Opinion: As Duchenne Innovation Booms, Let’s Ensure It Becomes Real Progress

Sarepta Outlines Key Considerations for Duchenne Therapy Development

Sarepta Therapeutics' President of Research & Development, Louise Rodino-Klapac, reflects on the evolving landscape of Duchenne muscular dystrophy (DMD) innovation, emphasizing critical considerations for translating scientific progress into tangible patient benefits. The opinion piece highlights the need for extensive patient data, long-term durability, and alignment of biomarkers with functional outcomes. Sarepta's experience with its gene therapy Elevidys, which received full FDA approval in 2024 after treating over 1,200 individuals, and its exon-skipping therapies (Exondys 51, Vyondys 53, Amondys 45), which have treated over 1,800 patients, underscores these points. The company is preparing submissions for traditional approval of Vyondys 53 and Amondys 45, advocating for responsible development and broad patient access in DMD.

• Given Duchenne's progressive and fatal nature, early clinical data are insufficient; Sarepta advocates for longitudinal, multi-dimensional approaches combining confirmatory trials, extended follow-up, and real-world evidence. This strategy supported Elevidys' full FDA approval in 2024, with over 1,200 patients treated, and over 1,800 patients receiving exon-skipping therapies, providing a robust understanding of long-term performance.
• In Duchenne, where muscle damage is irreversible, the key question is whether a therapy's effect is sustained for years, not just months. Sarepta's experience with its exon-skipping and gene therapies, supported by five-year-plus data across hundreds of patients, demonstrates that true progress means meaningfully altering disease trajectory and slowing progression over time, ensuring treated patients continue to separate from natural history.
• While biomarkers like dystrophin restoration are important, they don't always predict functional benefits. The most critical evidence for families is whether a child's disease trajectory changes, preserving walking, maintaining upper limb function, and improving daily life. A totality of evidence, combining biological markers, functional measures, and clinician, patient, and caregiver observations, is essential for defining real progress.
• As gene therapies reach more patients, understanding and managing risks through continued study, vigilance, and refined clinical protocols is vital. Expanding who can be treated requires studying diverse patient populations (younger, more advanced disease) and ensuring access through specialized clinical expertise, supportive care networks, and insurance coverage, making therapies available to as many patients as possible.

Addressing the Persistent Challenges in Duchenne Muscular Dystrophy Treatment

Despite significant therapeutic advances in Duchenne muscular dystrophy (DMD), including seven FDA-approved medications since 2016, fundamental challenges persist in achieving meaningful clinical outcomes. Current treatments remain largely symptomatic, and while newer dystrophin-targeting therapies show promise, their clinical efficacy evidence remains limited.

• Limited clinical efficacy of approved therapies - FDA-approved treatments including exon-skipping antisense oligonucleotides (eteplirsen, golodirsen, vitolarsen, casimersen) and microdystrophin gene therapy (delandistrogene moxeparvovec) show promise in targeting dystrophin restoration, but clinical evidence supporting their efficacy remains insufficient to prevent poor disease prognoses

• Cardiac targeting and delivery challenges - Substantial obstacles persist in achieving effective cardiac-specific delivery, which is critical given that cardiomyopathy is a leading cause of mortality in DMD patients, requiring optimized delivery strategies to address both skeletal and cardiac muscle pathology

• Long-term safety and scalability concerns - Ensuring long-term safety profiles and developing scalable treatment approaches remain unresolved, particularly for newer genetic therapies where long-term effects are not yet fully characterized

• Regulatory and developmental barriers - Essential requirements for regulatory approval, including implemented care standards, validated outcome measures correlating with clinical benefit, and comprehensive natural history data, are often not in place when potential therapies enter clinical trials for DMD and other rare diseases

• Healthcare system disparities - Significant treatment access inequalities exist, exemplified by Brazil's public health system showing 25-month diagnostic delays versus 10 months in private care, earlier ambulation loss (11-12 years versus 13-14 years), and substantially reduced life expectancy (19-20 years versus 26-27 years)

• Premature state of cell-based therapies - Advanced approaches including 2D cell sheets, patches, and engineered 3D cardiac models show potential for improving cell engraftment, but their therapeutic application remains speculative due to extensive muscle mass loss, complex cardiac-skeletal muscle interactions, and unresolved challenges in cell integration and long-term function

• Insufficient genetic counseling infrastructure - Professional norms for genetic counseling on dystrophinopathies are lacking, and genetic counseling capacity remains inadequate despite increased identification of DMD gene variant carriers through expanded screening programs

Sarepta's Journey: Demonstrating Durability and Long-Term Impact in DMD

Published evidence demonstrates significant improvements in long-term survival and functional outcomes for Duchenne muscular dystrophy patients over recent decades. Life expectancy has dramatically increased from mid-teenage years to mid-20s with glucocorticoid use, and extends beyond the third decade with comprehensive ventilatory support and multidisciplinary care. Studies from France show median survival improved from 25.77 years for patients born between 1955-1969 to 40.95 years for those born between 1970-1994. Danish registry data revealed decreased mortality rates and increased prevalence of DMD patients using ventilators, with recent estimates suggesting 85% probability of survival to age 30 years and median survival of 35 years.

Glucocorticoid corticosteroids remain the cornerstone therapy with demonstrated durability of functional benefits. Randomized controlled studies confirm that prednisolone 0.75 mg/kg/day stabilizes muscle strength and function for up to two years in the short-term studies available. However, the durability of long-term benefits cannot be fully evaluated from published randomized trials due to their limited duration, though non-randomized studies support sustained functional benefits alongside clinically significant adverse effects. Current treatment paradigms combining corticosteroids for skeletal muscle weakness, afterload reduction for cardiomyopathy, and noninvasive ventilation for respiratory failure have enabled patients to walk and live longer than historical cohorts.

Emerging therapeutic approaches show promising but limited long-term data. Recent 2024 evidence for eteplirsen in children with exon 51 skip-amenable mutations demonstrates that after 3-24 months of treatment, caregivers reported improvements or maintenance in walking ability, fine-motor movements, fatigue, and muscle weakness, with maintenance often perceived as positive outcomes given the progressive nature of DMD. However, the therapeutic landscape remains challenging, as gene therapy strategies that show remarkable success in dystrophic mice have not yet realized therapeutic benefit in DMD patients. The substantial differences in disease onset and progression between mouse models and human patients represent a critical gap that impacts the translation of promising preclinical durability data to clinical outcomes.

Beyond Biomarkers: Aligning Endpoints with Functional Outcomes in DMD

Duchenne muscular dystrophy clinical trials employ a comprehensive array of endpoints encompassing functional assessments, imaging biomarkers, and quality of life measures. These endpoints are carefully selected to capture disease progression across multiple domains, with increasing emphasis on combining traditional functional measures with advanced imaging techniques to improve sensitivity and reduce sample size requirements.

Motor Function Assessments:
• North Star Ambulatory Assessment (NSAA) demonstrates good reliability and serves as a primary functional endpoint across multiple studies, showing moderate correlations with muscle strength and imaging biomarkers
• 6-minute walk test (6MWD) remains widely used despite moderate reliability and high missingness rates, demonstrating moderate correlation with neck flexor strength
• Motor Function Measure (MFM), particularly dimension 1 (standing and transfer function), shows significant sensitivity for detecting change over 6-month periods and represents the most sensitive functional marker after quantitative MRI
• Timed function tests including 10-meter run/walk velocity (RWV) and 4-stair climb velocity (CLIMBV) exhibit good reliability and correlate with muscle fat fraction measurements

Advanced Imaging Biomarkers:
• Quantitative MRI mean fat fraction emerges as the most sensitive disease progression marker, requiring only four subjects for adequate power at 1-year follow-up compared to 12 subjects for functional measures
• IDEAL-IQ (6-point Dixon MRI sequence) demonstrates exceptional correlation with histopathologic fatty infiltration (ρ = 0.98, p < 0.001) and shows non-linear progression with inflection point averaging 7.3 years
• Composite biomarkers combining electrical impedance myography with quantitative ultrasound achieve stronger correlations with functional measures (correlation coefficient 0.79 with NSAA) than isolated biomarkers

Laboratory and Additional Measures:
• Serum creatinine levels correlate significantly with motor function, muscle fatty infiltration, and dystrophin levels, representing a promising biomarker for disease progression assessment
• Handheld dynamometry and quantitative muscle testing show poor to moderate reliability with high missingness rates, limiting their utility as primary endpoints
• PedsQL quality of life measures correlate with baseline impairment levels but demonstrate limited sensitivity to 12-month functional changes

Expanding Reach: Understanding the Diverse Duchenne Patient Population

Duchenne muscular dystrophy (DMD) demonstrates a clear demographic profile with distinct epidemiological patterns across global populations. The condition exclusively affects males due to its X-linked inheritance pattern, with prevalence estimates varying significantly by geographic region and study methodology.

• Male-only population: DMD affects males exclusively, with prevalence estimates ranging from 1 per 3,600-6,000 male births globally, though regional variations exist with prevalence rates from 1.7-4.2 per 100,000 in systematic reviews

• Age at diagnosis and disease milestones: Patients are typically diagnosed between ages 4-7 years, with symptoms beginning before age 5 in 85% of cases, loss of ambulation occurring around age 10-13 years, and median survival of 30 years with 85% probability of survival to age 30

• Geographic prevalence variations: The Americas show the highest prevalence at 5.1 per 100,000 people, while specific regional data includes Italy (1.65/100,000 overall, 3.4/100,000 males), Hong Kong (1.03 per 10,000 males aged 0-24 years), and Slovenia (2.9/100,000 for DMD)

• Age distribution in diagnosed populations: Contemporary patient cohorts show approximately 59% of patients under age 18 and 41% adults, with mean ages around 16.5 years in large registry studies, and age ranges extending from 6 months to 48 years

• Functional status demographics: Among diagnosed patients, approximately 43% remain ambulant while 57% are non-ambulant, with 75% currently receiving steroid therapy and varying levels of ventilatory support requirements (27% requiring some form of respiratory assistance)

• Treatment utilization patterns: Glucocorticoid treatment typically begins around age 5 years, with 75% of patients receiving steroids (mean age 14.6 years for current users), though steroid utilization varies by region with some countries showing lower adoption rates