Medical Policy

Policy Num:      05.003.004
Policy Name:    Gene Therapies for Duchenne Muscular Dystrophy
Policy ID:          [05.003.004]  [Ac / B / M- / P-]  [5.01.46]

Last Review:      October 16, 2024
Next Review:      October 20, 2025
 

Related Policies: None

Gene Therapies for Duchenne Muscular Dystrophy

Summary

Description

Duchenne muscular dystrophy (DMD) is an inherited disorder that results in progressive muscle weakness and loss of muscle mass, primarily affecting males. DMD results from non-sense or frame-shifting variant(s) in the DMD gene, which is responsible for producing dystrophin, a cohesive protein essential for maintaining muscle support and strength. Delandistrogene moxeparvovec-rokl is an adeno-associated virus vector-based gene therapy which encodes a novel, engineered protein micro-dystrophin protein. This novel micro-dystrophin protein is a shortened version (138 kDa, compared to 427 kDa size of dystrophin expressed in normal muscle cells) that contains selected domains of dystrophin expressed in normal muscle cells.

Summary of Evidence

For individuals with a confirmed diagnosis of Duchenne muscular dystrophy (DMD) who receive delandistrogene moxeparvovec-rokl, the evidence includes 2 randomized controlled trials (studies 102 and 301) and 1 prospective cohort trial (study 103). Relevant outcomes are disease-specific survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. In study 102, 41 study participants were randomized 1:1 to receive either delandistrogene moxeparvovec-rokl (n=20) or placebo (n=21). In study 301, 125 study participants were randomized 1:1 to receive either delandistrogene moxeparvovec-rokl (n=63) or placebo (n=62). Both studies failed to show a statistically significant difference in the primary endpoint of change in the North Star Ambulatory Assessment (NSAA) total score between the treated and the placebo group. In study 102, the least squares (LS) mean change in the NSAA total score from baseline to week 48 was 1.7 points for the delandistrogene moxeparvovec-rokl group and 0.9 points for the placebo group (p=.37). In study 301, the LS mean change in the NSAA total score from baseline to week 52 was 2.57 points for the delandistrogene moxeparvovec-rokl group and 1.92 points for the placebo group (p=.24). Thus, clinical benefit was not demonstrated in the primary efficacy endpoint of NSAA total score from baseline in both studies. Multiple limitations were noted. The US FDA approval was based on the post-hoc exploratory analysis of secondary outcome measures such as 10-meter walk/run (10-MWR) and time to rise from floor. These results cannot be interpreted at face value due to the lack of pre-specification and control of type 1 error. Such post hoc analysis following an overall nonsignificant test in the overall population can only be considered as hypothesis-generating. In addition, the observed treatment effect on secondary outcomes was not substantial and of uncertain clinical significance. Further, the results of 10-MWR timed test were inconsistent with opposing results observed in the 2 RCTs. Because of these limitations, an adequately powered, randomized, double-blind, placebo-controlled trial is necessary to clearly ascertain the net health outcome in DMD. Lastly, biomarker data reported in studies only provides information about expression of the transgene product in cells transduced by delandistrogene moxeparvovec-rokl rather than insight into a pharmacologic effect on a known biomarker in the pathway of the disease. Delandistrogene moxeparvovec-rokl micro-dystrophin is a novel, engineered protein that contains selected domains of the normal, wild-type dystrophin expressed in healthy muscle cells. No epidemiologic or pathophysiologic evidence is available regarding the function of delandistrogene moxeparvovec-rokl micro-dystrophin. The protein differs in important ways from both the endogenous shortened forms of dystrophin in patients with Becker muscular dystrophy, and the internally truncated dystrophins expressed through exon-skipping drugs. Thus, the clinical benefit of treating DMD with delandistrogene moxeparvovec-rokl, including improved motor function and pulmonary function, has not been demonstrated. A confirmatory, prospective, and adequately powered trial is necessary to assess the net health outcome of delandistrogene moxeparvovec-rokl in patients with DMD. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether use of delandistrogene moxeparvovec-rokl improves the net health outcome in individuals with a confirmed diagnosis of DMD.

Policy Statements

The use of delandistrogene moxeparvovec-rokl is considered investigational for all indications including the treatment of Duchenne muscular dystrophy.

Policy Guidelines

National P&T Approved Policy

Delandistrogene moxeparvovec-rokl

Delandistrogene moxeparvovec-rokl is considered medically appropriate for individuals if they meet criteria 1 through 7 :

1. At least 4 years of age at the time of infusion.

2. Assigned male at birth.

3. Diagnosis of Duchenne muscular dystrophy confirmed by documented variant in the DMD gene.

4. Documentation that there is not a deletion in exons 1 to 17 and/or exons 59 to 71 in the DMD gene (see Other Considerations).

5. Anti-AAVrh74 total binding antibody titers are <1:400.

6. Physician attestation confirming no concomitant use of anti-sense oligonucleotides post-administration.

7. Individual does not have a history of receiving gene therapy or under consideration for treatment for another gene therapy for Duchenne muscular dystrophy.

Delandistrogene moxeparvovec-rokl is considered investigational when the above criteria are not met.

Delandistrogene moxeparvovec-rokl is considered investigational for all other indications.

Repeat treatment with delandistrogene moxeparvovec-rokl is considered investigational.

Recommended Dose

The recommended dose is 1.33 × 10¹⁴ vector genomes (vg)/kg for individuals weighing 10 to 70 kg; the recommended maximum dose is 9.31 × 10¹⁵ vg for individual weighing 70 kg or greater.

Dosing Limits

1 injection per lifetime.

Other Considerations

In clinical trials, immune-mediated myositis has been observed approximately 1 month following an infusion of delandistrogene moxeparvovec-rokl in individuals with deletion mutations involving exon 8 and/or exon 9 in the DMD gene. Therefore, delandistrogene moxeparvovec-rokl is contraindicated in individuals with deletion mutations in exon 8 and/or exon 9. There is limited data for delandistrogene moxeparvovec-rokl in individuals with mutations in the DMD gene in exons 1 to 17 and/or exons 59 to 71. Individuals with deletions in these regions may also be at risk for a severe immune-mediated myositis reaction.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Duchenne Muscular Dystrophy

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 females are also affected, but are usually asymptomatic. Even when symptomatic, most females typically 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 to 1 years). Although histologic and laboratory evidence of myopathy may be present at birth, the clinical onset of skeletal muscle weakness usually does not become evident until early childhood. The average age at diagnosis is approximately 5 years.^2, Symptoms include motor difficulties such as difficulty running, jumping, and walking up stairs, along with an unusual waddling gait. Some improvement in symptoms may be seen from 3 to 6 years of age, though gradual deterioration resumes, and most individuals lose ambulation by age 12 and require noninvasive ventilation by the late teenage years. Individuals progress from needing noninvasive ventilation only during night sleeping, followed by noninvasive ventilation during day and night sleeping, and then noninvasive ventilation during day and night over the course of 5 to 10 years. Median life expectancy more recently has increased into the fourth decade, primarily through improved respiratory management and cardiac care.

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 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.

Regulatory Status

In June 2023, delandistrogene moxeparvovec-rokl (Elevidys; Sarepta Therapeutics) was approved by the U.S. Food and Drug Administration (FDA) for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD with a confirmed mutation in the DMD gene. This indication was approved under accelerated approval based on expression of delandistrogene moxeparvovec-rokl micro-dystrophin in skeletal muscle observed in patients treated with delandistrogene moxeparvovec-rokl. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

In June 2024, the U.S. FDA expanded the approval of delandistrogene moxeparvovec-rokl (Elevidys; Sarepta Therapeutics) for ambulatory and non-ambulatory individuals 4 years of age and older with DMD with a confirmed mutation in the DMD gene. It received a traditional approval in ambulatory individuals 4 years of age and older with DMD with a confirmed mutation in the DMD gene, and accelerated approval in non-ambulatory individuals 4 years of age and older with DMD with a confirmed mutation in the DMD gene.

Rationale

This evidence review was created in June 2023 with a search of the PubMed database. The most recent literature update was performed through July 4, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to individuals and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Gene Therapy for Treatment of Duchenne Muscular Dystrophy

Clinical Context and Therapy Purpose

The purpose of delandistrogene moxeparvovec-rokl in individuals with Duchenne muscular dystrophy (DMD) who have a confirmed variant of the DMD gene is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with a confirmed variant of the DMD gene.

Interventions

The therapy being considered is delandistrogene moxeparvovec-rokl. It is an adeno-associated virus vector-based gene therapy which encodes a novel, engineered protein micro-dystrophin protein. This novel micro-dystrophin protein is a shortened version (138 kDa, compared to 427 kDa size of dystrophin expressed in normal muscle cells) that contains selected domains of dystrophin expressed in normal muscle cells. The novel microdystrophin produced after administration of single dose gene therapy has been demonstrated to localize to the sarcolemma.

Treatment with delandistrogene moxeparvovec-rokl is intended to slow or stabilize progression of DMD, to alter the disease trajectory to a milder, Becker muscular dystrophy-like phenotype. Becker muscular dystrophy is similar to DMD, except that in Becker, symptoms begin later and progress at a slower rate.

Comparators

There is no cure for DMD. The following practice is currently being used to treat individuals with a confirmed variant of the DMD gene: standard multidisciplinary care including pharmacotherapy. Pharmacotherapy primarily involves corticosteroids ( prednisone or deflazacort) for all individuals regardless of the genetic variant. Treatment is initiated once individuals reach a plateau of motor skill development, generally at ages 4 to 6 years, but before the onset of motor decline. The goal of corticosteroid therapy is to preserve ambulation and minimize respiratory, cardiac, and orthopedic complications. In addition, muscle weakness and pain, cardiac, pulmonary, orthopedic, and endocrine symptoms should be managed.^1,

Four antisense oligonucleotides—eteplirsen, golodirsen, viltolarsen, and casimersen have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of DMD via the Accelerated Approval pathway. Each targets a specific exon. For example, eteplirsen targets skipping of exon 51, golodirsen and viltolarsen target skipping of exon 53, and casimersen targets skipping of exon 45. In each case, approval was based on the surrogate endpoint of expression of internally truncated dystrophin protein. The clinical benefit of all 4 of these drugs remains to be verified.

Outcomes

The general outcomes of interest are a change in disease status, functional outcomes, quality of life, treatment-related mortality, and treatment-related morbidity. See Table 1 for the description and relevance of specific outcome measures considered in this review.

As per the FDA guidance document for developing drugs for the treatment of dystrophinopathies, the FDA has no defined set of required or recommended clinical outcome measures to be used in clinical studies. The guidance states that manufacturers should propose and, if necessary, develop endpoints that can validly and reliably assess individuals with a wide spectrum of symptoms and disease stages. Further, it states, “The sponsor should include an assessment of multiple efficacy endpoints, when feasible, to characterize the breadth of effects on dystrophin-related pathologies, including skeletal, respiratory, and cardiac muscle function, even if the primary endpoint is only 1 of these measures.” ^4,

Table 1. Health Outcome Measures That May Be Relevant to Muscular Dystrophinopathies

 6MWT: 6-minute walk test; DMD: Duchenne muscular dystrophy; NSAA: North Star Ambulatory Assessment.

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 events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

The clinical development program is summarized in Table 2 and consists of 5 interventional studies. Of these, the manufacturer submitted data from 3 clinical studies (Study 101, 102 and 103) for consideration to the FDA. The phase 3 randomized, double-blinded clinical trial (Study 303 or Embark) was the primary study to verify clinical benefit^8,.

Both the accelerated as well as subsequent traditional approval of delandistrogene moxeparvovec-rokl by the FDA was in contrast to the recommendations made by FDA internal review teams, which did not recommend approval based upon their overall evaluation of the data submitted. ^9,10, The initial decision for accelerated approval was based on a post-hoc subgroup exploratory analysis of NSAA total score in 16 individuals (of the total 41 in the Study 102) ages 4 through 5 years and also considered the use of biomarker data (delandistrogene moxeparvovec-rokl micro-dystrophin expression as measured by Western blot) from cohort 1 of Study 103 that included 20 ambulatory male individuals aged 4 through 7 years.^10, The subsequent decision for traditional approval was based on a statistically significant difference in 3 secondary efficacy endpoints, including time to rise from the floor, 10-meter walk/run (10-MWR) and time to ascend 4 steps even though the study failed to meet the primary endpoint of change in NSAA total score from baseline to week 52 post treatment.^9,

Table 2. Summary of the Clinical Development Program for Delandistrogene Moxeparvovec-rokl

DMD: Duchenne muscular dystrophy; DBRCT: double-blind randomized controlled study; NCT: national clinical trial.

Pivotal Studies

Study characteristics, baseline patient characteristics, and results are summarized in Tables 3 to 6, respectively. Study 102 was the 48-week, randomized, double-blind, placebo-controlled trial that randomized 41 study participants 1:1 to receive either delandistrogene moxeparvovec-rokl (n =20) or placebo (n =21), as a single intravenous infusion via a peripheral limb. All participants were on a stable dose of corticosteroids for DMD for at least 12 weeks prior to infusion of the gene therapy, had baseline anti-AAVrh74 antibody titers <1:400 and received at least 1 mg/kg of a glucocorticoid (prednisone equivalent) daily in addition to their baseline stable oral corticosteroid dose beginning 1 day prior to infusion and for at least 60 days after the infusion. Randomization was stratified by age (i.e., aged 4 to 5 years vs. aged 6 to 7 years). In the delandistrogene moxeparvovec-rokl group, 8 participants received the FDA approved dose of 1.33 X 10¹⁴ vg/kg while 12 received lower doses. The part 1 of the study included the randomized, double-blind, placebo-controlled phase. Part 2 was the cross-over phase in which participants who received delandistrogene moxeparvovec-rokl in part 1 were then administered placebo in part 2, and vice-versa. Unlike for cross-over studies with small-molecule drugs, no wash-out period is possible for gene therapies. Therefore, although the blind was maintained in part 2, by that point the subjects, caregivers, and evaluators were aware that all subjects had now received delandistrogene moxeparvovec-rokl, rendering part 2 effectively an open-label study.

Study 103 is an ongoing, open-label study that included 5 cohorts with total of 48 participants aged 3 through 20 years. Cohorts 3 and 5b included 8 non-ambulatory patients. All participants received a single intravenous infusion of 1.33 X 10¹⁴ vg/kg delandistrogene moxeparvovec-rokl if they weighed less than 70 kg or 9.31 X 10¹⁵ vg/kg total fixed dose if they weighed 70 kg or greater. Majority of study participants (77%) were white with a mean age of 7.7 years (range: 3.2 to 20.2), mean weight of 30.1 kg (range: 12.5 to 80.1), mean North Star Ambulatory Assessment (NSAA) total score of 20.3 points (range: 11 to 30), and mean time to rise from floor of 4.7 seconds (range: 2.4 to 9.7). All study participants received corticosteroids for DMD before infusion and had baseline anti-AAVrh74 antibodies titers ≤1:400.

Study 301 is a multicenter, randomized, double-blind, placebo-controlled study in which 125 ambulatory male patients aged 4 through 7 years received a single intravenous infusion of 1.33 X 10¹⁴ vg/kg delandistrogene moxeparvovec-rokl. The efficacy outcome measure of the study was to evaluate the effect of delandistrogene moxeparvovec-rokl on physical function as assessed by the NSAA total score. Key secondary outcome measures were to evaluate expression of micro-dystrophin in skeletal muscle, time to rise from floor, and time of 10-MWR.

Clinical Outcomes

Both 102 and 301 studies failed to show a statistically significant difference in the primary endpoint of change in the NSAA total score between the treated and the placebo group. In study 102, the least squares (LS) mean change in the NSAA total score from baseline to week 48 was 1.7 points for the delandistrogene moxeparvovec-rokl group and 0.9 points for the placebo group (p=.37). In study 301, the LS mean change in the NSAA total score from baseline to week 52 was 2.57 points for the delandistrogene moxeparvovec-rokl group and 1.92 points for the placebo group (p=.24). Thus, clinical benefit was not demonstrated in the primary efficacy endpoint of NSAA total score from baseline in either study.^15,

Data from studies 102 and 301 were not pooled for an efficacy analysis due to multiple reasons.^8, The study population in study 102 differed in age and genetic diagnosis of DMD eligibility criteria from study 301. In addition, study 102 used a study product that was not ready for commercial use and a dose that was different from study 301. A side by side comparison of main efficacy from the 2 randomized studies are summarized in Table 7^8,. Multiple inconsistencies in key secondary outcomes were observed between the 2 studies. For example, the key secondary endpoint of 10-MWR test showed an advantage for delandistrogene moxeparvovec-rokl in study 301 but an advantage for placebo in study 102.

Biomarker Data

Muscle biopsies were obtained at baseline prior to infusion of gene therapy and at week 12 in all study participants. The absolute amount of delandistrogene moxeparvovec-rokl micro-dystrophin in muscle biopsy tissue samples were measured by western blot assay, adjusted by muscle content, and expressed as a percent of control (i.e., as a percent of levels of normal, wild-type dystrophin in muscle tissues of healthy individuals). Micro-dystrophin expression in delandistrogene moxeparvovec-rokl-treated participants was the primary objective of study 103 and 102 and a key secondary objective for study 301. Results of participants receiving the FDA approved dose for delandistrogene moxeparvovec-rokl in study 103 and 102 are included in Table 6. In study 301, muscle biopsies were obtained in 31 patients. For the delandistrogene moxeparvovec-rokl-treated participants (n=17), the mean micro-dystrophin expression at week 12 was 34.3% (±41.0%) compared to 0% in placebo-treated participants (n=14).^15,

Safety

The safety database consists of the 156 individuals with a confirmed mutation in the DMD gene who received a single intravenous infusion of delandistrogene moxeparvovec-rokl in 4 clinical studies. Of these, 144 individuals received the intended dose of delandistrogene moxeparvovec-rokl (1.33 X 10¹⁴ vg/kg). No deaths were reported. In clinical trials, immune-mediated myositis was observed approximately 1 month following delandistrogene moxeparvovec-rokl infusion in patients with deletion mutations involving exon 8 and/or exon 9 in the DMD gene. Symptoms of severe muscle weakness, including dysphagia, dyspnea and hypophonia, were observed. In a life-threatening case of immune-mediated myositis, symptoms resolved during hospitalization following additional immunomodulatory treatment; muscle strength gradually improved but did not return to baseline level. These immune reactions may be due to a T-cell based response from lack of self-tolerance to a specific region encoded by the transgene corresponding to exons 1-17 of the DMD gene. Limited data are available for delandistrogene moxeparvovec-rokl treatment in patients with mutations in the DMD gene in exons 1 to 17 and/or exons 59 to 71. Patients with deletions in these regions may be at risk for a severe immune-mediated myositis reaction. Delandistrogene moxeparvovec-rokl is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene due to the increased risk for a severe immune-mediated myositis reaction. Common adverse reactions (incidence ≥5%) were vomiting and nausea, liver injury, pyrexia, and thrombocytopenia.^15,

Table 3. Summary of Pivotal Trials

DBRCT: double-blind randomized controlled trial; DMD: Duchenne muscular dystrophy; ECHO: echocardiogram; FDA: US Food and Drug Administration; NCT: national clinical trial identification number; NSAA: North Star Ambulatory Assessment.a It is unclear if the variation in dosing was prespecified or not. According to the FDA documents, manufacturer retrospectively determined that in the delandistrogene moxeparvovec-rokl group, 12 of 20 participants received less than the intended dose This discrepancy was identified following a change in the analytical method for dose determination.b Genetic report must describe a frameshift deletion, frameshift duplication, premature stop ("nonsense"), canonical splice site mutation, or other pathogenic variant in the DMD gene fully contained between exons 18 to 79 (inclusive) that is expected to lead to absence of dystrophin protein. The following mutations were not eligible: mutations between or including exons 1-17, in-frame deletions, in-frame duplications, and variants of uncertain significance and mutations fully contained within exon 45 (inclusive).c Assuming a standard deviation of 3.5 in all subjects and a 10% dropout rate at week 52, with a type I error of 0.05 (2-sided), a sample size of 120 with 1:1 randomization ratio will provide approximately 90% power to detect a mean difference of 2.2 in change in NSAA total score from baseline to week 52 between the treated arm and placebo arm.

Table 4. Summary of Baseline Demographics and Disease Characteristics in the Pivotal Studies

a NSAA and Time to rise from floor were not evaluated in non-ambulatory patients.

NSAA: North Star Ambulatory Assessment.

Table 5. Summary of Clinical Outcomes in Pivotal Trials

NSAA: North Star Ambulatory Assessment; SE: standard error.

Table 6. Summary of Results on Biomarker Data in Pivotal Studies

RCT: randomized controlled trial; SD: standard deviation.a All patients received 1.33 x 1014 vg/kg delandistrogene moxeparvovec-rokl, as measured by droplet digital polymerase chain reaction.b Change from baseline was statistically significant.c Adjusted for muscle content. Control was level of wild-type (normal) dystrophin in normal muscle.d Part 1 of the study was the double-blind RCT phase for 48 weeks.e Part 2 of the study was the cross-over phase where participants who received placebo in part 1 received now received delandistrogene moxeparvovec-rokl.Table 7. Side by Side Comparison of Efficacy Results of Study 301 and 102a

a Reproduced from Table 9 in the FDA Statistical Review8,.b Directionally consistent implies the point estimates were on the same side of null. 10-MWR: 10-meter walk/run; CI: confidence interval; LSM: least square mean; NSAA: North Star Ambulatory Assessment. 

The purpose of the study limitations tables (Tables 8 and 9) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence and provides the conclusions on the sufficiency of evidence supporting the position statement. Multiple major limitations were noted. Both randomized, placebo-controlled studies failed to show a statistically significant difference in the pre-specified primary endpoint which was change in the NSAA total score between the treated and the placebo group. The US FDA approval was based on the post-hoc exploratory analysis of secondary outcome measures such as 10-MWR and time to rise from floor. These results cannot be interpreted at face value due to the lack of pre-specification and control of type 1 error. Such post hoc analysis following an overall nonsignificant test in the overall population can only be considered as hypothesis-generating. In addition, the observed treatment effect was not substantial and of uncertain clinical significance. The upper bound of 95 percent confidence intervals of point estimates for time to rise and 10-MWR was near the zero point (no effect). Further, the observed effect on 10-MWR timed test was also inconsistent with opposing results observed in the 2 RCTs. The decisional memorandum released by the Director of the Center for Biologics Evaluation and Research to clarify his action of overruling the staff’s recommendation for a complete response letter referenced an exploratory study indicating a moderate correlation between micro-dystrophin levels and the 10-MWR as well as the time required to climb 4 steps, as supportive evidence.^9, However, it’s important to note that micro-dystrophin expression levels were measured in only 25% of the patients enrolled in study 301. Consequently, these findings might not accurately reflect the association between micro-dystrophin and the clinical efficacy outcomes across the full study cohort. Because of all these limitations in the current evidence, an adequately powered randomized, double-blind, placebo-controlled trial is necessary to clearly ascertain the net health outcome in DMD. Lastly, biomarker data reported in studies only provides information about expression of the transgene product in cells transduced by delandistrogene moxeparvovec-rokl rather than insight into a pharmacologic effect on a known biomarker in the pathway of the disease. Delandistrogene moxeparvovec-rokl micro-dystrophin is a novel, engineered protein that contains selected domains of the normal, wild-type dystrophin expressed in healthy muscle cells. No epidemiologic or pathophysiologic evidence is available regarding the function of delandistrogene moxeparvovec-rokl micro-dystrophin. The protein differs in important ways from both the endogenous shortened forms of dystrophin in patients with Becker muscular dystrophy, and the internally truncated dystrophins expressed through exon-skipping drugs.

Table 8. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 9. Study Design and Conduct Limitations

The study limitations 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; 5. Other.b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.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); 7. Other.e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.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; 5. Other.

Section Summary: Gene Therapy for Treatment of Duchenne Muscular Dystrophy

Evidence for the use of delandistrogene moxeparvovec-rokl for the treatment individuals with DMD includes 2 RCTs (studies 102 and 301) and 1 prospective cohort trial (study 103). In study 102, 41 study participants were randomized 1:1 to receive either delandistrogene moxeparvovec-rokl (n=20) or placebo (n=21). In study 301, 125 study participants were randomized 1:1 to receive either delandistrogene moxeparvovec-rokl (n=63) or placebo (n=62). Both studies failed to show a statistically significant difference in the primary endpoint of change in the NSAA total score between the treated and the placebo group. In study 102, the LS mean change in the NSAA total score from baseline to week 48 was 1.7 points for the delandistrogene moxeparvovec-rokl group and 0.9 points for the placebo group (p=.37). In study 301, the LS mean change in the NSAA total score from baseline to week 52 was 2.57 points for the delandistrogene moxeparvovec-rokl group and 1.92 points for the placebo group (p=.24). Thus, clinical benefit was not demonstrated in the primary efficacy endpoint of NSAA total score from baseline in both studies. Multiple limitations were noted. The US FDA approval was based on the post-hoc exploratory analysis of secondary outcome measures such as 10-MWR and time to rise from floor. These results cannot be interpreted at face value due to the lack of pre-specification and control of type 1 error. Such post hoc analysis following an overall nonsignificant test in the overall population can only be considered as hypothesis-generating. In addition, the observed treatment effect on secondary outcomes was not substantial and of uncertain clinical significance. Further, the results of 10-MWR timed test were inconsistent with opposing results observed in the 2 RCTs. Because of these limitations, an adequately powered randomized, double-blind, placebo-controlled trial is necessary to clearly ascertain the net health outcome in DMD. Lastly, biomarker data reported in studies only provides information about expression of the transgene product in cells transduced by delandistrogene moxeparvovec-rokl rather than insight into a pharmacologic effect on a known biomarker in the pathway of the disease. Delandistrogene moxeparvovec-rokl micro-dystrophin is a novel, engineered protein that contains selected domains of the normal, wild-type dystrophin expressed in healthy muscle cells. No epidemiologic or pathophysiologic evidence is available regarding the function of delandistrogene moxeparvovec-rokl micro-dystrophin. The protein differs in important ways from both the endogenous shortened forms of dystrophin in patients with Becker muscular dystrophy, and the internally truncated dystrophins expressed through exon-skipping drugs. Thus, the clinical benefit of treating DMD with delandistrogene moxeparvovec-rokl, including improved motor function and pulmonary function, has not been demonstrated. A confirmatory, prospective, and adequately powered trial is necessary to assess the net health outcome of delandistrogene moxeparvovec-rokl in patients with DMD.

Summary of Evidence

For individuals with a confirmed diagnosis of Duchenne muscular dystrophy (DMD) who receive delandistrogene moxeparvovec-rokl, the evidence includes 2 randomized controlled trials (studies 102 and 301) and 1 prospective cohort trial (study 103). Relevant outcomes are disease-specific survival, change in disease status, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. In study 102, 41 study participants were randomized 1:1 to receive either delandistrogene moxeparvovec-rokl (n=20) or placebo (n=21). In study 301, 125 study participants were randomized 1:1 to receive either delandistrogene moxeparvovec-rokl (n=63) or placebo (n=62). Both studies failed to show a statistically significant difference in the primary endpoint of change in the North Star Ambulatory Assessment (NSAA) total score between the treated and the placebo group. In study 102, the least squares (LS) mean change in the NSAA total score from baseline to week 48 was 1.7 points for the delandistrogene moxeparvovec-rokl group and 0.9 points for the placebo group (p=.37). In study 301, the LS mean change in the NSAA total score from baseline to week 52 was 2.57 points for the delandistrogene moxeparvovec-rokl group and 1.92 points for the placebo group (p=.24). Thus, clinical benefit was not demonstrated in the primary efficacy endpoint of NSAA total score from baseline in both studies. Multiple limitations were noted. The US FDA approval was based on the post-hoc exploratory analysis of secondary outcome measures such as 10-meter walk/run (10-MWR) and time to rise from floor. These results cannot be interpreted at face value due to the lack of pre-specification and control of type 1 error. Such post hoc analysis following an overall nonsignificant test in the overall population can only be considered as hypothesis-generating. In addition, the observed treatment effect on secondary outcomes was not substantial and of uncertain clinical significance. Further, the results of 10-MWR timed test were inconsistent with opposing results observed in the 2 RCTs. Because of these limitations, an adequately powered, randomized, double-blind, placebo-controlled trial is necessary to clearly ascertain the net health outcome in DMD. Lastly, biomarker data reported in studies only provides information about expression of the transgene product in cells transduced by delandistrogene moxeparvovec-rokl rather than insight into a pharmacologic effect on a known biomarker in the pathway of the disease. Delandistrogene moxeparvovec-rokl micro-dystrophin is a novel, engineered protein that contains selected domains of the normal, wild-type dystrophin expressed in healthy muscle cells. No epidemiologic or pathophysiologic evidence is available regarding the function of delandistrogene moxeparvovec-rokl micro-dystrophin. The protein differs in important ways from both the endogenous shortened forms of dystrophin in patients with Becker muscular dystrophy, and the internally truncated dystrophins expressed through exon-skipping drugs. Thus, the clinical benefit of treating DMD with delandistrogene moxeparvovec-rokl, including improved motor function and pulmonary function, has not been demonstrated. A confirmatory, prospective, and adequately powered trial is necessary to assess the net health outcome of delandistrogene moxeparvovec-rokl in patients with DMD. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Neurology

In 2016, the American Academy of Neurology published an updated practice guideline on the use of corticosteroids for the treatment of Duchenne muscular dystrophy (DMD).^17, These guidelines were reaffirmed on January 22, 2022. The Academy does not discuss the use of delandistrogene moxeparvovec-rokl for DMD.

American Heart Association

In 2017, a statement from the American Heart Association addressed the treatment of cardiac issues in individuals with any of several neuromuscular diseases, including DMD.^18, For individuals with DMD, the Association recommended the use of glucocorticoids, among other medications. The statement does not address the use of delandistrogene moxeparvovec-rokl for DMD.

Centers for Disease Control and Prevention

In 2010, the U.S. Centers for Disease Control and Prevention convened a DMD Care Considerations Working Group. In 2010, the Working Group developed care recommendations and updated them in 2018.^19,20, Their 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 DMD. The guidelines do not address the use of delandistrogene moxeparvovec-rokl.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 10.

Table 10. Summary of Key Trials

NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

References

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2. Center for Disease Control and Prevention. Muscular Dystrophy: MD STARnet Data and Statistics. Available at http://www.cdc.gov/ncbddd/musculardystrophy/data.html. Accessed July 7, 2024.
3. Falzarano MS, Scotton C, Passarelli C, et al. Duchenne Muscular Dystrophy: From Diagnosis to Therapy. Molecules. Oct 07 2015; 20(10): 18168-84. PMID 26457695
4. Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment Guidance for Industry. Published February 2018. Available at https://www.fda.gov/media/92233/download. Accessed July 7, 2024.
5. Zambon AA, Ayyar Gupta V, Ridout D, et al. Peak functional ability and age at loss of ambulation in Duchenne muscular dystrophy. Dev Med Child Neurol. Aug 2022; 64(8): 979-988. PMID 35385138
6. 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): 343-56. PMID 23681930
7. 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 08 2013; 5. PMID 23867975
8. Food and Drug Administration. Statistical Reviewer: Thomas Zhou. STN: 125781/34. Available at https://www.fda.gov/media/179489/download?attachment. Accessed July 24, 2024.
9. Food and Drug Administration. Center Director Decisional Memo for BLA 125781//AMENDMENT 34; Elevidys (delandistrogene moxeparvovec-rokl). Available at https://www.fda.gov/media/179485/download. Accessed July 24, 2024.
10. Food and Drug Administration. Center Director Decisional Memo for BLA 125781; Elevidys (delandistrogene moxeparvovec-rokl). Available at https://www.fda.gov/media/169707/download. Accessed July 5, 2024.
11. Mendell JR, Sahenk Z, Lehman K, et al. Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. JAMA Neurol. Sep 01 2020; 77(9): 1122-1131. PMID 32539076
12. Mendell JR, Sahenk Z, Lehman KJ, et al. Long-term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial. Muscle Nerve. Jan 2024; 69(1): 93-98. PMID 37577753
13. Mendell JR, Shieh PB, McDonald CM, et al. Expression of SRP-9001 dystrophin and stabilization of motor function up to 2 years post-treatment with delandistrogene moxeparvovec gene therapy in individuals with Duchenne muscular dystrophy. Front Cell Dev Biol. 2023; 11: 1167762. PMID 37497476
14. Zaidman CM, Proud CM, McDonald CM, et al. Delandistrogene Moxeparvovec Gene Therapy in Ambulatory Patients (Aged ≥4 to 8 Years) with Duchenne Muscular Dystrophy: 1-Year Interim Results from Study SRP-9001-103 (ENDEAVOR). Ann Neurol. Nov 2023; 94(5): 955-968. PMID 37539981
15. Prescribing Label: Elevidys (delandistrogene moxeparvovec-rokl) suspension, for intravenous infusion. Available at https://www.fda.gov/media/169679/download. Accessed on July 5, 2024.
16. Food and Drug Administration. Sponsor Briefing Document for SRP-9001 (delandistrogene moxeparvovec) for the treatment of duchenne muscular dystrophy. Cellular, Tissue, and Gene Therapies Advisory Committee. Meeting date 12 May 2023. Available at https://www.fda.gov/media/168022/download. Accessed July 12, 2024.
17. Gloss D, Moxley RT, Ashwal S, et al. Practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. Feb 02 2016; 86(5): 465-72. PMID 26833937
18. Feingold B, Mahle WT, Auerbach S, et al. Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association. Circulation. Sep 26 2017; 136(13): e200-e231. PMID 28838934
19. 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
20. 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

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