Description
Duchenne muscular dystrophy (DMD) 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. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with Viltepso. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Background 
Duchenne muscular dystrophy (DMD) is an X-linked disease that affects 1 in 3,600 – 6,000 live male births. DMD occurs as a result of mutations (mainly deletions) in the dystrophin gene. These mutations lead to an absence or a defect of the protein dystrophin, resulting in progressive muscle degeneration, leading to loss of ambulation and additional respiratory, orthopedic, and cardiac complications. If left untreated, mean age of death is approximately 19 years of age.^2,3,4

Viltolarsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMOs are synthetic molecules in which the five-membered ribofuranosyl rings found in natural DNA and RNA are replaced by a sixmembered morpholino ring. Each morpholino ring is linked through an uncharged phosphorodiamidate moiety rather than the negatively charged phosphate linkage that is present in natural DNA and RNA. Each phosphorodiamidate morpholino subunit contains one of the heterocyclic bases found in DNA (adenine, cytosine, guanine, or thymine).¹

Viltolarsen is 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. Approximately 8% of DMD patients have out-of frame deletion mutations amenable to exon 53 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.¹

Policy
Viltepso is considered MEDCIALLY NECESSARY when the following criteria is met:

1. Submission of medical records (e.g., chart notes, laboratory values) documenting both of the following:
   1. Diagnosis of Duchenne muscular dystrophy (DMD) AND
   2. Documentation of a confirmed mutation of the dystrophin gene amenable to exon 53 skipping AND
2. Patient is 4 years of age or older AND
3. Prescribed by or in consultation with a neurologist who has experience treating children AND
4. Dose will not exceed 80 milligrams per kilogram of body weight infused once weekly AND
5. Submission of medical records (e.g., chart notes, laboratory values) documenting the patient is ambulatory, as evaluated via the 6-minute walk test (6MWT) or North Star ambulatory assessment (NSAA) ^2,3 

Approval Criteria for reauthorization:

1. One of the following:
   1. All of the following:
      1. Patient has been on therapy for less than 12 months AND
      2. Patient is tolerating therapy AND
      3. Dose will not exceed 80 milligrams per kilogram of body weight infused once weekly AND
      4. Prescribed by or in consultation with a neurologist who has experience treating children AND
      5. Submission of medical records (e.g., chart notes, laboratory values) documenting the patient is maintaining ambulatory status, as evaluated via the 6-minute walk test (6MWT) or North Star ambulatory assessment (NSAA) OR
   2. All of the following:
      1. Patient has been on therapy for 12 months or more AND
      2. Patient has experienced a benefit from therapy (e.g., disease amelioration compared to untreated patients) AND
      3. Patient is tolerating therapy AND
      4. Dose will not exceed 80 milligrams per kilogram of body weight infused once weekly AND
      5. Prescribed by or in consultation with a neurologist who has experience treating children AND
      6. Submission of medical records (e.g., chart notes, laboratory values) documenting the patient is maintaining ambulatory status, as evaluated via the 6-minute walk test (6MWT) or North Star ambulatory assessment (NSAA)

Policy Guidelines
Coding 
See the Codes table for details.

Benefit Application
BlueCard/National Account Issues
Not applicable

Rationale 
This Viltolarsen is 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

A phase II study evaluated 2 doses of viltolarsen in 16 ambulatory boys aged 4 to 9 years with a DMD diagnosis and DMD gene amenable to exon 53 skipping over 24 weeks. Ambulatory boys on a stable corticosteroid regimen for at least 3 months who could complete time to stand from supine, time to run/walk 10 m, and time to climb 4 stairs assessments were included. The study was a multicenter, 2-period dose-finding clinical trial. The first study period, which corresponded to the first 4 weeks of treatment following enrollment, was double-blinded and placebo-controlled. Participants in both dose cohorts were randomized 3:1 to receive viltolarsen or placebo. The second study period began at week 5 for each participant. During this period, all participants received viltolarsen according to their cohort dose for a 20-week open-label treatment. Primary study outcomes included safety, tolerability, and pharmacokinetics of low-dose (40 mg/kg per week) and high-dose (80 mg/kg per week) viltolarsen in ambulant boys with DMD. Efficacy was assessed based on change from baseline in dystrophin protein level (measured as % of the dystrophin level in healthy subjects, i.e., % of normal) at Week 25. Muscle dystrophin production was assessed as protein production by Western blot for the primary study efficacy outcome and as dystrophin mRNA splicing on RT-PCR, dystrophin protein production by MS, and dystrophin localization by IF staining for secondary study efficacy outcomes. Additional secondary efficacy outcomes were gross motor skill assessments of timed function tests, including time to stand from supine, time to run/walk 10 m, time to climb 4 stairs, North Star Ambulatory Assessment, and 6-minute walk test as well as quantitative muscle testing. These outcomes were compared with a matched natural history control group from the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS).

In patients who received viltolarsen 80 mg/kg once weekly, mean dystrophin levels increased from 0.6% of normal at baseline to 5.9% of normal by week 25, with a mean change in dystrophin of 5.3% of normal levels (p = 0.01) as assessed by validated Western blot; the median change from baseline was 3.8%. All patients demonstrated an increase in dystrophin levels over their baseline values. As assessed by mass spectrometry, mean dystrophin levels increased from 0.6% of normal at baseline to 4.2% of normal by Week 25, with a mean change in dystrophin of 3.7% of normal levels; the median change from baseline was 1.9%.

Comparison of viltolarsen-treated participants with 65 age-matched and treatment matched natural history controls from CINRG DNHS suggested evidence of clinical benefit of viltolarsen treatment. Viltolarsen-treated participants showed improvement or stabilization of function over the 25-week period, whereas the CINRG DNHS external comparator group exhibited a decline in all timed function tests, except for time to climb 4 stairs. Velocity in the time to run/walk 10 m test significantly improved in viltolarsen-treated participants at weeks 13 and 25 compared with a decline in controls from CINRG DNHS (change at 25 weeks compared with baseline: viltolarsen, 0.23 m/s; control, −0.04m/s). The 6-minute walk test showed significant improvement at week 25 in viltolarsen treated participants, whereas results from CINRG DNHS controls declined over the same period (change at 25 weeks compared with baseline: viltolarsen, 28.9 m; control, −65.3 m). Significant improvements in time to stand from supine were observed (change at 25 weeks compared with baseline: viltolarsen, −0.19 s; control, 0.66 s). Velocity in the time to stand from supine test and time to climb 4 stairs test as well as North Star Ambulatory Assessment similarly displayed improvement or stabilization, but the differences between viltolarsen treatment and external comparator controls were not significant. Measures of muscle strength by isometric testing showed no differences between viltolarsen-treated participants and the CINRG DNHS external comparator control group.⁷

RACER53 is an ongoing 48-week, phase 3 double-blind, placebo controlled, randomized clinical trial that will evaluate the efficacy of viltolarsen in ambulatory DMD patients with out-of-frame deletion mutations amenable to skipping exon 53. The Viltepso^® (Viltolarsen) Page 4 of 6 UnitedHealthcare Commercial Medical Benefit Drug Policy Effective 04/01/2021 Proprietary Information of UnitedHealthcare. Copyright 2021 United HealthCare Services Inc. study will enroll 74 boys from 4 to 8 years of age with genotypically confirmed DMD on a stable dose of corticosteroids who can walk independently without assistive devices with a time to stand of less than 10 seconds. The primary endpoint is the change from baseline to Week 96 in the time to stand. Secondary outcomes include the change in time to run/walk 10 meters, change in 6MWT, change in the NSAA, change in time to climb 4 steps, and change in muscle force contraction measured by dyanometry.⁸

The SKIP-NMD trial of golodirsen is a U.S.-based, blinded, placebo-controlled, dose-escalation two-part Phase I/II RCT of male patients aged six to 15 years with a DMD diagnosis and DMD gene amenable to exon 53 skipping. Patients age 6 to 15 years with stable cardiac and pulmonary function, and on a stable dose of corticosteroids for at least six months were included. Additional inclusion criteria included a baseline six-minute walk test (6MWT) of greater than 250m, a North Star Ambulatory Assessment (NSAA) score of greater than 17 or a rise time of less than 7 seconds. In part one, 12 patients were randomized to receive once-weekly intravenous infusions at escalating doses of 4, 10, 20, 30 mg/kg of golodirsen or matching placebo for 12 weeks. Part two consists of an open-label period of all patients from part one and 13 newly recruited patients who are receiving once-weekly infusions of 30 mg/kg of golodirsen for up to 168 weeks.

Part one of the SKIP-NMD trial assessed safety and tolerability. In part two, the primary endpoints are change from baseline in 6MWT at 144 weeks and change in dystrophin protein levels at 48 weeks. Secondary endpoints include drug pharmacokinetics, change from baseline in FVC percent predicted, and change from baseline in dystrophin intensity at 144 weeks.

At the time of pre-planned interim analysis, data from baseline and Week 48 muscle biopsies, exon 53 skipping, and dystrophin localization were available for 25 patients on golodirsen. The study is ongoing, and results for the primary efficacy endpoint of 6MWT at Week 144 are not yet available. Mean baseline of dystrophin in the trial was reported to be 0.095% of normal. At 48 weeks, the mean level of dystrophin had increased to 1.019% of normal resulting in an absolute increase of 0.918% of normal (p<0.001). A clinically meaningful change in level of dystrophin has not yet been established in humans. As such, the clinical significance of these results is not clear. Among individual patients, dystrophin levels at Week 48 ranged from 0.09% to 4.30%.^9,10,11

ESSENCE is an ongoing 96-week, Phase 3, double-blind, placebo controlled, randomized clinical trial that will evaluate the efficacy of golodirsen and casimersen in DMD patients with out-of-frame deletion mutations amenable to skipping exon 53 and exon 45, respectively. The study will enroll 222 boys from 7 to 13 years of age with genotypically confirmed DMD and 6MWT ≥ 300 m and ≤ 450 m. The primary endpoint is the change from baseline to Week 96 in 6MWT.¹²

Viltolarsen or golodirsen have not been studied in DMD that is not amenable to exon 53 skipping, nor in other forms of muscular dystrophy (e.g., Becker muscular dystrophy).^1,6

References:

1. Viltepso [package insert]. Paramus, NJ; NS Pharma, Inc, August 2020.
2. Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol; 2010 Jan; 9(1):77 93.
3. Bushby K, Finkel R, Birnkrant DJ, et al. (2010) Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol; 2010 Jan; 9(2):177-189. Viltepso® (Viltolarsen) Page 5 of 6 UnitedHealthcare Commercial Medical Benefit Drug Policy Effective 04/01/2021 Proprietary Information of UnitedHealthcare. Copyright 2021 United HealthCare Services, Inc.
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. doi: 10.1016/S1474-4422(18)30024.
5. Exondys 51 [package insert]. Cambridge, MA: Sarepta Therapeutics, Inc, October 2018.
6. Vyondys 53 [package insert]. Cambridge, MA: Sarepta Therapeutics, Inc, December 2019.
7. Clemens PR, Rao VK, Connolly AM, et al. Safety, tolerability, and efficacy of viltolarsen in boys with duchenne muscular dystrophy amenable to exon 53 skipping: a phase 2 randomized clinical trial. JAMA Neurol. 2020; 26;77(8):1-10. doi: 10.1001/jamaneurol.2020.2025.
8. Study to Assess the Efficacy and Safety of Viltolarsen in Ambulant Boys With DMD (RACER53) https://clinicaltrials.gov/ct2/show/NCT04060199?term=viltolarsen&draw=2&rank=1. Accessed August 12, 2020.
9. Frank DE, Mercuri E, Servais, L, et al. Golodirsen induces exon skipping leading to sarcolemmal dystrophin expression in patients with genetic mutations amenable to exon 53 skipping. Poster presented at: Annual Clinical Genetics Meeting of the American College of Medical Genetics and Genomics; April 2-6, 2019; Seattle, WA.
10. Muntoni F, Frank DE, Morgan J, et al. Golodirsen induces exon skipping leading to sarcolemmal dystrophin expression in patients with genetic mutations amenable to exon 53 skipping [abstract]. Neuromuscul Disord. 2018;28:S5. Abstract D01.
11. Muntoni F, Frank DE, Sardone V, et al. SRP-4053 induces exon skipping leading to sarcolemmal dystrophin expression in Duchenne muscular dystrophy patients amenable to exon 53 skipping. Poster presented at: 22nd International Annual Congress of the World Muscle Society; October 3-7 2017; Saint Malo, France.
12. Study of SRP-4045 and SRP-4053 in DMD Patients (ESSENCE) https://clinicaltrials.gov/ct2/show/NCT02500381?term=golodirsen&cond=Duchenne+Muscular+Dystrophy&rank=3. Accessed July 22, 2019.
13. Institute for Clinical and Economic Review (ICER). Deflazacort, eeplirsen, and golodirsen for Duchenne muscular dystrophy: Effectiveness and value: Evidence Report. https://icer-review.org/wpcontent/uploads/2018/12/ICER_DMD_Evidence Report_071119.pdf. July 11, 2019. Accessed August 12, 2020.
14. Viltepso Prescribing Information. NS Pharma, Inc. Paramus, NJ. August 2020.
15. ClinicalTrials.gov. Safety and Dose Finding Study of NS-065/NCNP-01 in Boys With Duchenne Muscular Dystrophy (DMD). NCT02740972. Website. Available at: https://clinicaltrials.gov/ct2/show/NCT02740972?term=NCT02740972&draw=2&rank=1. Accessed August 26, 2020.
16. Per Clinical Consultation with a Pediatrician, April 25, 2019 and January 22, 2020.

Coding Section  

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

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

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