, or c): a. For age < 2 years, must meet one of the following (i or ii): i. For CHOP-INTEND, must demonstrate score improvement or maintenance of previous score improvement of ≥ 4 points from baseline; Page 2 of 9

    CLINICAL POLICY Nusinersen ii. For HINE motor milestone score, must demonstrate score improvement or maintenance of previous improvement in one or more categories AND improvement in more motor milestone categories than worsening; b. For age > 2 years, one of the following (i, ii, or iii):
    i. If first renewal since turning 2 years old, must provide submission of baseline HFMSE score, RHS score, RULM or ULM score, or 6MWT distance AND meet one of the following (1 or 2):
    1) For CHOP-INTEND, must demonstrate score improvement or maintenance of previous score improvement of ≥ 4 points from baseline; 2) For HINE motor milestone score, must demonstrate score improvement or maintenance of previous improvement in one or more categories AND improvement in more motor milestone categories than worsening; ii. If ≤ 2 years at therapy initiation and request is for subsequent renewal since turning 2, must meet one of the following (1 or 2) (see Appendix D):
    1) For HFMSE, RHS, ULM or RULM, must demonstrate score improvement or maintenance of previous score improvement from baseline score submitted at first renewal since turning 2 years old; 2) For 6MWT distance, must demonstrate improvement or maintenance of baseline distance; iii. If > 2 years at therapy initiation, must meet one of the following (1, 2, 3, or 4) (see Appendix D):
    1) For HFMSE or RHS, must demonstrate score improvement or maintenance of previous score improvement of ≥ 3 points from baseline; 2) For ULM, must demonstrate score improvement or maintenance of previous improvements in ≥ 2 points from baseline; 3) For RULM, must demonstrate score improvement or maintenance of previous improvements in ≥ 4 points from baseline; 4) For 6MWT distance, must demonstrate improvement or maintenance of baseline distance; c. Member has not had a decline in motor function test score(s) from baseline AND medical justification demonstrates and supports that member is responding positively to therapy;

13. Spinraza is not prescribed concurrently with Evrysdi and/or Zolgensma;
    5. If request is for a dose increase, new dose does not exceed 12 mg every 4 months prescribed for intrathecal use. Approval duration: 12 months
       B. Other diagnoses/indications (must meet 1 or 2):

14. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or Page 3 of 9

    CLINICAL POLICY Nusinersen b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

15. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid. III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents.
    IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key CHOP-INTEND: Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorder
    FDA: Food and Drug Administration HFMSE: Hammersmith functional motor scale expanded HINE: Hammersmith Infant Neurological Examination RHS: Revised Hammersmith Scale RULM: Revised Upper Limb Module SMA: spinal muscular atrophy SMN: survival motor neuron ULM: Upper Limb Module
    6MWT: 6-Minute Walk Test Appendix B: Therapeutic Alternatives This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose 5 mg/day Evrysdi® (risdiplam) Weight-based dose PO QD: • 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, weigh 20 kg or more: 5 mg Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings None reported Page 4 of 9

    CLINICAL POLICY Nusinersen Appendix D: General Information • SMA is an autosomal recessive genetic disorder. It is caused by mutations in the SMN1 (survival motor neuron) gene that is found on chromosome 5 (hence the name 5q-SMA). To develop SMA, an individual must inherit two faulty (deletion or mutation) SMN1 genes, one from each parent. • There are other types of SMA that are not related to chromosome 5 or SMN. Safety and efficacy of Spinraza in non-SMN-related SMA have not been established. • SMN-related SMA is classified as type 1 through 4 depending on time of onset. The age of disease onset of symptoms correlates with disease severity: the earlier the age of onset, the greater the impact on motor function. Children who display symptoms at birth or in infancy typically have the lowest level of functioning (type 1). SMA onset in children (types 2 and 3), teens or adults (type 4) generally correlates with increasingly higher levels of motor function. • Efficacy of Spinraza was established primarily in infantile disease (SMA type 1). Spinraza was approved based on interim results of an unpublished Phase III study of patients with spinal muscular atrophy type I (infantile-onset). The phase III study, referred to as ENDEAR, enrolled infants diagnosed with symptomatic, genetically confirmed spinal muscular atrophy (SMA) type I with two copies of SMN2 gene. Key inclusion criteria were: genetic documentation of 5q SMA homozygous gene deletion, homozygous mutation or compound heterozygote, onset of clinical signs and symptoms consistent with SMA at ≤ 6 months, at study entry, receiving adequate nutrition and hydration) with or without gastrostomy), seven month of age or younger at screening, body weight ≥ 3rd percentile for age, gestational age of 37 to 42 weeks. Key exclusion criteria were: Hypoxemia and signs or symptoms of SMA present at birth within the 1st week after birth • Based on the mechanism of action of Spinraza, SMN2 must be present in sufficient amount for the production of full length SMN protein required to alleviate or minimize the symptoms of SMA.
    • All subjects in the ENDEAR study had at least 2 copies of SMN2 genes (98% of the • subjects in the pivotal study had 2 copies of SMN2 genes, while other had 3 or 4 copies).
    It is unknown whether patients with less than 2 copies would make sufficient SMN protein to mitigate the symptoms of SMA as the efficacy of this agent has not been demonstrated in patients with less than 2 copies of SMN 2 genes. • SMN2 gene copy and SMA types o SMN2 gene copy numbers are variable in individuals with spinal muscular atrophy. Higher numbers typically correlate with less severe disease. o More than 95% of individuals with spinal muscular atrophy retain at least 1 copy of the SMN2 gene o About 80% of individuals with Type I spinal muscular atrophy have 1 or 2 copies of the SMN2 gene o About 82% of individuals with Type II spinal muscular atrophy have 3 copies of the SMN2 gene o About 96% of individuals with Type III spinal muscular atrophy have 3 or 4 copies of the SMN2 gene Page 5 of 9

    CLINICAL POLICY Nusinersen • The CHOP-INTEND score is a validated 16-item, 64-point scale shown to be reliable and sensitive to change over time for SMA Type 1. In a prospective cohort study of SMA type I patients (n = 34), the mean rate of decline in the CHOP-INTEND score was 1.27 points/year (95% CI 0.21-2.33, p = 0.02). • The HINE Section 2 motor milestone exam is an easily performed and relatively brief standardized clinical neurological examination that is optimal for infants aged between 2 and 24 months with good inter-observer reliability. This endpoint evaluates seven different areas of motor milestone development, with a maximum score between 2-4 points for each, depending on the milestone, and a total maximum score of 26 points. • The HFSME score combines the Hammersmith Functional Motor Scale with a 13-item expansion module for ability to distinguish motor skills among individuals who may be older or with SMA types II and III. Each item is graded from 0 to 3, with 0 signifying no response, with a total of 66 points. HFMSE has demonstrated reliability and validity in patients with SMA. An increase of greater than 2 points in total score is unlikely in untreated SMA. • The RHS is an ordinal scale which consist of 33 items with grades of 0,1 and 2. For individuals who can achieve the task without any compensation it is given a score of 2. For those who only attempt the movement or finish it with some form of compensation is scored 1 and sore of 0 is given when patients are unable to perform any part of the item. The total maximum score is 69 points. • The RULM is a set of 19 tasks that measure motor function in non-ambulatory SMA patients. Each task is assessed with a 3 point ordinal scale, with a total maximum score of 37 points. Meanwhile, the maximum score for ULM was 18. • The 6MWT is a clinical outcome measure for ambulatory SMA that has been determined to be functionally meaningful and capable of capturing disease severity.
    V. Dosage and Administration
    Indication SMA Dosing Regimen Initial (4 loading doses): 12 mg intrathecally every 14 days for 3 doses (loading doses); then, a fourth loading dose of 12 mg intrathecally 30 days after the third loading dose Maximum Dose 12 mg intrathecally every 4 months Maintenance: 12 mg intrathecally every 4 months VI. Product Availability
    Single-dose vial for intrathecal injection: 12 mg/5 mL
    VII.