Description
Duchenne muscular dystrophy is an inherited disorder that results in progressive muscle weakness and loss of muscle mass. It primarily affects boys. It occurs as a result of variant(s) in the gene responsible for producing dystrophin, a cohesive protein essential for maintaining muscle support and strength. Eteplirsen is an antisense oligonucleotide that induces skipping of exon 51, thereby repairing the mutated reading frame. As a result, eteplirsen enables the production of an internally truncated, yet functional, dystrophin protein.

Background
DUCHENNE MUSCULAR DYSTROPHY
DMD is an X-linked, recessive disorder that occurs in approximately 1 in every 3500 to 5000 males.¹ It primarily affects males. However, a small number of girls are also affected, but they are usually asymptomatic, and even when symptomatic, only present with a mild form of the disease. According to U.S. epidemiologic data, the first signs or symptoms of DMD are noted at a mean age of 2.5 years (range, 0.2 – 1 years), and the mean age at definitive diagnosis is 4.9 years (range, 0.3 – 8.8 years).² Symptoms include motor difficulties such as running, jumping, walking up stairs, and an unusual waddling gait. Some improvement in symptoms may be seen from three to six years of age, though gradual deterioration resumes and most patients lose ambulation by age 12 and require noninvasive ventilation (NIV) by late teenage years. Patients progress from needing NIV only during night sleeping, followed by NIV during day and night sleeping, and then NIV during day and night over the course of five to ten years.

DMD occurs as a result of variant(s) in the gene responsible for producing dystrophin, a cohesive protein that is essential for maintaining muscle support and strength.DMD is the longest known human gene, and several variants can cause DMD. Most deletion variants disrupt the translational reading frame in the dystrophin messenger RNA (mRNA) resulting in an unstable, nonfunctional dystrophin molecule. As a result, there is progressive muscle degeneration leading to loss of independent ambulation, as well as other complications, including respiratory and cardiac complications.³ Genetic testing is required to determine the specific DMD gene variant(s) for a definitive diagnosis, even when the absence of dystrophin protein expression has been confirmed by muscle biopsy. There are over 4700 variants in the Leiden DMD mutation database, and the most common variants are concentrated between exons 45 and 53.

Policy 
Vyondys 53™ (golodirsen) is considered MEDICALLY NECESSARY in the treatment of Diagnosis of Duchenne muscular dystrophy (DMD) when ALL of the following criteria are met:

1. Diagnosis of Duchenne muscular dystrophy (DMD)
2. Submission of medical records (e.g., chart notes, laboratory values) confirming the mutation of the DMD gene is amenable to exon 53 skipping
3. Patient has had a trial of greater than or equal to 6 months and failure or intolerance to corticosteroids
4. One of the following:
   1. Submission of medical records (e.g., chart notes, laboratory values) confirming that the patient has a 6-Minute Walk Time (6MWT) greater than or equal to 300 meters while walking independently (e.g., without side-by-side assist, cane, walker, wheelchair, etc.) prior to beginning Vyondys 53 therapy
   2. Patient has achieved a score of greater than 17 on the North Star Ambulatory Assessment (NSAA) AND Patient has achieved a time to rise from the floor (Gower’s test) of less than 7 seconds
5. Prescribed by or in consultation with a neurologist with expertise in the treatment of DMD
6. Dosing for DMD is in accordance with the approved labeling
7. Not used concomitantly with other exon skipping therapies for DMD

Continuation of Vyondys 53™ (golodirsen) is considered MEDICALLY NECESSARY in the treatment of Diagnosis of Duchenne muscular dystrophy (DMD) when ALL of the following criteria are met:

1. Patient is responding positively to therapy as evidenced by both of the following [requires submission of medical records (e.g., chart notes)]:
   1. Patient is ambulatory without needing an assistive device (e.g., without side-by-side assist, cane, walker, wheelchair, etc.) AND
   2. Patient has a 6 minute walk test (6MWT) distance greater than or equal to 250 meters
2. Patient has stable cardiac function with left ventricular ejection fraction (LVEF) greater than 50%
3. Patient has stable pulmonary function with predicted forced vital capacity forced vital capacity (FVC) greater than or equal to 50%
4. Serial monitoring of renal function (e.g., serum creatinine, proteinuria, serum cystatin C, 24-hour urine collection, etc.) has failed to identify evidence of renal toxicity with Vyondys 53
5. Prescribed by or in consultation with a neurologist with expertise in the treatment of DMD
6. Dosing for DMD is in accordance with the approved labeling
7. Not used concomitantly with other exon skipping therapies for DMD

Exondys 51 (eteplirsen) and Amondys 45 (casimersen) is considered MEDICALLY NECESSARY in the treatment of Diagnosis of Duchenne muscular dystrophy (DMD) when ALL of the following criteria are met:

1. Diagnosis of Duchenne muscular dystrophy (DMD)
2. Submission of medical records (e.g., chart notes, laboratory values) confirming the mutation of the DMD gene is amenable to exon 51 (Exondys 51) skipping or amenable to exon 45 (Amondys 45) skipping
3. Patient is 7 years of age or older
4. Prescribed by or in consultation with a neurologist who has experience treating children
5. Dose will not exceed 30 milligrams per kilogram of body weight infused once weekly
6. 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)
7. Not used concomitantly with other exon skipping therapies for DMD

Viltolarsen (Viltepso) is considered MEDICALLY NECESSARY in the treatment of Diagnosis of Duchenne muscular dystrophy (DMD) when ALL of the following criteria are met:

1. Diagnosis of Duchenne muscular dystrophy (DMD)
2. Submission of medical records (e.g., chart notes, laboratory values) confirming the mutation of the DMD gene is amenable to exon 53 skipping
3. Patient is 9 years of age or less at initiation of therapy
4. Prescribed by or in consultation with a neurologist who has experience treating children
5. Viltepso is prescribed concurrently with an oral corticosteroid, unless contraindicated, or clinically significant adverse effects
6. Dose will not exceed 80 milligrams per kilogram of body weight infused once weekly
7. 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)
8. Not used concomitantly with other exon skipping therapies for DMD

Continuation of Exondys 51 (eteplirsen), Amondys 45 (casimersen) and Viltolarsen (Viltepso) is considered MEDICALLY NECESSARY in the treatment of Diagnosis of Duchenne muscular dystrophy (DMD) when ALL of the following criteria are met:

9. Patient is tolerating therapy
10. Dose will not exceed max milligrams per kilogram of body weight infused once weekly as approved by FDA
11. Prescribed by or in consultation with a neurologist who has experience treating children
12. 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)
13. Not used concomitantly with other exon skipping therapies for DMD

Rationale
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the VYONDYS 53 clinical development program, 58 patients received at least one intravenous dose of VYONDYS 53, ranging between 4 mg/kg (0.13 times the recommended dosage) and 30 mg/kg (the recommended dosage). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 6 to 13 years. Most (86%) patients were Caucasian.

VYONDYS 53 was studied in two double-blind, placebo-controlled studies.

In Study 1 Part 1, patients were randomized to receive once-weekly intravenous infusions of VYONDYS 53 (n = 8) in four increasing dose levels from 4 mg/kg to 30 mg/kg or placebo (n = 4), for at least two weeks at each level. All patients who participated in Study 1 Part 1 (n = 12) were continued into Study 1 Part 2, an open-label extension, during which they received VYONDYS 53 at a dose of 30 mg/kg IV once weekly.

In Study 2, patients received VYONDYS 53 (n = 33) 30 mg/kg or placebo (n = 17) IV once weekly for up to 96 weeks, after which all patients received VYONDYS 53 at a dose of 30 mg/kg. 

Adverse reactions observed in at least 20% of treated patients in the placebo-controlled sections of Studies 1 and 2 are shown in Table 1.

Table 1: Adverse Reactions That Occurred in At Least 20% of VYONDYS 53-Treated Patients and at a Rate Greater than Placebo in Studies 1 and 2

Other adverse reactions that occurred at a frequency greater than 5% of VYONDYS 53-treated patients and at a greater frequency than placebo were: administration site pain, back pain, pain, diarrhea, dizziness, ligament sprain, contusion, influenza, oropharyngeal pain, rhinitis, skin abrasion, ear infection, seasonal allergy, tachycardia, catheter site-related reaction, constipation, and fracture.

Hypersensitivity reactions have occurred in patients treated with VYONDYS 53.

Clinical Studies
The effect of VYONDYS 53 on dystrophin production was evaluated in one study in DMD patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping.

Study 1 Part 1 was a double-blind, placebo-controlled, dose-titration study in 12 DMD patients. Patients were randomized 2:1 to receive VYONDYS 53 or matching placebo. VYONDYS 53-treated patients received four escalating dose levels, ranging from 4 mg/kg/week (less than the recommended dosage) to 30 mg/kg/week by intravenous infusion for 2 weeks at each dose level.

Study 1 Part 2 was a 168-week, open-label study assessing the efficacy and safety of VYONDYS 53 at a dose of 30 mg/kg/week in the 12 patients enrolled in Part 1, plus 13 additional treatment-naive patients with DMD amenable to exon 53 skipping. At study entry (either in Part 1 or Part 2), patients had a median age of 8 years and were on a stable dose of corticosteroids for at least 6 months. 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 VYONDYS 53-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 (p < 0.001); the median change from baseline was 0.88%.

Individual patient dystrophin levels from Study 1 are shown in Table 2.

Table 2: Dystrophin Expression by Individual Patient From Study 1

Eteplirsen for Treatment of Duchenne Muscular Dystrophy
Clinical Context and Therapy Purpose
The purpose of eteplirsen in patients who have a confirmed variant of the DMD gene that is amenable to exon 51 skipping, is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of eteplirsen in patients with the DMD gene variant that is amenable to exon 51 skipping improve the net health outcome compared with medical management with glucocorticoids?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest are patients with a confirmed variant of the DMD gene that is amenable to exon 51 skipping. 

Interventions
The therapy being considered is eteplirsen, which is a stable oligonucleotide analogue that selectively binds to RNA to alter gene expression. Eteplirsen binds to exon 51, causing the exon to be skipped. Skipping exon 51 enables the production of functional dystrophin in muscle.

The recommended dosage is 30 mg/kg body weight once weekly, administered as an intravenous infusion over 35 to 60 minutes.

Comparators
The current standard of pharmacotherapy for DMD is corticosteroids (mainly prednisone or deflazacort) for all patients regardless of the geneticvariant. Treatment is initiated once patients reach a plateau of motor skill development, generally at ages four to six years, but before the onset of motor decline. The goal of corticosteroid therapy is to preserve ambulation and minimize respiratory, cardiac, and orthopedic complications.

Outcomes
The general outcomes of interest are dystrophin level, functional outcomes such as the 6-minute walk test (6MWT), lung function (forced vital capacity), and the North Star Ambulatory Assessment (NSAA). Additional outcomes of interest include adverse events.

Measuring dystrophin level in muscle fibers has been a proposed outcome, though the correlation between dystrophin levels and clinically meaningful outcomes is unclear. Measuring dystrophin levels may be conducted by:

• An immunohistochemical analysis of muscle biopsy tissue. Thin slices of biopsy tissue are evaluated to detect the presence or absence of dystrophin. Each muscle fiber showing any amount of dystrophin counts as positive, regardless of the actual quantity of dystrophin present. The amount of dystrophin is not calculated with this method.
• Western blot analysis. In this method, muscle tissue samples undergo a protein denaturization, followed by gel electrophoresis which can quantify the amount of dystrophin in the muscle tissues.

The 6MWT measures the distance that a patient can walk on a flat, hard surface in a period of 6 minutes. The 6MWT can offer information on the global and interrelated components of exercise such as extremity strength, biomechanical inefficiencies, endurance, and cardiorespiratory status. It has also been used as a measure of the quality of life. Determining the minimum clinically important difference in 6MWT is challenging in patients with DMD, as the rate of progression of the disease varies among patients. Estimates of minimum clinically important difference for DMD patients of a change of 30 meters have been reported.^5,6 Interpretation of 6MWT results is limited by the variability in testing procedures and patient motivation.

Forced vital capacity (FVC), measured by spirometry, is the amount of air forcibly exhaled after taking the deepest breath possible. FVC is used to monitor lung function in DMD patients. Steroid therapy has the potential to stabilize or delay the loss of lung function in DMD patients.

The NSAA, developed by the North Star Clinical Network and supported by the Muscular Dystrophy Campaign, is a method to monitor the progression of DMD and treatment effects. Seventeen activities are graded as “normal” (2 points); “modified” (1 point); or “unable to achieve independently” (0 points). For each activity, the NSAA has clear instructions to the health care provider on coaching the patient on starting positions and test details. The activities include: standing still; walking; standing from a chair; standing on the right leg; standing on the left leg; climbing onto a box 15 cm in height using right leg first; climbing onto the box using left leg first; descending the box using right leg first; descending the box using the left leg first; sitting up from lying position; rising from the floor; lifting head to look at toes; standing on heels; jumping; hopping on right leg; hopping on left leg; and running 10 meters.

Adverse events include balance disorder and vomiting.

Timing
Follow-up measurements can be taken within weeks of initial treatment. As DMD is a progressive disease, follow-up continues during the entire course of treatment.

Setting
Eteplirsen is administered intravenously, which can be performed in infusion centers or in tertiary care facilities. Monitoring of treatment may be conducted by neurologists, orthopedists, physiatrists, and/or primary care physicians.

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 effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Randomized Controlled Trial and Open-Label Extension Study
Studies 201 and 202 (Pivotal Trial)
In a single-center, double-blind, placebo-controlled trial (Study 201), 12 males ages 7 to 13 years with DMD amenable to exon 51 skipping and on stable corticosteroid dose for at least 6 months were randomized to eteplirsen (30 or 50 mg/kg/wk) or placebo (4 patients per group) (see Table 1). Treatment continued for 24 weeks and then placebo patients switched to eteplirsen 30 or 50 mg/kg (n = 2 per group) at week 25 (Study 202). All treatment subsequently became open-label and patients were followed for an additional 24 weeks (48 weeks in total) (see Table 1).^7,8

Dystrophin Levels
The primary trial endpoint was a measure of change in dystrophin-positive fibers as measured in muscle biopsy tissue using immunohistochemistry.⁹ Serial biopsies were performed at 12, 24 and 48 weeks, although biopsies were performed on only half of the treated patients at each of the 12- (only for the eteplirsen 50-mg/kg group) and 24- (only for the eteplirsen 30-mg/kg group) week periods; all 12 patients were receiving drug treatment by week 48. The results published in 2013 reported a substantial increase (range, 23% – 52%) in the percentage of dystrophin-containing fibers in the biopsy specimens at weeks 24 and 48 in the eteplirsen-treated groups (see Table 2).⁸ However, immunohistochemistry analysis is not a quantitative measure of dystrophin. This analysis evaluates thin slices of muscle biopsies to assess whether dystrophin is present or absent. Each muscle fiber showing any amount of dystrophin counts as positive, regardless of the actual quantity of dystrophin present. On the other hand, Western blot analyzes how much dystrophin is present in a sample. Results reported in the prescribing label showed the average dystrophin protein level after 180 weeks of treatment with eteplirsen measured by Western blot analysis of biopsy was 0.93% of the dystrophin level in healthy subjects.⁷ Further, a more rigorous and fully blinded reanalysis by 3 investigators of the immunohistochemical assay by the Food and Drug Administration (FDA) cast further doubt about the consistency of immunohistochemical analysis because there was little difference in positive fibers between original baseline samples and week 180.¹⁰

6-Minute Walking Test
The prespecified clinical endpoints on the 6MWT for study 201 (week 24) and study 202 (week 48) were negative (see Table 2).¹⁰ The article reported a 67.3-meter benefit in 6MWD at week 48 in ambulation-evaluable eteplirsen-treated patients (n = 6) compared with placebo/delayed patients (p < 0.005).⁸ However, this was a post hoc analysis excluding two eteplirsen-treated patients who quickly deteriorated while receiving therapy and lost ambulation beginning at week four of the trial. The FDA has recommended retraction of the published study due to concerns about the interpretation of its findings.¹¹ Further, in an exploratory analysis, the FDA found no correlation between dystrophin levels and 6MWD.¹⁰ For example, among the four patients with the most preserved 6MWT, two had the lowest and two had the highest dystrophin levels determined by Western blot. As per the prescribing label, there was no significant difference in change in 6MWT distance between patients treated with eteplirsen and placebo. While the 6MWT may be an objective instrument, its results can be influenced by expectation bias, motivation and coaching especially in the context that patients in the pivotal 201/202 trial were aware of treatment assignment for most the investigation period.

Eteplirsen’s manufacturer reported a gain of 162 meters on the 6MWT at 4 years after treatment with eteplirsen in 12 patients in study 202 compared with 13 patients from an external control at the FDA Peripheral and Central Nervous System Drugs Advisory Committee meeting.9 Results were subsequently published by Medell et al. (2016) in a peer-reviewed journal.¹² Data for external controls were extracted from pooled data from an Italian and Belgian registry by matching corticosteroid use at baseline, availability of longitudinal data for the 6MWT, age, and genotype amenable to exon 51 skipping therapy. However, the FDA¹³ and others¹⁴ have identified several issues related to the use of an external control such as differences in the use of steroids and physical therapy between the two groups. Most importantly, the impact of unknown prognostic factors cannot be ascertained in an externally controlled study.

The FDA was unable to conclude from the pivotal trial data about whether eteplirsen increased dystrophin production because quantitative estimates of pretreatment dystrophin levels were not available. In June 2016, the FDA requested that Sarepta et al. (2016) submit additional eteplirsen data for review.¹⁵ Sarepta et al. (2016) complied with this request, submitting preliminary data of 12 patients from the ongoing PROMOVI trial in which quantitative estimates of dystrophin at baseline and week 48 were available. PROMOVI is a 96-week, open-label, multicenter, phase 3 study with a planned enrollment of 160 patients with genotype-confirmed DMD; 80 patients amenable to exon 51 skipping will be treated with eteplirsen (30 mg/kg) and compared with 80 untreated patients not amenable to exon 51 skipping (see Table 1).¹⁶ The estimated completion date of this trial is February 2020. The FDA’s approval was based on data for these 12 patients (mean age, 8.9 years).⁷ Levels of dystrophin were significantly higher after 48 weeks of treatment compared with baseline (see Table 2). The clinical benefit of this dystrophin increase is unknown.

Harms
The most frequently reported adverse events in the first 24 weeks of the study among the 8 patients treated with eteplirsen were balance disorder (n = 3), vomiting (n = 3), and contact dermatitis (n = 2).⁷

Common treatment-emergent adverse events reported among the 12 patients during the 12-week RCT include: procedural pain (n = 7), oropharyngeal pain (n = 6), hypokalemia (n = 6), gastrointestinal disorders (n = 5), cough (n = 4), and extremity pain (n = 4).⁸

Table 1. Summary of Key Study Characteristics

DMD: Duchenne muscular dystrophy; RCT: randomized controlled trial; 6MWT: 6-minute walk test.
^a This study is ongoing (PROMOVI; NCT02255552). The Food and Drug Administration asked Sarepta for additional data for review and Sarepta provided information on 13 patients currently enrolled in the PROMOVI trial who had baseline and 48-week data. 

Table 2. Summary of Key Study Results 

NR: not reported; SD: standard deviation; SE: standard error; 6MWT: 6-minute walk test.
^a p < 0.01 vs baseline
^b Excluding 2 patients who showed rapid disease progression at week 4 of study.
^c p < 0.001 vs delayed eteplirsen group.

The purpose of gaps tables (see Tables 3 and 4) is to display notable gaps identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 3. Relevance Gaps 

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
IHC: immunohistochemical.
^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 4. Study Design and Conduct Gaps 

The evidence gaps 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.

Gaps tables bullet points:

• Small sample size.
• Primary outcome was a physiologic measurement without a known correlation with clinical benefit. In addition, the physiologic outcome was not measured using the most accurate technique available in two of the three studies. 

Observational Study
Kinane et al. (2018) conducted a case-control study of long-term pulmonary function in patients with DMD treated with eteplirsen compared with historical controls.¹⁷ Cases were patients from the RCT by Mendell et al. (2013) described above (n = 12) and historical controls were patients between 7 years and 15.5 years in the United Dystrophinopathy Project who had undergone pulmonary function testing (n = 34). All patients in the United Dystrophinopathy Project had confirmed dystrophin variant. The annual decline in FVC was not significantly different between groups. The annual decrease in FVC in the historical controls was 4.1% (95% confidence interval, 1.9% to 6.3%) and the annual decrease in FVC in the cases treated with eteplirsen was 2.3% (95% confidence interval, 1.2% to 3.4%). 

Systematic Reviews 
Randeree et al. (2018) conducted a pooled analysis of studies evaluating the use of eteplirsen for the treatment of patients with DMD.¹⁸ A literature search, conducted through November 2017, identified 3 studies (n = 38 patients) for inclusion in the analyses. The 3 studies consisted of a nonrandomized dose-escalation study (n = 7), an open-label dose-escalation study (n = 19), and the Mendell et al. (2013) study described above (n = 12). A quality assessment of the studies was not performed. The average increase in percent dystrophin-positive fibers was 24.2% (standard deviation, 24.4%) and the average rate of decline in 6MWT was 65 m (standard deviation = 100.1).  

Section Summary: Eteplirsen for Treatment of DMD 
Evidence for the use of eteplirsen for the treatment of DMD amenable to exon 51 skipping includes an RCT, an open-label extension of the RCT, a case-control study using historical controls, and preliminary results from a larger open-label study. The single RCT had a sample of 12 patients and the larger open-label study providing preliminary results also had 12 patients. No power calculations were made to determine if these sample sizes were adequate to detect treatment effect. 

The outcome of 6MWT showed significant differences between patients receiving eteplirsen at the beginning of the RCT compared with patients receiving delayed eteplirsen. However, interpreting the 6MWT results has limitations due to differences in how the test is conducted and how motivated the patients are. A more objective measure of pulmonary function, FVC, was evaluated in a case-control study using data from patients in the RCT compared with historical controls. This analysis reported a lower decrease in FVC in patients receiving eteplirsen; however, the difference was not statistically significant, possibly due to insufficient power. 

Summary of Evidence 
For individuals with a confirmed variant of the DMD gene that is amenable to exon 51 skipping who receive eteplirsen, the evidence includes a randomized controlled trial (RCT) and its open-labeled follow-up study, a case-control study using historical controls, and interim data from an ongoing larger open-label comparative study. The relevant outcomes are disease-specific survival, change in disease status, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. The single RCT had a sample of 12 patients and the larger open-label study providing interim results also had 12 patients. No power calculations were made to determine if these sample sizes were adequate to detect treatment effect. The primary physiologic outcome of dystrophin level in these studies is questionable, both in how the level was measured and in how the level correlates with a meaningful clinical outcome. While treatment with eteplirsen may increase dystrophin levels detected in muscle fibers, the impact of these levels on clinically meaningful outcomes is unclear. The outcome of the 6-minute walk test showed significant differences between patients receiving eteplirsen at the beginning of the RCT compared with patients receiving delayed eteplirsen. However, interpreting the 6-minute walk test results has limitations due to differences in how the test may be conducted and patient motivation. A more objective measure of pulmonary function (forced vital capacity) was evaluated in a case-control study using data from patients in the RCT compared with historical controls. This analysis reported a lower decrease in forced vital capacity in patients receiving eteplirsen; however, the difference was not statistically significant, possibly due to insufficient power. In summary, the clinical benefit of treatment for DMD with eteplirsen, including improved motor function, has not been demonstrated. Establishing a clinical benefit is necessary for ongoing clinical trials. The most frequently reported adverse events across clinical trials were balance disorder, vomiting, and contact dermatitis. The evidence is sufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements
Centers for Disease Control and Prevention
The U.S. Centers for Disease Control and Prevention convened a DMD Care Considerations Working Group. The Group developed care recommendations in 2010 and updated them in 2018.^{1,19,20,21,22} They recommendations focus on the overall perspective on care, pharmacologic treatment, psychosocial management, rehabilitation, orthopedic, respiratory, cardiovascular, gastroenterology and nutrition, and pain issues, as well as general surgical and emergency room precautions. The Centers for Disease Control and Prevention recommended the use of corticosteroids to slow the decline in muscle strength and function in Duchenne muscular dystrophy (DMD). The Working Group did not make recommendations on the use of eteplirsen. However, eteplirsen is discussed briefly under the section on “Emerging treatments.”²² The Working Group stated that eteplirsen was approved by the Food and Drug Administration in 2016 for males with the dystrophin gene variant amenable to exon 51 skipping, which is about 13% of the males with DMD.

American Heart Association
A statement from the American Heart Association (2017) addressed the treatment of cardiac issues in individuals with any of several neuromuscular diseases, including DMD.²³ For patients with DMD, the Association recommended the use of glucocorticoids, among other medications. The statement does not address the use of eteplirsen. One of the statement’s coauthors disclosed being an industry-supported investigator for the drug.

American Academy of Neurology
The American Academy of Neurology (2016) published an updated practice guideline on the use of corticosteroids for the treatment of DMD.²⁴ The Academy does not discuss the use of eteplirsen for DMD.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 5.

Table 5. Summary of Key Trials

^a Denotes industry sponsorship or co-sponsorship.

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.
17. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. Jan 2010;9(1):77-93. PMID 19945913
18. Center for Disease Control and Prevention. Muscular Dystrohpy: MD STARnet Data and Statistics. 2016; http://www.cdc.gov/ncbddd/musculardystrophy/data.html. Accessed November 12, 2018.
19. Falzarano MS, Scotton C, Passarelli C, Ferlini A. Duchenne muscular dystrophy: from diagnosis to therapy. Molecules. Oct 07 2015;20(10):18168-18184. PMID 26457695
20. Food and Drug Administration. Accelererated Approval Letter to Sarepta Therapeutics: NDA 206488. 2016, September 19; https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/206488Orig1s000ltr.pdf. Accessed November 12, 2018.
21. McDonald CM, Henricson EK, Abresch RT, et al. The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. Muscle Nerve. Sep 2013;48(3):343-356. PMID 23681930
22. Henricson E, Abresch R, Han JJ, et al. The 6-Minute Walk Test and Person-Reported Outcomes in Boys with Duchenne Muscular Dystrophy and Typically Developing Controls: Longitudinal Comparisons and Clinically-Meaningful Changes Over One Year. PLoS Curr. Jul 8 2013;5. PMID 23867975
23. Sarepta Therapeutics Inc. Prescribing Label: EXONDYS 51 (eteplirsen) injection, for intravenous use. 2016; https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206488lbl.pdf. Accessed November 12, 2018.
24. Mendell JR, Rodino-Klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. Nov 2013;74(5):637-647. PMID 23907995
25. Ruff S. Sarepta Presentations for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee 2016; https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM500822.pdf. Accessed November 12, 2018.
26. Woodcock J, Dunn B. FDA Presentations for the April 25, 2016 Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. 2016; https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM500821.pdf. Accessed November 12, 2018.
27. Center for Drug Evaluation and Research. Application Number: 206488orig1s000. Summary Review. 2016; http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206488_summary%20review_Redacted.pdf. Accessed November 7, 2017.
28.  Mendell JR, Goemans N, Lowes LP, et al. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. Feb 2016;79(2):257-271. PMID 26573217
29. Food and Drug Administration. FDA Briefing Document: Peripheral and Central Nervous System Drugs Advisory Committee Meeting, April 25, 2016. NDA 206488. Eteplirsen. 2016; http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM497063.pdf. Accessed November 12, 2018.
30. Kesselheim AS, Avorn J. Approving a problematic muscular dystrophy drug: implications for FDA policy. JAMA. Dec 13 2016;316(22):2357-2358. PMID 27775756
31. Business Wire. Sarepta Therapeutics Announces FDA Request for Dystrophin Data Prior to Making a Decision on Eteplirsen NDA. 2016, June 6; http://www.businesswire.com/news/home/20160606006534/en/Sarepta-Therapeutics-Announces-FDA-Request-Dystrophin-Data. Accessed November 12, 2018.
32. Sarepta Therapeutics. Confirmatory Study of Eteplirsen in DMD Patients (PROMOVI). 2014; https://www.clinicaltrials.gov/ct2/show/NCT02255552?term=NCT02255552&rank=1. Accessed November 12, 2018.
33. Kinane TB, Mayer OH, Duda PW, Lowes LP, Moody SL, Mendell JR. Long-Term Pulmonary Function in Duchenne Muscular Dystrophy: Comparison of Eteplirsen-Treated Patients to Natural History. J Neuromuscul Dis. 2018;5(1):47-58. PMID 29278896
34. Randeree L, Eslick GD. Eteplirsen for paediatric patients with Duchenne muscular dystrophy: A pooled-analysis. J Clin Neurosci. Mar 2018;49:1-6. PMID 29254734
35. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. Feb 2010;9(2):177-189. PMID 19945914
36. 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. May 2018;17(5):445-455. PMID 29398641
37.  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. Apr 2018;17(4):347-361. PMID 29395990
38. 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. Mar 2018;17(3):251-267. PMID 29395989
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41. Vyondys 53 (golodirsen) [package insert] Sarepta Therapeutics December 2019
42. U.S. Food and Drug Administration (FDA) news release on agency's approval of Vyondys https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation December 12, 2019

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