Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that occurs in approximately one in every 3500 to 5000 males. Although it primarily affects males, a small number of 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 epidemiologic data from the United States, 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. Symptoms include motor difficulties such as difficulty running, jumping, and walking up the stairs, along with an unusual waddling gait. Some improvement in symptoms may be seen from 3 to 6 years of age, although 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. 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; the most common variants are concentrated between exons 45 and 53.
Delandistrogene moxeparvovec-rokl (Elevidys; Sarepta Therapeutics)
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 individuals 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 microdystrophin in skeletal muscle observed in individuals treated with delandistrogene moxeparvovec-rokl. Continued approval for this indication may be contingent on verification and description of clinical benefit in a confirmatory trial(s).
PEER-REVIEWED EVIDENCE
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 that encodes a novel, engineered microdystrophin protein. This novel microdystrophin protein is a shortened version (138- vs 427-kDa size of dystrophin expressed in normal muscle cells) that contains selected domains of dystrophin expressed in normal muscle cells.
Summary of the Clinical Development Program for Delandistrogene Moxeparvovec-rokl
| Study | NCT No | Phase | Study Population | Status | Study Dates | Design | Sample Size | Follow-Up |
| Study 101 | NCT03375164 | 1 | Ambulatory boys with DMD, age 4 to 7 years | Completed and unpublished | 2018-2023 | Open-label, single-arm | 4 | 12 weeks |
| Study 102 | NCT03769116 | 2 | Ambulatory boys with DMD, age 4 to 7 years | Ongoing | 2018-2026 | Part 1: DBRCT; placebo-controlled (48 weeks)
Part 2: Cross-over, blinding maintained (48 weeks)
Part 3: Open-label follow-up (5 years) | 41 | 48 weeks |
| Study 103 (Endeavor) | NCT04626674 | 1 | Cohort 1: Ambulatory boys ages 4 to 7 years old
Cohort 2: Ambulatory boys age 8 to 17 years old
Cohort 3: Nonambulatory boys, no age restriction
Cohort 4: Ambulatory boys ages 3 to 4 years old | Ongoing | 2020-2028 | Open-label, single-arm | 39 | 12 weeks |
| Study 301 (Embark) | NCT05096221 | 3 | Ambulatory boys with DMD, age 4 to 7 years | Ongoing | 2021-2024 | Part 1: DBRCT; placebo-controlled
Part 2: Cross-over, blinding maintained | 126 | 2 years |
| Study 303 (Envision) | NCT05881408 | 3 | Cohort 1: Nonambulatory
Cohort 2: Ambulatory and ≥8 to <18 years of age at the time of screening. | Ongoing | 2023-2027 | Part 1: DBRCT; placebo-controlled
Part 2: Cross-over, blinding maintained | 148 | 128 weeks |
DMD: Duchenne muscular dystrophy; DBRCT: double-blind randomized controlled study; NCT: national clinical trial.
For individuals with a confirmed diagnosis of DMD who are ambulatory and who receive delandistrogene moxeparvovec-rokl, the current published evidence includes one randomized controlled trial (RCT) and one prospective cohort study. 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 the single pivotal RCT, 41 study participants were randomly assigned 1:1 to receive either delandistrogene moxeparvovec-rokl (n=20) or placebo (n=21). Overall, there was no statistically significant difference in the primary endpoint of change in the North Star Ambulatory Assessment (NSAA) total score from baseline to week 48 between the treated group and the placebo group (1.7 vs 0.9 points, respectively; P=0.37). However, the least squares (LS) mean change in NSAA total score from baseline to week 48 among the subgroup of study participants aged 4 to 5 years was numerically greater for the treated (n=8) versus the placebo (n=8) group (4.3 vs 1.9 points, respectively).
Study 103 included a cohort of 20 participants aged 4 through 7 years who received delandistrogene moxeparvovec-rokl. Muscle biopsies were obtained at baseline prior to infusion of gene therapy and at week 12 in all study participants. The mean delandistrogene moxeparvovec-rokl microdystrophin expression levels (change from baseline) at week 12 following infusion was 95.7% in study 102 and 51.7% in study 103. Multiple limitations were noted. First, the exploratory subgroup analysis on which the approval was based was not prespecified for hypothesis testing, and no prespecified multiplicity adjustment strategy was employed. Such post hoc subgroup analysis following an overall nonsignificant test in the overall population can only be considered as hypothesis-generating. Second, while data from open-label studies are interpretable under certain conditions—such as when the disease being studied is homogeneous, the treatment has a large effect, and the clinical endpoint can be objectively assessed—none of these conditions are applicable for DMD. Lastly, biomarker data reported in studies 102 and 103 only provide 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.
Summary of Pivotal Trials
| Study | Study Type | Country | Sites | Dates | Participants | Intervention | | Follow-Up |
| | | | | | Active | Control | |
| Study 102 (NCT03769116) | Part 1: DBRCT; placebo-controlled (48 weeks)
Part 2: Cross-over, blinding maintained (48 weeks) | US | 2 | 20018-2026 | Inclusion - Male at birth ambulatory DMD patients aged 4 through 7 years
- Confirmed frameshift mutation, or a premature stop codon mutation between exons 18 to 58 in the DMD gene
- Indication of symptomatic muscular dystrophy by protocol-specified criteria
Exclusion - Impaired cardiovascular function on ECHO.
- Exposure to another investigational drug or exon skipping medication within 6 months of screening.
- Abnormal liver or renal function by protocol-specified criteria
Primary endpoint(s) - Change in the quantity of delandistrogene moxeparvovec-rokl microdystrophin protein from baseline to week 12 (Part 1), as measured by Western blot
- Change in NSAA total score from baseline to week 48 (Part 1)
| - Single intravenous infusion of delandistrogene moxeparvovec-rokl via a peripheral limb (n=20)
Dosinga - 8 received intended dose (1.33 X 1014 vg/kg)
- 6 received two-thirds of intended dose (8.94 X 1013 vg/kg)
- 6 received half of the intended dose (6.29 X 1013 vg/kg)
| Placebo (N = 21) | 48 weeks |
| Study 103 (NCT04626674) | Open-label, single-arm | US | 5 | 2018-2028 | Inclusion - Male at birth ambulatory DMD patients aged 4 through 7 years (Cohort 1)
- Has a definitive diagnosis of DMD based on documented clinical findings and prior genetic testing
Exclusion - Exposure to gene therapy, investigational medication, or any treatment designed to increase dystrophin expression within protocol-specified time limits.
- Abnormality in protocol-specified diagnostic evaluations or laboratory tests
Primary endpoint - Change from baseline in quantity of delandistrogene moxeparvovec microdystrophin protein expression at week 12
| - Single intravenous infusion of delandistrogene moxeparvovec-rokl via a peripheral limb at the intended dose (1.33 × 1014 vg/kg)
- N=20
| None | 12 weeks |
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, the manufacturer retrospectively determined that in the delandistrogene moxeparvovec-rokl group, 12/20 participants received less than the intended dose. This discrepancy was identified following a change in the analytical method for dose determination.
Summary of Clinical Outcomes in Pivotal Trial
| Study 102 | Least square mean changes (±SE) in NSAA total score from baseline to week 48
|
| Delandistrogene moxeparvovec-rokl | Placebo | P value |
| All ages | 1.7 (0.6) (n=20) | 0.9 (0.6) (n=21) | 0.37 |
| Age group 4 through 5 | 4.3 (±0.7) (n=8) | 1.9 (±0.7) (n=8) | Exploratory analysis |
| Age group 6 through 7 | −0.2 (±0.7) (n=12) | 0.5 (±0.7) (n=13) | Exploratory analysis
|
MICRODYSTROPHIN
Delandistrogene moxeparvovec-rokl microdystrophin 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 microdystrophin. The protein differs in important ways from both the endogenous shortened forms of dystrophin in individuals 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 individuals with DMD.
EMBARK (PART I of Confirmatory Trial)
In October 2023, Sarepta Therapeutics, manufacturer of gene therapy SRP-9001 (Elevidys) for the treatment of ambulatory patients with DMD, announced data from the Phase 3 EMBARK study (NCT05096221). Full results from EMBARK are expected to be shared at a future medical meeting and publication will be pursued in a medical journal.
On October 30, 2023, Sarepta Therapeutics announced the 1-year results of part 1 of the EMBARK Phase 3 clinical trial. This multinational, randomized, controlled, and double-blind study aims to assess the safety and efficacy of delandistrogene moxeparvovec in boys aged 4 to 7 with DMD.
The results show that the study failed to achieve its primary objective (also known as endpoint), which was to demonstrate a significant difference in the change of the North Star Ambulatory Assessment (NSAA) total score following Elevidys treatment. The NSAA is a recognized way of evaluating motor function (the ability to move) in people living with DMD (see the Benefits section of this policy document). Although some improvement in motor function was observed in children treated with Elevidys compared to the placebo group, these differences were not statistically significant. Trial participants treated with Elevidys improved by 2.6 points on the primary endpoint/main measure of NSAA, compared to 1.9 points among those given placebo. Despite the lack of this statistical significance and failure to meet the primary endpoint, Sarepta plans to ask the FDA to expand its clearance of the therapy and has shared the results with the agency.
The study appears to meet two of its secondary endpoints: the time required to rise from the floor and the 10-meter walk test. These secondary measures showed statistically significant improvements in children who received Elevidys over the course of 1 year.
Additionally, there were no new safety concerns raised during this part of the study.
The study involved 125 boys with DMD who can walk unassisted, and who were randomly assigned to either the treatment group or the placebo group. Participants will continue to be closely monitored for the next 5 years for both safety and clinical outcomes.
Part 2 of the EMBARK Phase 3 study is currently ongoing and should finish in late 2024, when it will provide further insights into the safety and efficacy of Elevidys in boys with DMD.
SUMMARY
For individuals with a confirmed diagnosis of DMD who are ambulatory and who receive delandistrogene moxeparvovec-rokl, the evidence includes one RCT and one prospective cohort study. 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 the single pivotal RCT, 41 study participants were randomly assigned 1:1 to receive either delandistrogene moxeparvovec-rokl (n=20) or placebo (n=21). Overall, there was no statistically significant difference in the primary endpoint of change in the NSAA total score from baseline to week 48 between the treated group and the placebo group (1.7 vs 0.9 points, respectively; P=0.37). However, the least squares (LS) mean change in NSAA total score from baseline to week 48 among the subgroup of study participants aged 4 to 5 years was numerically greater for the treated (n=8) versus the placebo (n=8) group (4.3 vs 1.9 points, respectively). Study 103 included a cohort of 20 participants aged 4 through 7 years who received delandistrogene moxeparvovec-rokl. Muscle biopsies were obtained at baseline prior to infusion of gene therapy and at week 12 in all study participants. The mean delandistrogene moxeparvovec-rokl microdystrophin expression levels (change from baseline) at week 12 following infusion was 95.7% in study 102 and 51.7% in study 103. Multiple limitations were noted. First, the exploratory subgroup analysis on which the approval was based was not prespecified for hypothesis testing, and no prespecified multiplicity adjustment strategy was employed. Such post hoc subgroup analysis following an overall nonsignificant test in the overall population can only be considered as hypothesis-generating. Second, while data from open-label studies are interpretable under certain conditions, such as when the disease being studied is homogeneous, the treatment has a large effect, and the clinical endpoint can be objectively assessed, none of these conditions are applicable for DMD. Lastly, biomarker data reported in studies 102 and 103 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 microdystrophin 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 microdystrophin. The protein differs in important ways from both the endogenous shortened forms of dystrophin in individuals 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 successful confirmatory, prospective and adequately powered trial is still necessary to assess the net health outcome of delandistrogene moxeparvovec-rokl in individuals with DMD, because in EMBARK, participants treated with Elevidys (delandistrogene moxeparvovec-rokl) showed an increase on the NSAA, a measure of motor function, compared to placebo-treated patients at 52 weeks, although the primary endpoint was not met. EMBARK was meant to confirm that approval by showing increased levels of a muscle-protecting protein translate to more definitive health benefits.
