Evidence-Based Treatment Guidelines and Advances in Therapeutic Agents

To claim CE credit for this activity, please visit https://www.pharmacytimes.org/courses/coverage-access-and-managed-care-decision-making-evidence-for-exon-skipping-therapies-in-duchenne-muscular-dystrophy

Supportive Treatment

Treatment of DMD has evolved from supportive multidisciplinary care to multimodal disease-modifying treatment, including therapies that target the underlying molecular defect. In addition to corticosteroids, the therapeutic landscape now includes gene transfer therapy, exon-skipping therapies, epigenetic modifiers, and multiple next-generation investigational platforms. Comprehensive supportive care is essential for patients with DMD. Current multidisciplinary care recommendations include physical and occupational therapy, respiratory management, cardiac surveillance, nutritional support, orthopedic interventions, psychosocial services, and pharmacologic therapy.^15-17

While corticosteroids remain foundational therapy in DMD, newer agents have expanded treatment options, including vamorolone, which was developed to retain anti-inflammatory efficacy while potentially reducing selected corticosteroid-associated toxicities, and the nonsteroidal histone deacetylase inhibitor givinostat.¹⁸

Corticosteroids

Prednisone/prednisolone has long served as a foundational corticosteroid therapy for DMD, with evidence supporting preservation of muscle strength and function and prolongation of ambulation. Selection among prednisone/prednisolone, deflazacort, and vamorolone should consider efficacy, adverse effect profiles, comorbidities, access, and patient and family preferences.

Deflazacort (Emflaza) is a corticosteroid prodrug approved by the FDA in 2017 for the treatment of patients with DMD 2 years and older.¹⁹ Approval was supported by a multicenter, randomized, double-blind, placebo-controlled, 52-week study demonstrating improvements in muscle strength compared with placebo.¹⁹ Muscle strength in 18 muscle groups was assessed at 12 weeks and compared with baseline, with the deflazacort group demonstrating a mean increase of 0.15 and the placebo group showing a 0.10 decrease in muscle strength score using a modified Medical Research Council (MRC) 11-point scale (P = .017).^19,20 The 1.2-mg/kg deflazacort group exhibited a slightly greater increase in strength but also a higher incidence of adverse effects, leading to the recommendation that patients receive a dose of 0.9 mg/kg.¹⁹ Post hoc analyses of corticosteroid-treated participants in the ACT DMD trial suggested better functional outcomes among patients receiving deflazacort compared with prednisone/prednisolone.²¹ Patients treated with deflazacort had less decline from baseline in 6-minute walk distance at week 48, and modeling based on these data estimated a longer time to loss of ambulation with deflazacort (8.58 years) than with prednisone/prednisolone (4.74 years).²¹ Because this was a post hoc comparison rather than a randomized comparison of corticosteroid regimens, these findings should be interpreted cautiously.

The most commonly reported adverse effects in clinical trials (≥ 10% and greater than placebo) were Cushingoid appearance, weight increase, increased appetite, upper respiratory tract infection, cough, pollakiuria, hirsutism, central obesity, and nasopharyngitis.¹⁹ Deflazacort and prednisone differ somewhat in their adverse effect profiles. Some studies suggest that deflazacort may be associated with less weight gain, behavioral challenges, Cushingoid appearance, and excessive hair growth, but has a greater risk of cataracts as compared with prednisone.²¹ Treatment selection should therefore be individualized based on patient characteristics, anticipated toxicities, and caregiver preferences.

Vamorolone (Agamree) is a novel corticosteroid approved by the FDA in 2023 for patients with DMD 2 years and older.^22,23 Unlike conventional glucocorticoids, vamorolone does not possess an 11β hydroxy-carbonyl group and was developed to retain anti-inflammatory efficacy while potentially reducing selected adverse effects associated with chronic conventional corticosteroid therapy.²³ The most common reported adverse reactions (> 10% and greater than placebo) were Cushingoid features, psychiatric disorders, vomiting, weight increase, and vitamin D deficiency.²²

FDA approval was based primarily on a randomized, double-blind, placebo- and active-controlled study.²² After 24 weeks of treatment, patients receiving vamorolone 6 mg/kg/d demonstrated significantly greater improvement in their time-to-stand velocity compared with placebo (mean increase of 0.048 rises/s vs −0.012 rises/s; P = .002), meeting the primary end point.^22,24 Longer-term extension studies demonstrated maintenance of motor function at 48 weeks comparable to prednisone while showing fewer adverse effects on linear growth.²⁴

Nonsteroidal Therapy

Givinostat (Duvyzat) is an orally administered histone deacetylase (HDAC) inhibitor approved by the FDA in 2024 for the treatment of DMD in patients 6 years and older.^25,26 HDAC inhibition is thought to modulate pathways involved in muscle regeneration, inflammation, fibrosis, and fatty replacement of skeletal muscle.²⁶ Givinostat provides a mutation-agnostic, nonsteroidal disease-modifying approach that can be used in patients receiving background corticosteroid therapy. In the pivotal EPIDYS trial (NCT02851797), all participants received a stable corticosteroid regimen, supporting the use of givinostat alongside corticosteroids rather than as a replacement for corticosteroid therapy.

EPIDYS was a phase 3, randomized, double-blind, placebo-controlled study of ambulatory boys receiving stable background corticosteroid therapy.^25,26 After 18 months of treatment, givinostat reduced worsening in the time to climb 4 stairs compared with placebo, meeting the study’s primary end point. Patients receiving givinostat demonstrated a mean decline of 1.25 seconds compared with 3.03 seconds in the placebo group, representing a difference of approximately 1.78 seconds (P = .037).²⁵ The most common adverse events included diarrhea (37%), vomiting (32%), and abdominal pain (34%).²⁵ Because thrombocytopenia and hypertriglyceridemia occurred more frequently than with placebo, periodic monitoring of platelet counts and triglycerides is recommended during treatment.²⁵ Decreased platelet counts, diarrhea, increased triglycerides, or QTc prolongation may necessitate dosage adjustments.²⁵

Long-term follow-up from the open-label extension with comparison to matched external controls suggested longer preservation of clinically important functional milestones. In this analysis, givinostat treatment was associated with estimated differences of approximately 2.9 years in time to loss of ambulation, 3.3 years in time to loss of 4-stair-climb ability, and 2 years in time to loss of the ability to rise from the floor compared with matched external controls. Because these estimates were derived from an external-control comparison rather than a randomized comparison, they should be interpreted accordingly.²⁶

Next-Generation Dystrophin Restoring Therapies

Corticosteroids remain first-line therapy because they have the longest-established evidence for preserving muscle strength and function, prolonging ambulation, and delaying pulmonary, cardiac, and orthopedic complications. However, as steroids do not address the root of the disease (ie, absent dystrophin), research continues to pursue other endeavors to correct DMD. Other disease-modifying therapies have generally been studied on a background of stable corticosteroid therapy and may be used alongside corticosteroids when clinically appropriate. As therapies targeting distinct disease mechanisms become available, combination treatment is increasingly relevant; however, evidence regarding additive efficacy, optimal combinations, and treatment sequencing remains limited. The development of novel therapies, particularly exon-targeted disease-modifying agents designed to restore dystrophin expression, has transformed the treatment landscape for DMD. Although exon-skipping therapies are applicable only to patients with specific genetic variants, they represent an important shift toward personalized medicine and increasingly multimodal treatment approaches.

Approved Exon-Skipping Therapies

The 4 currently approved exon-skipping therapies (eteplirsen, golodirsen, viltolarsen, and casimersen) received FDA accelerated approval based on increased dystrophin production in skeletal muscle, a surrogate end point considered reasonably likely to predict clinical benefit.^27-30 Because loss of functional dystrophin is central to the pathophysiology of DMD, dystrophin expression has emerged as an important biomarker and potential surrogate end point to support accelerated approval of dystrophin-restoring therapies.³¹ Accordingly, increased dystrophin expression should not be interpreted as definitive evidence of improved motor, pulmonary, or cardiac outcomes, and continued approval may depend on verification of clinical benefit in confirmatory studies. As of the time of this publication, all 4 indications remained listed by the FDA as ongoing accelerated approvals rather than having converted to traditional approval.³²

Eteplirsen (Exondys 51), an antisense oligonucleotide (ASO), was the first mutation-specific drug approved for DMD through the accelerated approval pathway in 2016 in patients with a confirmed DMD mutation amenable to exon 51 skipping. This accounts for approximately 13% of patients with DMD.^27,33 Eteplirsen binds dystrophin pre-mRNA and promotes skipping of exon 51 during splicing, restoring the reading frame for amenable variants and permitting production of an internally truncated dystrophin protein.^8,34 It is administered at a dosage of 30 mg/kg once weekly by intravenous (IV) infusion.²⁷

Approval was supported primarily by phase 2 clinical studies, which collectively enrolled 25 ambulatory, corticosteroid-treated patients with a confirmed mutation amenable to exon 51 skipping.²⁷ In Study 1, 12 participants were randomly assigned to receive weekly infusions of eteplirsen 30 mg/kg, eteplirsen 50 mg/kg, or placebo, followed by open-label treatment in Study 2 for an additional 4 years.²⁷ Clinical benefit was not established in Study 2; dystrophin levels were 0.93% of normal in eteplirsen-treated participants, although the absence of baseline dystrophin measurements limited assessment of treatment-related change.²⁷ In the open-label Study 3, 13 participants were treated with eteplirsen 30 mg/kg weekly for 48 weeks.²⁷ Muscle-biopsy analyses showed increased dystrophin expression from a mean of 0.16% at baseline to a mean of 0.44% at week 48.²⁷ Eteplirsen has generally been well tolerated. Commonly reported adverse reactions (> 35% and higher than placebo) include balance disorder and vomiting.²⁷ Hypersensitivity reactions have also been reported.²⁷

Additional longer-term evidence comes from the phase 3 PROMOVI trial (NCT02255552), a multicenter, open-label study evaluating weekly intravenous eteplirsen (30 mg/kg) in patients with DMD amenable to exon 51 skipping.³⁵ At 96 weeks, eteplirsen produced an 18.7-fold increase in exon skipping and a 7-fold increase in dystrophin protein expression relative to baseline.³⁵ Of the 79 enrolled participants, 78 completed the study, and treatment was generally well tolerated, with adverse events that were predominantly mild and consistent with the established safety profile of eteplirsen.³⁵

Observational real-world evidence has also evaluated cardiac outcomes associated with eteplirsen treatment.³⁶ A retrospective propensity score-matched analysis compared 122 eteplirsen-treated patients with 122 matched untreated controls.³⁶ During follow-up, no eteplirsen-treated patients developed a left ventricular ejection fraction (LVEF) less than 50%, compared with 27 patients (22.1%) in the control group.³⁶ Treatment with eteplirsen was also associated with a slower annual decline in LVEF and a lower risk of reaching LVEF thresholds of less than 55% and less than 60%.³⁶ Because this was a retrospective observational analysis, these findings demonstrate an association and do not establish a causal cardioprotective effect. Eteplirsen remains on the market under its original accelerated approval; as of this publication, the FDA has not converted the indication to traditional approval, and a final regulatory determination regarding the confirmatory evidence remains pending.

Golodirsen (Vyondys 53), a second ASO exon-skipping therapy, was granted accelerated approval in 2019 for patients with a confirmed DMD mutation amenable to exon 53 skipping.²⁸ Approximately 8% of patients with DMD have variants amenable to exon 53 skipping.³³

Approval was based on a 2-part trial: a double-blind, placebo-controlled dose-titration study, followed by a 168-week open-label extension in which participants received golodirsen 30 mg/kg weekly.^28,37 Among 25 patients who were stable on corticosteroids and had DMD amenable to exon 53 skipping, mean dystrophin levels increased from 0.10% of normal at baseline to 1.02% at week 48 (P < .001).²⁸ Available long-term data showed numerically fewer losses of ambulation at 3 years compared with natural-history controls; however, the difference was not statistically significant.³⁸ The extension study indicated that treatment was generally well tolerated through 168 weeks.³⁸

Frequently reported adverse events (≥ 20% and higher than placebo) included headache, pyrexia, falls, abdominal pain, nasopharyngitis, cough, vomiting, and nausea.²⁸ Hypersensitivity reactions, including anaphylaxis, were reported.²⁸ Renal toxicity was observed in animal studies, and kidney-function monitoring is recommended because potentially serious renal injury has occurred with other ASOs.²⁸

The ASO viltolarsen (Viltepso) was granted accelerated approval in 2020 for the treatment of patients with a confirmed DMD mutation amenable to exon 53 skipping.²⁹ It is administered at 80 mg/kg once weekly by intravenous infusion.²⁹ Approval was based on dystrophin-production data from a dose-finding clinical study conducted in the United States and Canada.^29,39 Sixteen corticosteroid-stable patients with a confirmed DMD mutation amenable to exon 53 skipping were randomly assigned to viltolarsen or placebo for 4 weeks, then all participants received 20 weeks of open-label viltolarsen 40 or 80 mg/kg weekly.^29,39 At week 25, mean dystrophin levels increased from 0.6% of normal to 5.9% in participants who received viltolarsen 80 mg/kg/wk.²⁹ The medication was well tolerated, with the most commonly reported adverse reactions (≥ 15%) including upper respiratory tract infection, injection site reactions, cough, and pyrexia.²⁹

The confirmatory phase 3 RACER53 trial (NCT04060199) did not meet its primary end point, with no statistically significant difference in time to stand from supine between viltolarsen and placebo at 48 weeks.⁴⁰ At the time of this writing, ongoing analyses and prior clinical results are being evaluated and will inform continued use of viltolarsen.⁴⁰

In 2021, the FDA granted accelerated approval to the ASO casimersen (Amondys 45) to treat patients with DMD who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping.³⁰ Approximately 8% of individuals with DMD have variants amenable to exon 45 skipping.³³ Casimersen is administered at 30 mg/kg once weekly by intravenous infusion.³⁰

Approval was based on an interim analysis of a randomized, double-blind, placebo-controlled trial in corticosteroid-stable patients with a confirmed mutation amenable to exon 45 skipping.³⁰ Participants received casimersen or placebo for 96 weeks before entering an open-label extension.³⁰ In the interim muscle-biopsy analysis from 43 participants, mean dystrophin expression increased from approximately 0.93% of normal at baseline to 1.74% at week 48 in patients receiving casimersen 30 mg/kg/wk, an absolute increase of approximately 0.81 percentage points (P < .001).³⁰ Common adverse reactions reported in clinical studies (> 20% and at least 5% higher than placebo) included upper respiratory tract infection, cough, pyrexia, headache, arthralgia, and oropharyngeal pain.³⁰ Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported.³⁰ As with golodirsen, renal toxicity was observed in animal studies, and baseline and ongoing renal monitoring are recommended.³⁰

The confirmatory ESSENCE trial (NCT02500381) did not meet its prespecified primary end point of 4-step ascend velocity at 96 weeks, although numerical differences favoring casimersen and golodirsen were reported on selected outcomes. The FDA subsequently accepted supplemental new drug applications seeking conversion of both casimersen and golodirsen from accelerated to traditional approval, with a Prescription Drug User Fee Act (PDUFA) action date of February 28, 2027.^41,42

Limitations of First-Generation Exon-Skipping Therapies

Despite establishing exon skipping as a viable therapeutic strategy for DMD, first-generation ASO therapies have several important limitations. Limited cellular uptake and intracellular delivery contribute to relatively low levels of dystrophin restoration in skeletal muscle, while delivery to cardiac muscle is also limited. Treatment requires once-weekly intravenous infusions for as long as therapy is continued, creating a substantial treatment burden for patients and caregivers. In addition, each therapy targets a specific exon and is therefore restricted to the relatively small proportion of patients whose DMD mutations are amenable to that particular exon-skipping strategy. These limitations have driven the development of next-generation oligonucleotide platforms designed to improve delivery to skeletal and cardiac muscle, increase dystrophin production, and potentially reduce treatment burden.

Gene Therapy

Delandistrogene moxeparvovec-rokl (Elevidys) is the first FDA-approved gene therapy for DMD.⁴³ Despite not meeting primary end points, delandistrogene moxeparvovec received FDA accelerated approval in 2023 for ambulatory patients 4 to 5 years of age based on increased microdystrophin levels.⁴³ In 2024, the FDA converted this to traditional approval for ambulatory patients 4 years and older, and then expanded approval to nonambulatory patients.⁴⁴ However, following reports of fatal acute liver failure in 2 nonambulatory patients treated with delandistrogene moxeparvovec, the FDA revised the indication in November 2025 to remove use in nonambulatory patients, restricting treatment to ambulatory patients 4 years and older.⁴⁵ The update added a boxed warning for acute liver failure, along with enhanced monitoring requirements, including serial assessment of liver function, platelet counts, and troponin-I following treatment.⁴⁵

Delandistrogene moxeparvovec utilizes a recombinant adeno-associated virus serotype rh74 (AAVrh74) vector to deliver a transgene encoding microdystrophin, an internally truncated dystrophin protein designed to retain key functional domains of full-length dystrophin.⁴⁶ Delandistrogene moxeparvovec is administered as a single-dose IV infusion.⁴⁶ Therapy should be postponed in patients with active or recent infection due to increased risk of serious systemic immune response.⁴⁶ A peri-infusion corticosteroid regimen is required, including adjustment of baseline corticosteroid therapy when applicable, with duration and tapering guided by the prescribing information and clinical/laboratory findings.⁴⁶ Delandistrogene moxeparvovec is contraindicated in patients with any deletion in exon 8 and/or exon 9 in the DMD gene.⁴⁶ The most commonly reported adverse reactions (≥ 5%) were vomiting and nausea, liver injury, pyrexia, thrombocytopenia, and troponin-I increased.⁴⁶ Serious immune-mediated adverse events, including acute liver injury, myocarditis, and infusion-related hypersensitivity reactions, have also been reported.⁴⁶ The long-term safety and efficacy of delandistrogene moxeparvovec were evaluated in the ongoing phase 3 EMBARK trial (NCT05096221).⁴⁷ In the randomized, double-blind, placebo-controlled first year of the phase 3 EMBARK trial, delandistrogene moxeparvovec did not meet the prespecified primary end point of change in NSAA score from baseline to week 52 compared with placebo (between-group difference, 0.65 points; P = .2441). Differences favoring treatment were observed on selected secondary functional end points, although statistical significance could not be formally claimed because the primary end point was not met.

Longer-term analyses have subsequently demonstrated increasing separation from untreated external controls. At 3 years after treatment, patients treated with delandistrogene moxeparvovec in EMBARK Part 1 had significantly better outcomes than a prespecified propensity-weighted external control cohort for NSAA (between-group difference +4.39 points; P = .0002), time to rise (−6.05 seconds; P < .0001), and 10-m walk/run (−2.70 seconds; P = .0039). These 3-year findings are based on comparison with an external control cohort rather than a contemporaneous randomized placebo group and should be interpreted accordingly.⁴⁸ As a one-time gene transfer therapy, delandistrogene moxeparvovec offers the potential for sustained microdystrophin expression following a single administration. However, long-term durability, optimal patient selection, and the sequencing of gene therapy with other disease-modifying treatments continue to evolve as additional clinical data become available.

Therapy Sequencing

TABLE 2 provides a comparison of DMD-specific therapies.^{19,22,25,27-30,46} As the number of disease-modifying therapies for DMD increases, treatment is evolving from a sequential model toward an individualized, multimodal approach. Corticosteroids remain foundational therapy for most patients, while additional treatments may target distinct aspects of disease biology, including dystrophin restoration, downstream muscle pathology, and other mechanisms. Consequently, therapies with different mechanisms of action may be complementary rather than mutually exclusive.

However, evidence regarding the efficacy and safety of specific treatment combinations, optimal timing of initiation, and sequencing of therapies remains limited.⁴⁹ Most pivotal trials have evaluated new therapies on a background of stable corticosteroid treatment, while relatively few studies have prospectively evaluated combinations of multiple disease-modifying therapies. Treatment decisions, therefore, require individualized consideration of genotype and treatment eligibility, age and disease stage, ambulatory and functional status, prior therapies, comorbidities, safety considerations, treatment burden, and patient and family preferences.

Gene transfer therapy introduces additional sequencing considerations. AAV-directed immune responses currently limit the feasibility of repeat administration with the same or related vectors, and the safety and efficacy of administering other disease-modifying therapies before or after gene transfer continue to be defined. Similarly, the potential benefits and risks of combining exon-skipping therapies, givinostat, or emerging therapies with other disease-modifying treatments require further study.

Investigational Therapies

Although first-generation FDA-approved ASO therapies have established exon-skipping as a viable therapeutic strategy for DMD, their clinical impact may be constrained by limited cellular uptake, relatively low levels of dystrophin restoration, and limited delivery to cardiac muscle.⁵⁰ Therefore, the development of next-generation exon-skipping therapies has focused on improving targeted delivery to skeletal and cardiac muscle.⁵⁰ Strategies under investigation include novel delivery systems, such as lipid nanoparticles and extracellular vesicles, as well as bioconjugate technologies that enhance cellular uptake through receptor-mediated delivery.⁵⁰ Among these, cell-penetrating peptides (CPPs) have shown promise in preclinical animal models, demonstrating increased dystrophin expression in cardiac tissues.⁵⁰ These approaches are intended to increase tissue delivery and dystrophin production and potentially improve clinically meaningful outcomes, although their comparative clinical benefit relative to approved therapies remains to be established.⁵⁰

Zeleciment rostudirsen (z-rostudirsen) is an investigational exon 51-skipping therapy that couples a phosphorodiamidate morpholino oligomer (PMO) to an antigen-binding fragment (Fab) targeting the transferrin receptor protein 1 (TfR1).⁵¹ This receptor-mediated delivery platform is designed to enhance delivery of the PMO to muscle and increase production of exon 51 skipped dystrophin; whether these biomarker effects translate into durable clinical benefit continues to be evaluated.⁵¹

Clinical data reported by the manufacturer from the ongoing phase 1/2 DELIVER trial (NCT05524883) have shown increases in dystrophin expression and changes in selected functional outcomes.⁵¹ After 6 months, participants receiving z-rostudirsen 20 mg/kg administered every 4 weeks achieved muscle-adjusted dystrophin expression exceeding 5% of normal, representing approximately a sevenfold increase from baseline.⁵¹ Differences favoring z-rostudirsen relative to placebo were reported across several functional end points, including time-to-rise velocity and 10-m walk/run velocity, while pulmonary function remained stable over the treatment period.⁵¹ Longer-term company-reported follow-up through 18 to 24 months has described continued changes across ambulatory, upper-limb, and pulmonary assessments, with no major new safety signals reported.⁵¹ The most commonly reported adverse events were pyrexia and headache.⁵¹ Based on the available clinical and biomarker data, the manufacturer submitted a biologics license application (BLA) seeking accelerated approval, with a PDUFA target action date of January 21, 2027.^51,52

Additional exon targets for exon-skipping and, separately, other mutation-agnostic therapeutic strategies are being investigated.⁵⁰ These therapies have the potential for broader applicability, treating a substantially larger proportion of patients with DMD by restoring the reading frame across multiple mutation types and broadening the population eligibility.⁵⁰ Next-generation exon-skipping therapies should not be viewed as incremental improvements over first-generation PMOs, but rather as fundamentally different delivery platforms capable of substantially greater dystrophin restoration and improved cardiac penetration.

Delpacibart zotadirsen (del-zota) is an investigational antibody-oligonucleotide conjugate (AOC) designed to allow for targeted delivery of oligonucleotides to skeletal and cardiac muscle tissue.⁵³ It is comprised of an anti-TfR1 antibody conjugated to exon 44-skipping PMOs; it is designed to restore the dystrophin reading frame and produce an internally truncated dystrophin protein in patients with DMD amenable to exon 44 skipping, an exon not currently targeted by an FDA-approved exon-skipping therapy.⁵³

In the phase 1/2 EXPLORE44 trial (NCT05670730), treatment with del-zota 5 mg/kg every 6 weeks or 10 mg/kg every 8 weeks was associated with increased exon skipping and dystrophin expression, with mean muscle dystrophin levels of approximately 25% of normal and levels up to 58% reported in some participants.⁵³ These dystrophin values should not be directly compared with those reported for other exon-skipping therapies because biopsy timing, tissue sampling, assay methodology, normalization, and dosing differ across clinical development programs. CK levels were significantly reduced, with 50% of participants achieving normal CK levels at 1 year.⁵³ Although CK provides a biomarker of muscle injury, the clinical significance of treatment-associated CK reductions in DMD remains uncertain. Changes from baseline across multiple motor outcome measures were reported over 1 year in the ongoing EXPLORE44 open-label extension (NCT06244082); however, the absence of a concurrent control group limits conclusions regarding treatment-related functional benefit.⁵³ Based on these findings, the manufacturer has indicated plans to pursue accelerated approval.⁵³

Additional exon-skipping approaches including WVE-N531, ENTR-601-44, ENTR-601-45, ENTR-601-50, and brogidirsen are being developed to improve muscle delivery, exon-skipping efficiency, dystrophin restoration, and/or dosing convenience, with programs targeting several exons, including 44, 45, 50, and 53, to potentially expanding the range of DMD variants addressable through exon-skipping approaches.^54-56

Deramiocel (CAP-1002) is an investigational, mutation-agnostic allogeneic cardiosphere-derived cell therapy that represents a distinct therapeutic approach from dystrophin-restoration strategies.⁵⁷ Rather than correcting the underlying genetic defect, deramiocel is proposed to reduce inflammation and fibrosis through immunomodulatory mechanisms, including modulation of macrophage-mediated inflammatory responses.⁵⁷

In the phase 3 HOPE-3 trial (NCT05126758), intravenous deramiocel administered every 3 months met its primary end point, demonstrating a statistically significant reduction in decline in Performance of the Upper Limb (PUL) 2.0 scores compared with placebo over 12 months (P = .029).^57,58 Cardiac measures were also evaluated, although these findings should be interpreted separately from the prespecified primary functional end point and in the context of the trial’s statistical testing hierarchy.^57,58 These findings suggest a potential effect on upper-limb function in a population with advanced DMD, while the magnitude and clinical significance of potential cardiac effects remain under regulatory evaluation.⁵⁷

Deramiocel has generally been well tolerated across clinical studies, with a safety profile consistent with previous cardiosphere-derived cell therapy trials.⁵⁷ Initially submitted for BLA in January 2025 without data from HOPE-3, the FDA issued a complete response letter stating that evidence of effectiveness was not met. The BLA was subsequently resubmitted with HOPE-3 data.⁵⁹ In July 2026, the FDA Cellular, Tissue, and Gene Therapies Advisory Committee voted 3 to 9 that the available evidence did not provide substantial evidence of the effectiveness of deramiocel for the treatment of DMD-associated cardiomyopathy.⁶⁰ The committee’s voting question specifically addressed cardiomyopathy and did not include a vote on the HOPE-3 upper-limb primary end point or overall benefit-risk profile. Following submission of additional 24-month open-label extension data and analyses supporting a refined proposed indication focused on upper-limb function, the FDA classified the submission as a major amendment and extended the PDUFA target action date from August 22, 2026, to November 22, 2026.⁶¹

Sevasemten (EDG-5506) is an investigational oral therapy designed to reduce contraction-induced muscle damage in dystrophies.⁶² Although development has prominently included BMD, sevasemten is also being evaluated in clinical trials for DMD.⁶³

Collectively, these investigational therapies, summarized in TABLE 3,^{51-53,57,58,62} illustrate the evolution of DMD treatment beyond the current clinical landscape. By improving tissue targeting, intracellular delivery, and introducing novel mechanisms of action, next-generation platforms are intended to address limitations of existing therapies and potentially expand treatment options across a broader range of patients with DMD. Early clinical studies have reported encouraging biomarker and functional signals, including potential effects on cardiac outcomes in selected programs. However, direct comparisons with currently approved therapies are generally unavailable, and cross-trial comparisons are limited by differences in patient populations, study design, outcome measures, follow-up duration, and biomarker methodology. Larger controlled studies and longer-term follow-up are needed to establish the magnitude, durability, and clinical relevance of these effects. As therapeutic options expand and evidence continues to evolve, clinicians and payers will increasingly face questions regarding patient selection, optimal sequencing, combination therapy, long-term monitoring, and value assessment.

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40. Meglio M. Puzzling preliminary results announced for viltolarsen’s confirmatory trial in Duchenne muscular dystrophy. Neurology Live. May 28, 2024. Accessed July 20, 2026. https://www.neurologylive.com/view/puzzling-preliminary-results-announced-viltolarsen-confirmatory-trial-duchenne-muscular-dystrophy

41. Sarepta Therapeutics announces third quarter 2025 financial results and recent corporate developments, including completion of its confirmatory study, ESSENCE. News release. Sarepta Therapeutics. November 3, 2025. Accessed September 15, 2026. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-third-quarter-2025-financial

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45. FDA approves new safety warning and revised indication that limits use for Elevidys following reports of fatal liver injury. News release. FDA; November 14, 2025. Accessed July 21, 2026. https://www.fda. gov/news-events/press-announcements/fda-approves-new-safety-warning-and-revised-indicationlimits-use-elevidys-following-reports-fatal

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48. Sarepta announces positive topline three-year EMBARK results showing ELEVIDYS significantly slows disease progression on key functional measures in ambulatory Duchenne patients. News release. Sarepta Therapeutics Inc; January 26, 2026. Accessed September 9, 2026. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-announces-positive-topline-three-year-embark-results

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51. Dyne Therapeutics announces positive topline results from phase 1/2 DELIVER trial of Z-Rostudirsen in Duchenne muscular dystrophy (DMD). News release. Dyne Therapeutics; December 8, 2025. Accessed July 20, 2026. https://www.globenewswire.com/news-release/2025/12/08/3201363/0/en/Dyne-Therapeutics-Announces-Positive-Topline-Results-from-Phase-1-2-DELIVER-Trial-of-Z-Rostudirsen-in-Duchenne-Muscular-Dystrophy-DMD.html

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55. Wave Life Sciences announces positive data from FORWARD-53 clinical trial in DMD including significant functional benefit and reversal of muscle damage after 48 weeks of dosing with WVE-N531. News release. Wave Life Sciences. March 26, 2025. Accessed September 15, 2026. https://ir.wavelifesciences. com/news-releases/news-release-details/wave-life-sciences-announces-positive-data-forward-53- clinical?_sp=8e208152-a52f-4ed9-9e51-6efe8f01e350&

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57. Capricor Therapeutics announces positive topline results from pivotal phase 3 HOPE-3 study of deramiocel in Duchenne muscular dystrophy. News release. Capricor Therapeutics; December 3, 2025. Accessed July 21, 2026. https://www.capricor.com/investors/news-events/press-releases/detail/331/capricor-therapeutics-announces-positive-topline-results

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59. Capricor Therapeutics announces establishment of new PDUFA date for deramiocel BLA. News release. Capricor Therapeutics; March 10, 2026. Accessed July 21, 2026. https://www.capricor.com/investors/news-events/press-releases/detail/338/capricor-therapeutics-announces-establishment-of-new-pdufa

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61. Capricor Therapeutics announces extension of PDUFA target action date as FDA continues review of deramiocel BLA. Capricor Therapeutics; August 24, 2026. Accessed September 6, 2026. https://www.capricor.com/investors/news-events/press-releases/detail/354/capricor-therapeutics-announces-extension-of-pdufa-target

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