Elevidys (delandistrogene moxeparvovec-rokl) / Sarepta Therapeutics, Nationwide Children's, Roche - LARVOL DELTA

MTE #24: Gene Therapies and Hepatotoxicity (Ticketed) (AASLD 2026) - "Multiple gene therapies have been approved in recent years by the US Food and Drug Administration (FDA) for a variety of inherited disorders, including: Duchenne muscular dystrophy (delandistrogene moxeparvovec-rokl, 2023) Hemophilia A (valoctocogene roxaparvovec-rvox, 2023) Hemophilia B (etranacogene dezaparvovec-drlb, 2022; fidanacogene elaparvovec-dzkt, 2024) Spinal muscular atrophy (onasemnogene abeparvovec-brve, 2025) Sickle cell disease (exagamglogene autotemcel, 2023)...Identify clinically available AAV gene therapy treatments. Discuss ways to identify and potentially mitigate hepatotoxicity, and to optimize care for patients and study participants receiving AAV gene therapy."

Gene therapy • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophilia • Hemophilia A • Hemophilia B • Hepatology • Liver Failure • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Rare Diseases • Sickle Cell Disease

MTE #5: Gene-Based Therapy in Liver Disease—Promise, Ethics, and Responsibilities (Ticketed) (AASLD 2026) - "Evaluate how emerging gene therapies influence investigator responsibilities related to safety oversight, communication of uncertainty, and stewardship of irreversible interventions, all in the context of the latest liver safety data pertaining to emerging gene therapies (eg, delandistrogene moxeparvovec-rokl recombinant gene therapy). Review the application of expert insights to improve clinical trial design, patient engagement, and ethical decision-making in gene-based therapy research."

Alpha-1 Antitrypsin Deficiency • Gene Therapies • Genetic Disorders • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Metabolic Disorders • Movement Disorders • Pulmonary Disease • Respiratory Diseases

Safety and efficacy of AAV-based mini- and micro-dystrophin gene therapies in Duchenne muscular dystrophy: a systematic review and meta-analysis of clinical trials. (PubMed, J Med Genet) - "AAV-based gene therapies provide modest functional benefits in ambulatory boys with DMD, particularly at younger ages, but carry important safety risks. Larger trials with longer follow-up are needed to clarify long-term efficacy and optimise risk-benefit profiles."

Journal • Retrospective data • CNS Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

289th ENMC international workshop: assessing and managing emerging AAV related toxicities after gene therapy for neuromuscular disorders, 26 - 28 September 2025, Hoofddorp, The Netherlands. (PubMed, Neuromuscul Disord) - "Adeno-associated virus (AAV) mediated gene therapies has emerged as a potentially transformative treatment approaches for neuromuscular disorders, with two FDA-approved products now in widespread clinical use: onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy and delandistrogene moxeparvovec-rokl (Elevidys) for Duchenne Muscular Dystrophy...Emerging toxicities, including capillary leak syndrome, endothelial and dorsal root ganglia injuries, were reviewed alongside corresponding preclinical data from non-human primates. Participants agreed on the need to harmonize standard operating procedures, clinical guidelines, and data-sharing practices, and endorsed collaborative initiatives to proactively address critical gaps and unresolved key questions through a patient-centered framework."

Journal • CNS Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Rare Diseases

ENHANCE: Study to Evaluate the Safety and Effectiveness of ELEVIDYS in Participants With Duchenne Muscular Dystrophy Treated in a Post-Marketing Setting (clinicaltrials.gov) - P4 | N=20 | Not yet recruiting | Sponsor: Sarepta Therapeutics, Inc. | Trial completion date: Mar 2027 ➔ Aug 2027 | Trial primary completion date: Mar 2027 ➔ Aug 2027

Trial completion date • Trial primary completion date • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Anesthetic Management of a Patient With Duchenne Muscular Dystrophy Following Recent Gene Therapy With Delandistrogene Moxeparvovec (ASA 2026) - "In addition, the patient was carefully assessed for the known adverse effects of Elevidys, which include myocarditis, acute liver failure, thrombocytopenia, and immune-mediated myositis. As gene-based therapies become more prevalent, anesthesiologists must become familiar with their multisystem effects in order to provide safe anesthetic care."

Clinical • Gene therapy • Cardiovascular • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Hematological Disorders • Hepatology • Immunology • Inflammation • Liver Failure • Muscular Dystrophy • Musculoskeletal Diseases • Myositis • Orthopedics • Thrombocytopenia

Safety, Tolerability, and Efficacy of a Prophylactic Sirolimus Protocol for Patients Receiving Delandistrogene Moxeparvovec-Rokl Gene Therapy. (PubMed, Hum Gene Ther) - "Sirolimus prophylaxis appears to be safe and well-tolerated in DMD patients receiving DMR. While not statistically significant, these results suggest that further study of sirolimus prophylaxis is warranted."

Journal • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Hepatology • Liver Failure • Muscular Dystrophy

Recalibrating Therapeutic Priorities for Duchenne Muscular Dystrophy: A Critical Synthesis of Approved and Emerging Strategies Through the Lens of an Underrepresented Population. (PubMed, Genes (Basel)) - "We argue that the conventional priority ordering (gene therapy first, exon-skipping second, standard care as background) does not hold up when weighed against patient-relevant outcomes and cost, and may reasonably be inverted for resource-limited systems. This is our interpretation of an indirect comparison, not an evidence-based clinical recommendation. On that reading, the highest-value investments for Central Asia are early molecular diagnosis, universal access to glucocorticoids and specialised physiotherapy, and individual-import pathways for ataluren, while AAV gene therapy is, in our view, a lower near-term priority until its durability and safety data improve."

Journal • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Real-World Experience With Gene Therapy in Duchenne Muscular Dystrophy: Experience From Qatar. (ICNMD 2026) - "This study demonstrates that Elevidys is well tolerated in DMD patients aged 4–11 years. Also indicate the safety and efficacy of gene therapy in DMD when combined with a protocol ."

Clinical • Gene therapy • Real-world • Real-world evidence • Cardiovascular • CNS Disorders • Congestive Heart Failure • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Heart Failure • Muscular Dystrophy

Duchenne Muscular Dystrophy and Delandistrogene Moxeparvovec Gene Therapy in Children: A Systematic Review and Meta-Analysis. (PubMed, Neurol Genet) - "Delandistrogene moxeparvovec, despite high heterogeneity for the analysis, improved functional outcomes in ambulatory pediatric patients with DMD. Further long-term RCTs are needed to confirm its safety and efficacy."

Journal • Retrospective data • Review • CNS Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy • Pediatrics • Respiratory Diseases

Cardiac Safety Outcomes in Delandistrogene Moxeparvovec Clinical Trials for Duchenne Muscular Dystrophy with Up to 5 Years of Follow-up. (PubMed, Cardiol Ther) - P1, P1/2, P3 | "Results from delandistrogene moxeparvovec trials with 1 to 5 years of follow-up suggest a manageable cardiac safety profile in this study population of predominantly younger, ambulatory patients with DMD who had no signs of persistent treatment-related cardiac injury."

Journal • Cardiovascular • Duchenne Muscular Dystrophy • Fibrosis • Gene Therapies • Genetic Disorders • Immunology • Inflammation • Muscular Dystrophy

Five-Year Outcomes With Delandistrogene Moxeparvovec in Patients With Duchenne Muscular Dystrophy: A Phase 1/2a Study. (PubMed, Muscle Nerve) - P1/2 | "Findings support the long-term, manageable safety profile of delandistrogene moxeparvovec in ambulatory patients with appropriate monitoring and demonstrate stabilization or delayed disease progression with treatment compared with matched untreated ECs."

Journal • P1/2 data • Cardiomyopathy • Cardiovascular • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

ENHANCE: Study to Evaluate the Safety and Effectiveness of ELEVIDYS in Participants With Duchenne Muscular Dystrophy Treated in a Post-Marketing Setting (clinicaltrials.gov) - P4 | N=20 | Not yet recruiting | Sponsor: Sarepta Therapeutics, Inc. | Initiation date: Apr 2026 ➔ Jul 2026

Trial initiation date • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Lower AAV-SLB101 Cross-Reactive Antibodies in Elevidys-treated Patients (ASGCT 2026) - "The findings presented here reveal a previously unexpected lower cross-reactivity of AAV-SLB101 capsids in Elevidys-treated patients. Furthermore, our data suggests that antibody reduction strategies will be more beneficial in reducing anti-AAV-SLB101 titers over other serotypes that are more similar to AAVrh74 when attempting to retreat Elevidys-treated patients."

Clinical • CNS Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Metabolic Disorders • Muscular Dystrophy

Comparative in vitro and Clinical Assessment of Muscle-Specific Promoters for Cardiac Gene Expression and Function in Duchenne Muscular Dystrophy (ASGCT 2026) - P1, P1/2 | "Current and former clinical candidate products include zildistrogene varoparvovec (SGT-001), an AAV9 vector containing the CK8 promoter; fordaditrogene movaparvovec (PF-06939926), an AAV9 vector containing the hCK promoter; and delandistrogene-moxeparvovec (SRP-9001, Elevidys), an AAVrh74 vector with the MHCK7 promoter. This trend seems to be reflected in clinical LVEF observations, although participants at later age will need to be assessed. Further studies will test the efficacy of each promoter in a mouse model using therapeutic micro-dystrophin constructs, with additional follow-up timepoints to understand the long-term impact of promoter selection on DMD cardiac outcomes following gene therapy."

Preclinical • Cardiomyopathy • Cardiovascular • CNS Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Infectious Disease • Muscular Dystrophy

AAVrh74-based novel capsids for striated muscle gene therapy (ASGCT 2026) - "Subsequent total antibody (TAb) assays for top three novel capsids confirmed their markedly reduced seroreactivity, down to 10-14% of the AAVrh74 parental control, as assayed with pooled plasma of post-Elevidys patients (30 days). Conclusion Significant improvement in striated muscle-specific transduction, liver de-targeting and reduced seroreactivity create an opportunity to introduce a much safer AAV-based gene therapy for multiple skeletal muscle and cardiac dystrophies at moderate doses."

Gene therapy • Cardiovascular • Gene Therapies

AAV9 outperforms AAV8 and rh74 in human muscle following systemic delivery (ASGCT 2026) - "Notably, an AAV9-based drug (Zolgensma) and an AAVrh74- based drug (Elevidys) have been approved by the US Food and Drug Administration to treat spinal muscular atrophy and DMD, respectively...Our work establishes a practical strategy for preclinical screening of AAV for systemic muscle gene therapy in patients and for studying the biology of AAV transduction in human muscle. Supported by NINDS (R01- NS90634 and R01-NS131416), NIAID (R01-AI177600), and NIAMS (R21-AR81018)."

CNS Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Myositis • Rare Diseases • Respiratory Syncytial Virus Infections • Sarcoma • Solid Tumor • ALPP

What is the formula for commercial success of a gene therapy? Reflections on approved GTx (ASGCT 2026) - "Indication selection: Commercial success across Casgevy®, Vyjuvek®, Elevidys® and Zolgensma® reinforce five criteria that appear pivotal for gene therapy success...Beqvez® (hemophilia B) appears to have treated no patients between FDA approval (2024) and market withdrawal (2025), while Hemgenix® treated 12 patients in its first year (<0.1% penetration). Uptake has also remained minimal for Zevaskyn® and Zynteglo® (beta-thalassemia).By contrast, Elevidys® (DMD) treated approximately 900 patients in the US within two years of FDA approval, although it did not receive EU authorization... The number of clinical study initiations increased continuously over the observation period, rising by 430% from 27 ongoing company sponsored programs in 2016 to 143 in 2025. After steady growth until 2021, development activity accelerated markedly from 2022 onward, with the pipeline almost doubling between 2022 and 2023. After a peak in 2024,..."

Gene therapy • Beta-Thalassemia • CNS Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia B • Hepatology • Liver Failure • Metabolic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Ophthalmology • Rare Diseases

Analysis of a small cohort demonstrated no evidence of AAV seroconversion in household contacts following systemic AAV vector infusion (ASGCT 2026) - "Survey responses at 3 month post-rAAV from 12 gene therapy household contacts (Zolgensma n=3, Elevidys n=9) show a risk of bodily fluid exposure (A). Neutralizing antibody titers were calculated using a One-Phase Decay equation (GraphPad Prism) and broken into negative (1:0) and positive titers (>1:1). Plotted data represent a single point and Baseline vs 3-Month was analyzed using a two-tailed paired t-test (B)."

Gene Therapies

Cell & Gene Therapy Clinical Trial Trends (2021–2025) and Strategic Outlook (2026–2028): Mechanism Shifts and Regulatory Drivers (ASGCT 2026) - "Key milestones include the first CRISPR-based approval (Casgevy™), lentiviral therapy (Lyfgenia™), and AAV gene therapy (Elevidys™). Europe recorded $0.4B, with investment dominated by public-market activity and supported by strategic alliances, while Asia-Pacific generated $0.2B, led mainly by early-stage venture financing. Together, these patterns highlight a capital landscape in which North America continues to anchor CGT funding, Europe maintains steady public-equity engagement, and Asia-Pacific expands through venture-driven growth, underscoring the need for region-specific strategies to support CGT development and commercialization."

Clinical • First-in-human • Gene therapy • Gaucher Disease • Gene Therapies • Immunology • Metabolic Disorders • Ophthalmology • Pompe Disease • Retinal Disorders • Solid Tumor • FOXG1

Lowering pre-existing immunity to adeno-associated virus-based gene therapy: Pre‑treatment with imlifidase or plasmapheresis prior to administration of delandistrogene moxeparvovec in Duchenne muscular dystrophy (ASGCT 2026) - P1 | "Transduction and micro-dystrophin expression were observed in both studies, though at reduced levels relative to values observed in patients without pre-existing AAVrh74 antibody titers ≥1:400 in previous clinical studies. Results suggest that pre-treatment with imlifidase or plasmapheresis are potential approaches to lower pre- existing anti-AAV antibodies prior to treatment with AAV-based gene therapies such as delandistrogene moxeparvovec, though further studies are needed to better understand the mechanism of reduced gene therapy transduction and expression."

Gene therapy • Cardiovascular • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Immunology • Muscular Dystrophy

Rational for dose selection for intracerebroventricular AAV9 gene therapy using a CTNNB1 gene therapy model (ASGCT 2026) - P1/2 | "These include AAV9- based therapies for spinal muscular atrophy (SMA), administered intravenously (Zolgensma™) or intrathecally (Itvisma™); an intravenously delivered AAV-based therapy for Duchenne muscular dystrophy (Elevidys™); and AAV2-based therapies delivered subretinally to the eye (Luxturna™) or directly to the brain parenchyma (e.g. intraputaminal administration of Upstaza™)...Prioritizing CNS mRNA expression as an efficacy reference point, while achieving exposures at least two-fold below the NOAEL with supportive safety data, enables ethically justified first-in-human dosing decisions in AAV-based CNS gene therapy trials. This framework is intended to inform dose selection strategies across emerging CNS gene therapy programs beyond a single indication."

First-in-human • Gene therapy • CNS Disorders • Developmental Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Rare Diseases • CTNNB1

Family experience data with delandistrogene moxeparvovec gene therapy treatment for Duchenne muscular dystrophy. (ASGCT 2026) - "Improvements observed, even modest gains or stabilization, following dosing with Elevidys, were reported to have made a substantial difference in the lives of their families. These insights add to delandistrogene moxeparvovec’s knowledge base, shedding light on the lived experiences of those living with Duchenne and exploring the notable quality of life impacts reported following treatment."

Gene therapy • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

rAAVrh74 total binding antibodies seroprevalence and antibody titers over time in patients with DMD and LGMD (ASGCT 2026) - P | "Summary of seroprevalence shift in patients with DMD eligible for delandistrogene moxeparvovec based on postmarketing data (A) and in patients with LGMD enrolled in JOURNEY (B). DMD, Duchenne muscular dystrophy; LGMD, limb-girdle muscular dystrophy."

Clinical • Duchenne Muscular Dystrophy • Gene Therapies • Infectious Disease

Cross-species barcoded AAV capsid library screening addresses diaphragm inefficiency and liver off-targeting (ASGCT 2026) - "Although Elevidys (AAVrh.74- delivered micro-dystrophin) is approved for DMD, clinical benefits have been modest, likely reflecting both the functional limitations of micro-dystrophin and incomplete transduction across diverse muscle groups...We identified a handful of candidates showing strong diaphragm enrichment with variable gains in other striated muscles and de- targeting from human liver. These results provide a practical translational filter to prioritize next-generation capsids that jointly optimize diaphragm delivery and liver safety for DMD gene therapy."

Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Hepatology • Liver Failure • Muscular Dystrophy