Current evidence on delandistrogene moxeparvovec for DMD

A recent AAN Evidence in Focus article reviews the current evidence on delandistrogene moxeparvovec, a one-time gene therapy approved by the FDA in June 2024 for treating Duchenne muscular dystrophy (DMD) in patients aged four and older. The therapy delivers a miniaturized dystrophin gene using a viral vector but has shown limited evidence of effectiveness, with key clinical trials failing to meet primary motor function goals. While it may slightly slow functional decline, its benefits are difficult to separate from those of concurrent high-dose steroids. Serious side effects, including muscle and heart inflammation, liver injury, and risk of death, require close monitoring. The treatment, which costs $3.2 million, does not cure DMD or definitively improve lifespan or quality of life, underscoring the need for further long-term studies.

This review evaluates current evidence on delandistrogene moxeparvovec for Duchenne muscular dystrophy (DMD), analyzing six clinical trials, including two Class I studies that did not meet primary motor outcomes. While some secondary outcomes showed minor improvements, they lacked statistical significance. Safety concerns included immune-related side effects such as myocarditis and liver toxicity, and one death has been reported. Despite limited efficacy, the FDA approved the drug based on safety and secondary data. Ongoing monitoring and further research are needed to assess long-term outcomes and guide clinical use.

Key Concepts

Etiology & Genetics

X-linked progressive muscle disease
Caused by pathogenic variants in the DMD gene
Results in absence of functional dystrophin protein

Prognosis and Traditional Management

Improved with:
- Multidisciplinary care
- Use of corticosteroids
Life expectancy remains reduced

Advances in Disease-Modifying Therapies

Antisense Oligonucleotide (ASO) Therapies

Target restoration of the reading frame via exon skipping

Challenges in Gene Therapy for DMD

DMD gene:
- Contains 79 exons
- 14-kb transcript — too large for AAV vectors (~5 kb capacity)
Solution: Microdystrophin constructs (truncated genes with critical domains)

Delandistrogene Moxeparvovec (Elevidys) – Gene Therapy for DMD

Composition

Recombinant AAV vector (rAAVrh74)
Encodes a microdystrophin transgene
Produces a truncated protein (~138 kDa vs. 427 kDa normal dystrophin)

Regulatory Status

Initial FDA Accelerated Approval:
- June 22, 2023
- Ambulatory boys aged 4–5 years
Label Expansion (June 20, 2024):
- Full approval: Ambulatory boys aged 4+ years
- Accelerated approval: Nonambulatory boys with DMD

Evidence Summary: Delandistrogene Moxeparvovec in Duchenne Muscular Dystrophy (DMD)

Search Results
A systematic literature search of PubMed, Cochrane, Clinicaltrials.gov, and the World Health Organization's International Clinical Trials Registry Platform for published articles and clinical trials on treatment of DMD with delandistrogene moxeparvovec was conducted on July 31, 2024

Initial search: 36 articles → 7 full-text reviewed → 5 articles included.
Updated search: 23 articles → 1 additional included.
ClinicalTrials.gov + FDA: 6 total trials identified; 4 had published data.

Primary Outcome Measure

North Star Ambulatory Assessment (NSAA):
- 17-item scale (0 = unable, 1 = assisted, 2 = independent).
- Healthy peak score: 34 by age 4.
- DMD trajectory: improvement to ~age 6, followed by decline (~3.7 points/year post age 7).
- Minimal Clinically Important Difference (MCID): 2.3–3.5 points.

Key Trials with Available Data

NCT03375164 – Phase 1/2a (Single-Site, Nonrandomized)
- Sample: 4 boys, age 4–8.
- Dose: 2.0×10¹⁴ vg/kg, IV; plus prednisone 1 mg/kg/day.
- Outcomes:
  - 1-year follow-up: exploratory motor outcomes (Class IV).
  - 4-year post-hoc comparison: LSM NSAA difference = +9.4 points vs. external control (Class III).
- Conclusion: Suggestive of benefit, but low-level evidence.
NCT03769116 – Phase 2 (Randomized, Double-Blind, Placebo-Controlled)
- Sample: 41 boys, age 4–8.
- Design: Crossover (placebo/delandistrogene); stratified by age.
- Findings:
  - Primary (48-week NSAA):
    - Overall: +0.8 points, 95% CI –0.95 to 2.55 (Not significant, Class I).
    - Age 4–5 subgroup: +2.5 points, CI 0.44 to 4.56.
    - Age 6–7 subgroup: –0.7 points, CI –2.93 to 1.53.
  - 96-week outcome:
    - LSM NSAA difference = +2.0 points vs. external control (Class III).
- Conclusion: Modest, age-dependent motor benefit; greater response in younger children.
ENDEAVOR (NCT04626674) – Phase 1b (Open-Label)
- Sample: 20 boys, age 4–8.
- Dose: 1.33×10¹⁴ vg/kg IV.
- Outcome at 1 year:
  - NSAA LSM difference = +3.2 points vs. external control, CI 1.59 to 4.81.
  - TTR: –1.2s (CI –1.81 to –0.60); 10MWR: –1.0s (CI –1.63 to –0.37).
- Cohort 3 (nonambulatory): Upper limb decline slower than natural history.
- Conclusion: Functional improvements and slowing of decline in upper limb function; still exploratory.
- Class III evidence.
EMBARK (NCT05096221) – Phase 3 (Multinational, RCT)
- Sample: 126 boys, age 4–8.
- Outcome at 52 weeks:
  - NSAA LSM difference = +0.65 points (CI –0.45 to 1.75, Not significant, Class I).
  - No subgroup differences based on age or baseline NSAA.
- Secondary:
  - TTR: –0.64s (CI –1.06 to –0.23).
  - 10MWR: –0.42s (CI –0.71 to –0.13).
  - Small numerical motor benefits.
  - Corticosteroid exposure higher in treatment group post-week 2, may confound results.
- Conclusion: Primary endpoint not met. Secondary measures favor treatment but do not reach MCID.

Summary of Efficacy

Trial ID	Design	Class	NSAA Difference	Meets MCID?	Notes
NCT03375164	Phase 1/2a, nonrandomized	III	+9.4 (4 years)	Yes (exploratory)	Post-hoc, small sample
NCT03769116	Phase 2, RCT	I/III	+0.8 (overall)	No	Age 4–5: +2.5 points (near MCID)
ENDEAVOR	Phase 1b, open-label	III	+3.2 (1 year)	Yes	Interim data, external comparator
EMBARK	Phase 3, RCT	I	+0.65 (52 weeks)	No	Primary endpoint not met

Conclusion

Delandistrogene moxeparvovec shows modest to moderate functional motor benefits in younger ambulatory boys with DMD, particularly those aged 4–5 years.
Only one trial (ENDEAVOR) achieved a clinically meaningful difference in NSAA scores, based on comparison to an external control group.
RCTs (especially EMBARK) did not meet primary endpoints; numerical trends favor treatment but fall short of statistical or clinical significance.
Longer follow-up and subgroup analyses suggest potential benefit in younger patients and warrant continued investigation.

Safety Summary: Delandistrogene Moxeparvovec in DMD

Patient Exposure

Total of 85 patients treated across key clinical trials:
- NCT03375164
- NCT03769116
- NCT04626674

Treatment-Related Adverse Events (AEs)

13 adverse events requiring medical intervention documented, including:
- Vomiting
- Myocarditis
- Acute liver injury
- Immune-mediated myositis

Immune-Related Risk Management

Corticosteroid prophylaxis is standard to mitigate immune-mediated toxicity:
- For patients already on corticosteroids: add 1 mg/kg/day prednisolone equivalent (max 60 mg/day)
- Steroid-naïve patients: initiate 1.5 mg/kg/day one week prior to infusion and continue ≥60 days post-infusion

Common Adverse Reactions (≥5% incidence)

Vomiting
Nausea
Liver injury (transient ALT/AST elevations up to 4× ULN; peak around day 60; responsive to steroids)
Fever
Thrombocytopenia

Serious Adverse Events

Acute serious liver injury (typically within 8 weeks post-treatment)
Myocarditis (noted in early post-infusion phase; patients with LVEF <40% were excluded from trials)
No thrombotic microangiopathy or cardiogenic shock reported in trials
One case of fatal acute liver failure reported outside clinical trial settings

Immune-Mediated Myositis

Reported approximately 4 weeks after infusion in patients with DMD deletions involving exons 8 or 9
Clinical features:
- Severe weakness
- Myalgia
- Dysphagia
- Dyspnea
Limited data on risk in deletions spanning exons 1–17 (these patients were excluded from trials)

Immunological Profile

Consistent with other intravenous AAV vector therapies
Characterized by:
- Peri-infusion reactions
- Innate and adaptive immune activation, especially within the first 90 days post-infusion

Traditional Perspective and Forward View

Traditional View: Safety profile aligns with expectations from systemic AAV-based gene therapies
Corticosteroid prophylaxis remains a cornerstone of immune-related adverse event management
Forward Perspective:
- Improved safety through patient selection (e.g., exclude patients with compromised cardiac function)
- Vigilant monitoring of liver enzymes and immune responses post-infusion
- Genotype-specific stratification (especially deletions involving exons 8 and 9) for personalized risk assessment
- Need for expanded postmarketing surveillance and inclusion of previously excluded genotypes in future studies
- The reported fatal liver failure case highlights the need for strict adherence to safety protocols and long-term monitoring

FDA Approval Timeline and Controversies

June 22, 2023: Accelerated Approval Granted
Indication: Ambulatory patients aged 4–5 years with DMD.
This approval was controversial due to internal disagreement:
- The Clinical, Clinical Pharmacology, and Statistics review teams and supervisors recommended a Complete Response (CR) letter—effectively a rejection—citing insufficient evidence that microdystrophin expression reliably predicts clinical benefit.
- This recommendation was overruled by the Director of the Center for Biologics Evaluation and Research (CBER), who highlighted subgroup data from trial NCT03769116 demonstrating NSAA score improvements at 1 year versus placebo.
June 20, 2024: FDA Expanded Approval
- Full approval for ambulatory patients aged ≥4 years.
- Accelerated approval for nonambulatory patients aged ≥4 years.
- This expansion was again granted through CBER director override, despite continuing Complete Response recommendations from the Offices of Clinical Evaluation, Therapeutic Products, Biostatistics, and Pharmacovigilance.

CBER Director’s Rationale

Affirmed substantial evidence of effectiveness per the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Public Health Service Act (PHS Act) for ambulatory patients ≥4 years with confirmed DMD gene mutations — except those with deletions in exons 8 and/or 9, where ELEVIDYS use is contraindicated.

For nonambulatory patients ≥4 years, approval was accelerated based on evidence of microdystrophin protein elevation, considered reasonably likely to predict clinical benefit pending further efficacy demonstration.

Current Gaps and Ongoing Research

Clinical efficacy in nonambulatory patients remains unproven; ongoing trials (e.g., EMBARK, ENDEAVOR) aim to address this critical gap.

Recommended Dosing

Patient Weight	Dose	Volume Equivalent
< 70 kg	1.33 × 10¹⁴ vector genomes/kg (vg/kg)	~10 mL/kg body weight
≥ 70 kg	Fixed dose of 9.31 × 10¹⁵ vg total	Fixed volume (per formulation)

Traditional Perspective

From a traditional regulatory and clinical standpoint, the FDA’s cautious yet progressive approach reflects the balance between unmet medical need in DMD and the current limits of gene therapy evidence. The director’s override acknowledges promising subgroup data while emphasizing ongoing verification, a prudent path respecting the gravity of introducing a novel gene therapy.

Forward View

Future regulatory confidence will hinge on longer-term clinical outcomes, especially in nonambulatory patients and genetic subpopulations excluded from initial approval (exons 8/9 deletions). Enhanced post-marketing surveillance and real-world effectiveness data will be essential to refine indications and optimize patient safety.

Clinical Context

While AAV-microdystrophin gene therapies such as delandistrogene moxeparvovec offer a biologically plausible approach to treating Duchenne muscular dystrophy (DMD), they are not curative.
The FDA’s broad approval of this first-in-class therapy has been met with a mix of hope and uncertainty by clinicians, patients, and caregivers.

Populations for Use

Delandistrogene moxeparvovec (ELEVIDYS) has been approved for individuals:
- Aged ≥4 years, regardless of ambulatory status
- With a clinical and genetic diagnosis of DMD
- Excluding those with deletions encompassing exons 8–9

Current Exposure Data

Total exposed patients with available data: 134
Age range: Predominantly 4–<8 years
Ambulatory status: Mostly ambulatory
Nonambulatory patients: Only 6 individuals aged 9–20 years (Cohort 3, study NCT04626674); limited outcome data available in FDA documentation
Mutation Coverage in Existing Data:
- Exons 18–58: 45 patients
- Exons 18–79: 89 patients
- Exons 18–44 and 46–79: 63 patients
Ongoing Clinical Trials:
- Study NCT04626674 (ENDEAVOR) is expected to:
  - Add data on patients with mutations in exons 1–8 and 14–17 (N = 8, open-label)
  - Provide additional data for nonambulatory patients (N = 128)
  - Expand total treatment exposure data to approximately 304 boys with DMD

Gaps in Evidence

Delandistrogene moxeparvovec has not been studied in the following populations:
- Patients with moderate-to-severe cardiomyopathy (LVEF <40% were excluded; the lowest LVEF in the trials was 48%)
- Patients with severe pulmonary disease
- Patients with significant neurodevelopmental impairment

Patient and Family Perspectives

Qualitative studies and interviews of individuals with DMD and their caregivers underscore:
- A willingness to accept risk in the context of limited or no disease-modifying treatment options
- A strong emphasis on patient-centered, risk-benefit assessments
The clinical outcomes valued most by patients and families include:
- Functional motor performance
- Quality of life
- Pulmonary and cardiac function
- Maintenance of stability in these domains

Measuring Improvement in Motor Function

The Phase 3 EMBARK trial (NCT05096221) evaluating delandistrogene moxeparvovec did not demonstrate a statistically or clinically meaningful difference between treatment and placebo groups on its primary outcome, the North Star Ambulatory Assessment (NSAA).
Although modest numerical improvements were observed across several secondary motor outcomes, such as:
- Time to Rise (TTR)
- 10-Meter Walk/Run (10MWR) test
these did not reach statistical significance according to the trial’s hierarchical analysis plan.
Some of these secondary endpoints overlap with components of the NSAA, which may reflect its limitations as an ordinal scale in detecting small but potentially meaningful treatment effects.
To minimize random errors and false positives from multiple comparisons, pre-specified statistical handling of secondary outcomes is essential.

Confounding Factors

A critical confounder in interpreting efficacy data is the co-administration of high-dose corticosteroids during gene therapy:
- Corticosteroids are known to improve muscle strength, motor function, cardiac and pulmonary performance, and survival in DMD.
- They are used to dampen immune responses triggered by AAV-based gene therapy.
External control studies did not adequately adjust for variations in corticosteroid dose or duration, complicating comparative interpretation.
Robust evaluation requires discerning the true clinical benefit attributable to gene therapy, separate from corticosteroid effects.

Biomarkers of Efficacy

Microdystrophin Expression

The primary biomarker supporting the development and FDA accelerated approval of delandistrogene moxeparvovec is microdystrophin protein expression, measured via Western blot from muscle biopsies.
Key findings from Phase 2 SRP-9001-102 (NCT03769116):
- Part 1: Treated group achieved 23.82% microdystrophin expression vs 0.14% in placebo
- Part 2: Expression increased to 39.8%
- Long-term follow-up: At 60 months, 19.10% expression was retained
Levels were compared against full-length dystrophin in healthy male controls and interpreted as potentially clinically meaningful.
This formed a key rationale for accelerated approval, drawing upon:
- Preclinical data indicating functional benefit from partial dystrophin restoration
- The design of microdystrophin, which preserves critical domains
- Observations from patients with large in-frame deletions exhibiting milder DMD phenotypes

Limitations of Microdystrophin Data

No clear correlation exists between microdystrophin and full-length dystrophin on a 1:1 basis.
The clinical relevance of the exact levels measured remains uncertain.
The Phase 2 correlation between microdystrophin levels and NSAA improvements in 4–5-year-olds was not replicated in the Phase 3 EMBARK trial, which found no NSAA difference at 1 year.
The predictive value of microdystrophin levels as a surrogate biomarker for clinical benefit remains unclear outside early-phase trials.
Microdystrophin assessment is not available in routine clinical settings and is not expected to be part of ongoing patient monitoring.

Serum Creatine Phosphokinase (CPK) as a Secondary Biomarker

The EMBARK study reported on serum creatine phosphokinase (CPK), an enzyme elevated in nearly all ambulant DMD patients.
Despite aggregate CPK reductions post-treatment, several limitations affect its utility:
- CPK levels are highly variable across individuals and time, influenced by:
  - Activity level
  - Time of day
  - Age
  - Steroid exposure
CPK reduction cannot be reliably interpreted as evidence of therapeutic efficacy.
Routine CPK monitoring post-gene therapy is not recommended.

Suggestions for Future Research

Given the limited efficacy signals observed in pivotal trials and the substantial uncertainties surrounding long-term benefit, several areas of research warrant urgent and sustained attention:

Improving Outcome Measures for Motor Function

The NSAA may lack sensitivity to detect subtle yet meaningful changes in motor function, especially in early or slowly progressing DMD.
Future studies should develop or incorporate novel outcome measures that combine ordinal and continuous data.
Technologies like digital biomarkers, wearable sensors, and patient-reported outcomes could enhance precision and ecological validity.

Defining the Predictive Value of Microdystrophin Expression

Further investigation is needed to clarify the relationship between microdystrophin levels and long-term clinical benefit.
Prospective natural history studies and postmarketing registries can help define dose-response or threshold effects.
Harmonization of dystrophin quantification methods and functional comparisons to full-length dystrophin are essential.

Longitudinal Follow-Up of Treated Patients

Long-term safety and durability of delandistrogene moxeparvovec require study beyond 5–10 years.
Post-approval surveillance should monitor for late-emerging safety signals, gene expression durability, and vector-related complications (e.g., oncogenesis or immune responses).

Characterizing the Role of Corticosteroids

Corticosteroid use remains a confounding factor in evaluating gene therapy outcomes.
Future trials should stratify or standardize corticosteroid exposure.
Studies in corticosteroid-naïve or withdrawn populations are needed to assess the independent gene therapy effect.

Expanding the Evidence Base for Diverse Populations

Real-world data should include ethnically and clinically diverse populations and those with comorbidities or advanced disease.
Factors like immune profile, baseline function, and vector tropism may significantly impact efficacy and safety.

Cost-effectiveness and Access Equity Analyses

Comprehensive health economic modeling is necessary due to the high cost of treatment.
Real-world cost-effectiveness and budget impact analyses should be pursued.
Alternative reimbursement models, including outcomes-based payments, should be explored.
Studies should assess psychosocial and economic effects on families to inform policy.

Biomarker Discovery and Validation

New biomarkers are needed that correlate with disease progression and therapeutic response.
Potential markers include MRI T2 mapping, blood-based inflammatory/metabolic markers, or gene expression profiles.

Optimization of Vector and Delivery Strategies

Refinement of vector design should aim to improve tissue specificity, expression durability, and immune tolerance.
Exploring new delivery routes and capsid designs may overcome immunity barriers and enable re-dosing.

By addressing these research priorities, the field can move closer to realizing the full therapeutic potential of gene transfer approaches while maintaining rigorous standards for patient safety, scientific integrity, and equitable access.

Clarifying the Duration and Sustainability of Therapeutic Benefit

Longitudinal studies are needed to evaluate the durability of microdystrophin expression and its associated clinical benefit.
Research should assess whether initial improvements are sustained or plateau over time, particularly in relation to muscle regeneration and turnover.
Understanding the long-term benefit profile is essential for informed clinical decision-making.

Addressing the Challenge of Redosing

Neutralizing antibodies to AAV vectors limit the potential for redosing.
Research into novel capsid designs, immunomodulatory strategies, and non-viral or RNA-based approaches is needed to overcome this challenge.
Given DMD's lifelong nature, effective redosing strategies may be necessary to maintain therapeutic benefit.

Investigating Immune Responses to the Transgene and Vector

Some patients develop immune responses to the transgene itself, posing safety and efficacy risks.
Future research should identify mechanisms and predictors of immune reactions.
Standardized immune monitoring protocols should be implemented in trials and postmarketing surveillance.

Evaluating Safety and Efficacy Outside Clinical Trial Populations

Approval of delandistrogene moxeparvovec extends to populations beyond those included in trials.
Postmarketing registries and global data-sharing are necessary to gather real-world evidence for broader patient groups.
This includes patients with different genotypes, advanced disease, or comorbid conditions.

Defining Optimal Timing of Therapy Initiation

The therapeutic window for gene therapy in DMD remains unclear.
Early intervention may be more effective, particularly before significant muscle degeneration occurs.
Research should explore the feasibility and impact of early diagnosis via newborn screening programs.
New outcome measures must be developed for early-stage disease detection and monitoring.

Development of Age-Appropriate and Sensitive Outcome Measures

NSAA has limitations in detecting short-term or subtle functional changes, particularly in younger patients.
Innovative tools such as wearables, video-based assessments, and composite endpoints should be developed.
These tools should address motor, cognitive, and quality-of-life domains and gain regulatory endorsement for trial use.

Expanding the Role of Real-World Evidence (RWE)

Real-world data will be critical for evaluating the effectiveness of delandistrogene moxeparvovec in diverse settings.
Observational studies, digital health tools, and patient registries should be utilized for long-term monitoring.
High-quality RWE can support reimbursement decisions and inform the design of future clinical trials.

Ethical and Policy Considerations for Screening and Early Treatment

The expansion of newborn screening for DMD raises important ethical and policy questions.
Topics include informed consent, timing of treatment, parental expectations, and equitable access.
Multidisciplinary collaboration is essential to develop appropriate guidelines and support frameworks.

Lecture Notes