Original Department: Pharmacy Management 10/12/2020 Approval: Policy #: PM165 Last Approval: 10/12/2020 Title: Duchenne Muscular Dystrophy genetic Approved By: UM Pharmacy Subcommittee

Line(s) of Business WAH-IMC (HCA) BHSO Medicare Advantage (CMS) Medicare SNP (CMS) Cascade Select

Documentation required to determine medical necessity for IV infusion (Exondys 51): History and/or physical examination notes and relevant specialty consultation notes that address the problem and need for the service: Diagnosis-Age- list (current and past)- Labs/Diagnostics.

BACKGROUND Exondys 51 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed of the DMD that is amenable to 51 skipping.1 Exondys 51 was approved for this indication under accelerated approval based on an increase in observed in the skeletal muscle of some patients who received the . However, a clinical benefit of Exondys has not been established. The prescribing information notes that continued FDA-approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Golodirsen (Vyondys 53) and (Viltepso) are indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.1,12 Vyondys 53 and Viltepso were approved for this indication under accelerated approval based on an increase in dystrophin observed in the skeletal muscle of patients who received the drug. The prescribing information notes that continued FDA-approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

Disease Overview DMD is an X-linked recessive disease affecting 1 in 3,600 to 6,000 newborn male infants.2 The disease is attributed to large frame-shift deletions in the DMD gene (chromosome Xp21) which lead to loss of a structural protein of muscle cells (dystrophin).3 Over 4,700 on the DMD gene have been identified which lead to a deficiency in production of dystrophin.2 Therefore, the type of mutation and its effect on the production of dystrophin accounts for the variable phenotypic expression.4 Females carriers are usually asymptomatic but some may show mild symptoms.2 There are wide variances in how quickly DMD progresses, but without intervention death is at approximately 19 years of age.2-4 With respiratory, cardiac, orthopedic and rehabilitative interventions and use of corticosteroids, children born today can have a life expectancy of up to 40 years.

Exondys 51 is an antisense designed to bind to exon 51 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to

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exon 51 skipping.1 These patients represent approximately 13% of all patients with DMD.5 This genetic manipulation intends to restore the reading frame of the resulting mRNA. The result would be production of a shortened, but partially functional dystrophin protein as seen in less severe forms of muscular dystrophy (e.g., Becker muscular dystrophy).

Vyondys 53 is an antisense oligonucleotide designed to bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping.12 These patients represent up to 10% of all patients with DMD.5 This genetic manipulation intends to restore the reading frame of the resulting mRNA. The result would be production of a shortened, but partially functional dystrophin protein as seen in less severe forms of muscular dystrophy (e.g., Becker muscular dystrophy). Of note, the reading frame of certain deletions (e.g., exon 52 deletions) can be restored by skipping either exon 51 or exon 53.6 Approximately 8% of mutations are amenable to skipping exon 53 with Vyondys 53 but are not amenable to skipping of exon 51.

Guidelines There are guidelines for the diagnosis and management of DMD available from the DMD Care Considerations Working Group (2018).4 Genetic testing for a DMD mutation in a blood sample is always required. By fully characterizing the mutation, the predicted effect on the reading frame can be identified, which is the major determinant of phenotype and will determine eligibility for mutation-specific clinical trials. In patients with no mutation identified but with signs/symptoms of DMD, a muscle biopsy is clinically indicated. Glucocorticoids slow decline in muscle strength and function in DMD. Use of corticosteroids reduces the risk of scoliosis and stabilizes pulmonary function. Continued treatment after the patient loses ambulation provides a reduction in the risk of progressive scoliosis and stabilization of pulmonary function tests. Therefore, glucocorticoids should be considered for all patients with DMD. Exondys 51 is mentioned as an emerging product, approved by an accelerated pathway for those with a mutation in the dystrophin gene amenable to exon 51 skipping.

DEFINITIONS none

INDICATIONS/CRITERIA

CHPW AH-IMC Excluded benefit. Authorization and billing required directly through WA members Apple Health Fee For Service only. Call 800-562-3022. CHNW Cascade Select Continue to criteria for approval below. members Medicare Members Step-utilization of Part D not required. Continue to criteria for approval below.

Coverage of Eteplirsen IV infusion (Exondys 51) is recommended in those who meet the following criteria:

FDA-Approved Indications

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Treatment of Duchenne muscular dystrophy (DMD) Initial Approval Approve for 3 months for patients who meet ALL the following criteria: 1. Diagnosis of Duchenne muscular dystrophy by, or in consultation with, a neurologist with expertise in the diagnosis of DMD; 2. Results of genetic testing confirm Duchenne muscular dystrophy amenable to exon 51 skipping; 3. Patient is 4 years of age or older 4. Patient has stable pulmonary (absence of invasive ventilation or tracheostomy) and cardiac function 5. Patient is receiving glucocorticoid or glucocorticoid treatment was discontinued at the recommendation of the treating physician 6. Results of 6-Minute Walk Time (6MWT) ≥ 300 meters while walking independently (e.g., without side-by-side assist, cane, walker, wheelchair, etc.) prior to beginning Eteplirsen (Exondys 51) therapy; OR Brooke Upper Extremity Functional Rating Scale for non-ambulatory patients: baseline of 5 or lower 7. Eteplirsen (Exondys 51) is prescribed by, or in consultation with, a neurologist with expertise in the treatment of DMD; 8. Dosing is 30 mg/kg infused once weekly for DMD is in accordance with the United States Food and Drug Administration approved labeling; 9. Eteplirsen (Exondys 51) is not used concomitantly with other therapies for DMD (e.g., Vyondys 53, Viltepso, or other agents);

For reauthorization: Approve for 6 months for patients who meet ALL the following criteria: 1. Eteplirsen (Exondys 51) is prescribed by, or in consultation with, a neurologist with expertise in the treatment of DMD; 2. Maintenance or improvement of 6-Minute Walk Time (6MWT) ≥ 300 meters while walking independently (e.g., without side-by-side assist, cane, walker, wheelchair, etc.). This must be measured no earlier than 4 weeks prior to a continuation request; OR Maintenance or improvement in Brooke Upper Extremity Functional Rating Scale for non-ambulatory patients; 3. Patient has stable pulmonary (absence of invasive ventilation or tracheostomy) and cardiac function; 4. Patient is receiving glucocorticoid therapy or glucocorticoid treatment was discontinued at the recommendation of the treating physician; 5. Dosing is 30 mg/kg infused once weekly for DMD is in accordance with the United States Food and Drug Administration approved labeling; 6. Eteplirsen (Exondys 51) is not used concomitantly with other exon skipping therapies for DMD (e.g., Vyondys 53, Viltepso, or other clinical trial agents);

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Coverage of (Vyondys 53) or Viltolarsen (Viltepso) is recommended in those who meet the following criteria:

FDA-Approved Indications Treatment of Duchenne muscular dystrophy (DMD) Initial Approval Approve for 3 months for patients who meet ALL the following criteria: 1. Diagnosis of Duchenne muscular dystrophy by, or in consultation with, a neurologist with expertise in the diagnosis of DMD; 2. Results of genetic testing confirm Duchenne muscular dystrophy amenable to exon 53 skipping; 3. Patient is 4 years of age or older 4. Patient has stable pulmonary (absence of invasive ventilation or tracheostomy) and cardiac function 5. Patient is receiving glucocorticoid therapy or glucocorticoid treatment was discontinued at the recommendation of the treating physician 6. Results of 6-Minute Walk Time (6MWT) ≥ 300 meters while walking independently (e.g., without side-by-side assist, cane, walker, wheelchair, etc.) prior to beginning exon 53 skipping therapy; 7. Golodirsen (Vyondys 53) or Viltolarsen (Viltepso) is prescribed by, or in consultation with, a neurologist with expertise in the treatment of DMD; 8. Dosing: a. Golodirsen (Vyondys): Dosing is 30 mg/kg infused once weekly b. Viltolarsen (Viltepso): Dosing is 80 mg/kg infused once weekly 9. Golodirsen (Vyondys 53) or Viltolarsen (Viltepso) is not used concomitantly with other exon skipping therapies for DMD (e.g., Exondys 51, Viltepso, or other clinical trial agents);

For reauthorization: Approve for 6 months for patients who meet ALL the following criteria: 1. Exon 53 skipping therapy is prescribed by, or in consultation with, a neurologist with expertise in the treatment of DMD; 2. Maintenance or improvement of 6-Minute Walk Time (6MWT) ≥ 300 meters while walking independently (e.g., without side-by-side assist, cane, walker, wheelchair, etc.). This must be measured no earlier than 4 weeks prior to a continuation request; 3. Patient has stable pulmonary (absence of invasive ventilation or tracheostomy) and cardiac function; 4. Patient is receiving glucocorticoid therapy or glucocorticoid treatment was discontinued at the recommendation of the treating physician; 5. Dosing is 30 mg/kg infused once weekly for DMD is in accordance with the United States Food and Drug Administration approved labeling; 6. Golodirsen (Vyondys 53) or Viltolarsen (Viltepso) is not used concomitantly with other exon skipping therapies for DMD (e.g., Exondys 51, Viltepso, or other clinical trial agents);

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CONDITIONS NOT RECOMMENDED FOR APPROVAL Eteplirsen (Exondys 51), Golodirsen (Vyondys 53) and Viltolarsen (Viltepso) have not been shown to be effective, or there are limited or preliminary data or potential safety concerns that are not supportive of general approval for the following conditions.

Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available.

SPECIAL CONSIDERATIONS none

LIMITATIONS/EXCLUSIONS Please refer to a product line’s certificate of coverage for benefit limitations and exclusions for these services:

PRODUCT LINE LINK TO CERTIFICATE OF COVERAGE CHPW Medicare Advantage https://medicare.chpw.org/chpw-washington- state-medicare-advantage-plans/all-medicare- plans-2020/ Washington Apple Health (Medicaid) Integrated https://www.chpw.org/for-members/benefits- Managed Care and-coverage-imc/ CHNW Cascade Select

Citations & References CFR 42 CFR § 438.210 WAC WAC 284-43-2050 RCW Contract WAH - IMC AH section 17.3.2.1 General Description of Contracted Citation Services - Pharmacy Benefit and Services - Apple Health Preferred Drug List and Plan Formularies BHSO MA Cascade Select WAC 284-43-5642 - Essential health benefit categories Other Require ments

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NCQA Element s Referenc 1. Exondys 51™ intravenous infusion [prescribing information]. Cambridge, MA: , Inc.; es October 2018. 2. Annexstad EJ, Lund-Petersen I, Rasmussen M. Duchenne muscular dystrophy. Tidsskr Nor Laegeforen. 2014;134(14):1361-1364. 3. Wood MJA. To skip or not to skip: that is the question for Duchenne muscular dystrophy. Mol Ther. 2013;21(12):2131-2132. 4. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018;17(3):251-267. 5. Flanigan KM, Voit T, Rosales XQ, et al. Pharmacokinetics and safety of single doses of in non- ambulant subjects with Duchenne muscular dystrophy: results of a double-blind randomized clinical trial. Neuromuscul Disord. 2014;24(1):16-24. 6. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013;74(5):637-647. 7. FDA briefing document for the Peripheral and Central Nervous System Drugs Advisory Committee Meeting. Eteplirsen (NDA 206488). April 25, 2016. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCen tralNervousSystemDrugsAdvisoryCommittee/UCM497063.pdf. Accessed on April 10, 2020. 8. Mendell JR, Goemans N, Lowes LP, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016;79(2):257-271. 9. Peripheral and Central Nervous System Drugs Advisory Committee. Eteplirsen. April 25, 2016. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCen tralNervousSystemDrugsAdvisoryCommittee/UCM500822.pdf. Accessed on April 10, 2020. 10. Shimizu-Motohashi Y, Murakami T, Kimura E, et al. Exon skipping for Duchenne muscular dystrophy: a systematic review and meta-analysis. Orphanet J Rare Dis. 2018;13(1):93. 11. Kinane TB, Mayer OH, Duda PW, et al. Long-term pulmonary function in Duchenne muscular dystrophy: comparison of eteplirsen-treated patients to natural history. J Neuromuscul Dis. 2018;5(1):47-58. 12. Vyondys 53 intravenous infusion [prescribing information]. Cambridge, MA: Sarepta Therapeutics, Inc.; December 2019. 13. van Deutekom JC, Bremmer-Bout M, Janson AA, et al. Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells. Hum Mol Genet. 2001;10(15):1547-1554. 14. Bladen CL, Salgado D, Monges S, et al. The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations. Hum Mutat. 2015;36(4):395-402. 15. Frank DE, Mercuri E, Servais L, et al. Golodirsen induces exon skipping leading to sarcolemmal dystrophin expression in patients with generic mutations amenable to exon 53 skipping [abstract 228]. Presented at the Annual Clinical Genetics Meeting of the American College of Medical Genetics and Genomics; Seattle, WA; April 2-6, 2019. 16. Muntoni F, Frank D, Sardone V, et al. Golodirsen induces exon skipping leading to sarcolemmal dystrophin expression in Duchenne muscular dystrophy patients with mutations amenable to exon 53 skipping [abstract S22.001]. Neurology. 2018:90 (15 Supplement) S22.00. Available at: https://n.neurology.org/content/90/15_Supplement/S22.001. Accessed on December 13, 2019. 17. Viltepso intravenous infusion [prescribing information]. Paramus, NJ: NS Pharma; OTHER REFERENCES UTILIZED • Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol. 2018;17(4):347-361. • Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Lancet Neurol. 2018;17(5):445-455.

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Revision History Revision Date Revision Description Revision Made By 09/11/2020 New policy Jennifer Farley, PharmD 10/12/2020 Approval UM Committee

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