Coverage Policy Manual
Policy #: 2016023
Category: Pharmacy
Initiated: December 2016
Last Review: April 2024
  Treatments for Duchenne Muscular Dystrophy (eg. Eteplirsen, Golodirsen, Viltolarsen, and Casimersen)

Description:
Duchenne muscular dystrophy (DMD) is a devastating muscle disorder that affects 1 in 3,500 boys. Despite years of research and considerable progress in understanding the molecular mechanism of the disease and advancement of therapeutic approaches, there is no cure for DMD. The current treatment options are limited to physiotherapy and corticosteroids, and although they provide a substantial improvement in affected children, they only slow the course of the disorder. DMD is associated with mutations in the dystrophin gene that disrupt the open reading frame. Theoretically, excluding specific exons in proximity to frame-shifting mutations, open reading frame could be restored to an out-of-frame mRNA, leading to the production of a partially functional dystrophin protein. This type of molecular therapy has been validated in canine and mouse models of DMD with various oligonucleotides that can restore dystrophin expression by inducing exon skipping during messenger RNA splicing: administration of oligonucleotides that are complementary to sequences that are crucial to normal splicing of the exon into the transcript.
 
Eteplirsen (e.g., EXONDYS 51) is an antisense oligonucleotide 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 51 skipping. Exon skipping is induced by eteplirsen, a phosphorodiamidate morpholino oligomer (PMO) that selectively binds to exon of dystrophin pre-mRNA, restoring the open reading frame and enabling production of a hypothetically functional, but truncated, dystrophin. Eteplirsen's proposed mechanism of action is increasing the production of a quantity of abnormal, but potentially functional, dystrophin protein, the objective is to slow or prevent the progression of DMD. Eteplirsen (EXONDYS 51) administered by IV injection, Sarepta Therapeutics, Cambridge MA) received conditional FDA Approval in September 2016.
 
Golodirsen (e.g., VYONDYS 53) is an antisense oligonucleotide indicated for the treatment of DMD in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping (9% of the DMD population). This indication is based on a statistically significant increase in dystrophin production in skeletal muscle observed in patients treated with Vyondys 53.
 
Casimersen (e.g., AMONDYS 45) is designed to bind to exon 45 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 45 skipping. Exon 45 skipping is intended to allow for production of an internally truncated dystrophin protein in patients with genetic mutations that are amendable to exon 45 skipping.
 
Viltolarsen (e.g., VILTEPSO) is an antisense oligonucleotide indicated for the treatment of DMD in patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.  Vitolarsen was approved under an accelerated approval based on an increase in dystrophin production in skeletal muscle that were treated with vitolarsen.  Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.  
 
 
Regulatory Status
 
Eteplirsen (EXONDYS 51) was approved by the U.S. Food and Drug Administration (FDA) on September 19, 2016 for the treatment of patients who have Duchenne muscular dystrophy with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. Duchenne muscular dystrophy (FDA, 2016). The accelerated FDA approval noted, “A clinical benefit of EXONDYS 51 has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials” (FDA, 2016).
 
FDA Commissioner Robert Califf  sent a report to senior FDA officials on September 16, 2016  (made public on the 19th) calling for a retraction of a 2013 study of drug eteplirsen published in Annals of Neurology and funded by Sarepta Therapeutics. The study alleged a treatment benefit to patients which the FDA considered misleading.
 
In a footnote, Mr. Califf stated, "In view of the scientific deficiencies identified in this analysis, I believe it would be appropriate to initiate a dialogue that would lead to a formal correction or retraction (as appropriate) of the published report." FDA chief scientist Luciana Borio added, "I would be remiss if I did not note that the sponsor exhibited serious irresponsibility by playing a role in publishing and promoting selective data during the development of this product. As determined by the review team, and as acknowledged by Dr. [Janet] Woodcock, the article's scientific findings - with respect to the demonstrated effect of eteplirsen on both surrogate and clinical endpoints - do not withstand proper and objective analyses of the data."
 
Golodirsen (VONDYS 53) was approved by the FDA on December 12, 2019 to treat DMD patients amenable to exon 53 skipping. The approval was based on golodirsen’ s  increases in a surrogate marker, dystrophin production in skeletal muscle. Similar to EXONDYS 51, no functional outcome improvement has been shown in clinical trials for golodirsen  As a condition of its accelerated approval, the FDA label states that a post-marketing confirmatory trial for full approval is needed (ESSENCE, expected completion 2024).
 
Casimersen, (AMONDYS 45) was approved by the FDA on February 25, 2021 for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping. This indication was approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with casimersen. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.
 
Vitolarsen (Viltepso) was approved by the U.S. FDA on August 12, 2020 for the treatment of Duchenne muscular dystrophy (DMD) gene in individuals who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. This indication was approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with vitolarsen. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.
 
Coding
 
See CPT/HPCS section below

Policy/
Coverage:
Effective April 2021
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of antisense oligonucleotides (such as eteplirsen, golodirsen, viltolarsen, or casimersen) for the treatment of Duchenne’s muscular dystrophy or for any other condition does not meet member benefit certificate primary coverage criteria because there has been no clinical benefit demonstrated and eteplirsen, golodirsen, viltolarsen, and casimersen are the subject of ongoing clinical trials.
 
For contracts without primary coverage criteria, the use of antisense oligonucleotides (such as eteplirsen, golodirsen, viltolarsen, or casimersen) for the treatment of Duchenne’s muscular dystrophy or for any other condition is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective February 2021 to March 2021
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of antisense oligonucleotides (such as eteplirsen, golodirsen, and vitolarsen for the treatment of Duchenne’s muscular dystrophy or for any other condition does not meet member benefit certificate primary coverage criteria because there has been no clinical benefit demonstrated and eteplirsen, golodirsenand vitolarsen are the subject of ongoing clinical trials.
 
For contracts without primary coverage criteria, the use of antisense oligonucleotides (such as eteplirsen, golodirsen, and vitolarsen) for the treatment of Duchenne’s muscular dystrophy or for any other condition is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage
 
 
Effective December 2016 to January 2021
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of eteplirsen or golodirsen for the treatment of Duchenne’s muscular dystrophy or for any other condition does not meet member benefit certificate primary coverage criteria because there has been no clinical benefit demonstrated and eteplirsen and golodirsen are the subject of ongoing clinical trials.
 
For contracts without primary coverage criteria, the use of eteplirsen or golodirsen for the treatment of Duchenne’s muscular dystrophy or for any other condition is investigational. Investigational services are specific contract exclusions in  most member benefit certificates of coverage

Rationale:
  
Eteplirsen
Eteplirsen accelerated FDA approval noted “A clinical benefit of EXONDYS 51 has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.”
 
Eteplirsen was evaluated in three clinical studies in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping (Mendell, 2013; Mendell, 2016).
    • In Study 1, patients were randomized to receive weekly infusions of eteplirsen (30 mg/kg, n=4); eteplirsen (50 mg/kg, n=4), or placebo (n=4) for 24 weeks. The primary endpoint was dystrophin production; a clinical outcome measure, the 6-minute walk test (6MWT), was also assessed. The 6MWT measures the distance that a patient can walk on a flat, hard surface in a period of 6 minutes. Patients had a mean age of 9.4 years, a mean 6-minute walk distance (6MWD) at baseline of 363 meters and were on a stable dose of corticosteroids for at least 6 months. There was no significant difference in change in 6MWD between patients treated with eteplirsen and those treated with placebo.
 
    • All 12 patients who participated in Study 1 continued treatment with open label eteplirsen weekly for an additional 4 years in Study 2. The 4 patients who had been randomized to placebo were re-randomized 1:1 to EXONDYS 30 or 50 mg/kg/week such that there were 6 patients on each dose. Patients who participated in Study 2 were compared to an external control group. The primary clinical efficacy outcome measure was the 6MWT. Eleven patients in Study 2 had a muscle biopsy after 180 weeks of treatment with eteplirsen, which was analyzed for dystrophin protein level by Western blot. Study 2 failed to provide evidence of a clinical benefit of eteplirsen compared to the external control group. The average dystrophin protein level after 180 weeks of treatment with eteplirsen was 0.93% of the dystrophin level in healthy subjects. Because of insufficient information on dystrophin protein levels before treatment with eteplirsen in Study 1, it is not possible to estimate dystrophin production in response to eteplirsen in Study 1.
 
    • In Study 3, 13 patients were treated with open label eteplirsen (30 mg/kg) weekly for 48 weeks and had a muscle biopsy at baseline and after 48 weeks of treatment. Patients had a mean age of 8.9 years and were on a stable dose of corticosteroids for at least 6 months. Dystrophin levels in muscle tissue were assessed by Western blot. In the 12 patients with evaluable results, the pre-treatment dystrophin level was 0.16% ± 0.12% (mean ± standard deviation) of the dystrophin level in a healthy subject and 0.44% ± 0.43% after 48 weeks of treatment with eteplirsen (p < 0.05). The median increase after 48 weeks was 0.1%.
 
In 2016 Kesselheim and colleagues noted the following concerning the Mendell et al (Ann Neuro 2013) study in a JAMA editorial (Kesselheim, 2016). In the eteplirsen study, by contrast, the primary trial end point was a surrogate measure: an increase in the presence of dystrophin in muscle biopsy specimens. Serial biopsies were performed at 12, 24, and 48 weeks, although biopsies were performed on only half the treated patients at each of the 12- and 24-week periods; all 12 patients were receiving drug treatment by week 48. The biopsy specimens were analyzed by scientists blinded to the patients’ group assignments but not blinded to the time receiving treatment. In a 2013 publication, the authors reported increases to about 50% of normal in dystrophin-containing fibers in the biopsy specimens, results that were met with enthusiasm by the DMD community. However, these results were based on an immunohistochemical assay that assessed only an increase of newly produced dystrophin compared with baseline values. Quantitative Western blot analysis of a fourth biopsy performed in 11 of the study patients after 3 to 3.5 years of continued open-label extension showed an actual increase to only a mean (SD) of 0.9% (0.8%) of normal dystrophin levels, far less than what might be expected to provide clinical benefit. A more rigorous fully blinded reanalysis of the immunohistochemical assay, organized by the FDA, cast further doubt on the initial results.
 
The trial also assessed clinical progression. At 24 and 48 weeks, there was no consistent advantage in the 6-minute walk test capacity of patients who received eteplirsen compared with those initially given placebo. However, new post hoc calculations excluded 2 eteplirsen-treated patients who deteriorated quickly while receiving therapy; these analyses suggested a statistically significant advantage for the remaining treated patients. These more selective post hoc analyses were highlighted in the figure displaying this finding in the 2013 article and in the manufacturer’s press release announcing the success of the trial. Subsequent evaluation of 6-minute walk test data over 3 to 3.5 years of open-label therapy appeared to be associated with slower rates of decline when compared with a historical cohort, but the problematic nature of historical controls complicated the interpretation.
 
Golodirsen
The effect of golodirsen on dystrophin production was evaluated in one study in DMD patients with confirmed mutation of the DMD gene that is amenable to exon 53 skipping (Study 1: NCT02310906).
 
Study 1 Part 1 was a double-blind, placebo-controlled, dose –titration study in 12 DMD patients. Those patients received four escalating dose levels, ranging from 4 mg/kg/week (less than the recommended dosage) to 30 mg/kg/week by IV for 2 weeks at each dose level.
 
Study 1 Part 2 was a 168-week, open label study assessing the efficacy and safety of golodirsen at a dose of 30mg/kg/week in the 12 patients enrolled in Part 1, plus 13 additional treatment naïve patients with DMD amenable to exon 53 skipping. Efficacy was assessed based on change from baseline in the dystrophin protein level (measured as % of the dystrophin level in healthy subjects, i.e., % of normal) at Week 48 of Part 2. Muscle biopsies were obtained at baseline prior to treatment and at Week 48 of Part 2 in all golodirsen treated patients (n=25) and were analyzed for dystrophin protein level by Western blot. Mean dystrophin levels increased from 0.10% (SD 0.07) of normal at baseline to 1.02% (SD 1.03) of normal by Week 48 of Study 1 Part 2, with a mean change in dystrophin of 0.92% (SD 1.01) of normal levels.
 
The ICER final report for Deflazacort, Eteplirsen and Golodirsen for Duchenne Muscular Dystrophy: Effectiveness and Value states that, “The data for exon-skipping therapies consist primarily of surrogate outcomes (e.g., dystrophin levels) from very small trials. While the use of surrogate outcomes is often necessary in evaluating a treatment for an ultra-rare disease, this does not mean that a small improvement in a surrogate measure, without convincing human or animal evidence that the surrogate improvement is potentially clinically important, should be considered appropriate evidence for evaluating a therapy, even for an ultra-rare condition. The threshold for dystrophin expression sufficient for meaningful clinical improvement has not yet been defined. Furthermore, there is limited or no evidence demonstrating improvements in function, as comparison with historical controls with conditions such as DMD can be confounded or effort dependent. Thus, the clinical efficacy of exon-skipping therapies is still unclear.”  Thus the consideration for the data for both eteplirsen and golodirsen was insufficient.
 
Viltolarsen
Viltolarsen was studied in a phase II, multi center, 2-period, randomized, placebo-controlled, dose finding study in ambulant boys ages 4-9 years of age with DMD (NCT02740972). Inclusion criteria incorporated ambulation status – patients were required to be ambulatory – and the ability to complete the following assessments: time to stand from supine, time to run/walk 10 m, and time to climb 4 stairs. While primary outcome measures were centered around adverse events, dystrophin protein in muscle and drug concentration in plasma, secondary outcomes included 6-minute walk test (6MWT), change in time to climb 4 stairs (TTCLIMB), change in time to run/walk 10 meters (TTRW), change in time to stand (TTSTAND) and North Star Ambulatory Assessment results (NSAA). The secondary outcomes were measured against matched controls in an external comparator group provided by the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS).
There were 16 boys with DMD included.  After 20 to 24 weeks of treatment, significant drug-induced dystrophin production was seen in both viltolarsen dose cohorts (40 mg/kg per week: mean [range] 5.7% [3.2-10.3] of normal; 80 mg/kg per week: mean [range] 5.9% [1.1-14.4] of normal). Viltolarsen was well tolerated; no treatment-emergent adverse events required dose reduction, interruption, or discontinuation of the study drug. No serious adverse events or deaths occurred during the study. Compared with 65 age-matched and treatment-matched natural history controls, all 16 participants treated with viltolarsen showed significant improvements in timed function tests from baseline, including time to stand from supine (viltolarsen: 0.19 s; control: 0.66 s), time to run/walk 10 m (viltolarsen: 0.23 m/s; control: 0.04 m/s), and 6-minute walk test (viltolarsen: 28.9 m; control: 65.3 m) at the week 25 visit. (Clemens et. al., 2020)
 
An extension trial (NCT03167255) is the extension of a previously published 24-week trial in North America (NCT02740972) that examined dystrophin levels, timed function tests compared to a matched historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study, CINRG DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53 skipping who were treated with viltolarsen. Both groups were treated with glucocorticoids. All 16 participants elected to enroll in this long-term trial (up to 192 weeks) to continue evaluation of motor function and safety. (Clemens et. al., 2022)
 
Results showed time to stand from supine and time to run/walk 10 meters showed stabilization from baseline through week 109 for viltolarsen-treated participants whereas the historical control group showed decline (statistically significant differences for multiple timepoints). Safety was similar to that observed in the previous 24-week trial, which was predominantly mild. There have been no treatment-related serious adverse events and no discontinuations.
 
Casimersen
A multicenter, phase 1/2 trial (NCT02500380) enrolled 12 participants (aged 7-21 years, who had limited ambulation or were nonambulatory) and comprised a 12-week, double-blind dose titration, then an open-label extension for up to 132 weeks. During dose titration, participants were randomized 2:1 to weekly casimersen infusions at escalating doses of 4, 10, 20, and 30 mg/kg (2 weeks per dose), or placebo.
 
Participants received casimersen for a mean 139.6 weeks. Treatment-emergent adverse events (TEAEs) occurred in all casimersen- and placebo-treated participants and were mostly mild (over 91.4%) and unrelated to casimersen or its dose. There were no deaths, dose reductions, abnormalities in laboratory parameters or vital signs, or casimersen-related serious AEs. Casimersen plasma concentration increased with dose and declined similarly for all dose levels over 24 hours post infusion. All pharmacokinetic parameters were similar at weeks 7 and 60.
 
Casimersen was well tolerated in participants with DMD amenable to exon 45 skipping. Most TEAEs were mild, nonserious, and unrelated to casimersen. Plasma exposure was dose proportional with no suggestion of plasma accumulation. These results support further studies of casimersen in this population.
 
In summary, the evidence is insufficient in determining a clinical benefit for the use of eteplirsen in the treatment of Duchenne muscular dystrophy.
 
2018 Update
A literature search conducted through December 2018 did not reveal any new information that would prompt a change in the coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2021. No new literature was identified that would prompt a change in the coverage statement.
 
April 2021 Update
Casimersen was evaluated in a global randomized, double-blind, placebo=controlled Phase 3 Essence  trial (NCT02500381; also known as Study 4045-301), in male participants with DMD who have a confirmed mutation ot DMD gene that is amenable to exon 45 skipping. The study is ongoing and remains blinded to collect additional efficacy and safety data.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2024.  Updated rationale with studies for both Viltolarsen and Casimersen.  Otherwise, no other literature identified that would prompt a change in the coverage statement.   

CPT/HCPCS:
C9075Injection, casimersen, 10 mg
J1426Injection, casimersen, 10 mg
J1427Injection, viltolarsen, 10 mg
J1428Injection, eteplirsen, 10 mg
J1429Injection, golodirsen, 10 mg
J3490Unclassified drugs

References: Cirak S, Arechavala-Gomeza V, et al.(2011) Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet. 2011;378(9791):595.Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.

FDA News Release. FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. Accessed at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm. Last accessed October 31, 2016.

FDA(2016) Retraction Watch. Amid controversial Sarepta approval decision, FDA head calls for key study retraction http://retractionwatch.com/2016/09/21/amid-controversial-sarepta-approval-decision-fda-head-calls-for-key-study-retraction/

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials

Institute for Clinical and Evidence Review.(2019) Deflazacort, Eteplirsen, and Golodirsen for Duchenne Muscular Dystrophy: Effectiveness and Value (Final Evidence Report August 15, 2019)2019. https://icer-review.org/wp-content/uploads/2018/12/ICER_DMD-Final-Report_081519-1.pdf. Accessed January 16, 2020.

Kesselheim, Aaron S. JD, MPH, Avorn, Jerry MD(2016) Approving a Problematic Muscular Dystrophy DrugImplications for FDA Policy. JAMA. Published online October 24, 2016. doi:10.1001/jama.2016.1643

LU QL, Yokota T, Takeda S, et al.(2011) The status of exon skipping as a therapeutic approach to Duchenne muscular dystrophy. Mol Ther. 2011;19(1):9. McColl-Lockwood Laboratory for Muscular Dystrophy Research, Neuromuscular/ALS Center, Carolinas Medical Center, Charlotte, North Carolina, USA.

Mendell JR, Goemans N, Lowes LP, et al.(2016) Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016 Feb;79(2):257-71. Epub 2016 Jan 8. Nationwide Children's Hospital, Columbus, OH.

Mendell JR, Rodino-Klapac LR, Sahenk Z,(2013) Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013 Nov;74(5):637-47. doi: 10.1002/ana.23982.

Moulton, HM; Moulton, JD(2010) "Morpholinos and Their Peptide Conjugates: Therapeutic Promise and Challenge for Duchenne Muscular Dystrophy". Biochim Biophys Acta. 1798 (12): 2296–303. doi:10.1016/j.bbamem.2010.02.012. PMID 20170628.

Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. http://www.drugepi.org/portal/

Viltepso [package insert]. Paramus, NJ: NS Pharma, Inc.; 3/2021.

VYONDYS 53 (golodirsen) injection, package insert. Cambridge, MA: Sarepta Therapeutics, Inc; 5/2019


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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