Exondys 51 (eteplirsen) / Sarepta Therap - LARVOL DELTA

The Cost-Effectiveness of Eteplirsen vs. Standard of Care in Delaying the Progression of Duchenne Muscular Dystrophy (ISPOR 2025) - "Eteplirsen demonstrated clinical advantages in delaying the progression of DMD. However, its high cost restricts its cost-effectiveness relative to SoC. Further research is needed to generate current real-world utilities and costs associated with the use of eteplirsen among patients with DMD in the US, which can be leveraged to update this model."

Cost effectiveness • HEOR • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

MOMENTUM: Two-Part Study for Dose Determination of Vesleteplirsen (SRP-5051) (Part A), Then Dose Expansion (Part B) in Participants With Duchenne Muscular Dystrophy Amenable to Exon 51-Skipping Treatment (clinicaltrials.gov) - P2 | N=62 | Terminated | Sponsor: Sarepta Therapeutics, Inc. | Trial completion date: Jan 2029 ➔ Feb 2025 | Active, not recruiting ➔ Terminated; The study was terminated following review of safety data.

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

A historical perspective on the development of antisense oligonucleotide treatments for Duchenne muscular dystrophy and spinal muscular atrophy. (PubMed, J Neuromuscul Dis) - "Splice modulating antisense oligonucleotides (ASOs) have been approved for the treatment of spinal muscular atrophy (nusinersen) and Duchenne muscular dystrophy (eteplirsen) since 2016. In this historical perspective we look back to the development paths of these two ASOs focusing on the differences between the approaches, the target tissues and the diseases. Based on this we propose learnings for future development of ASOs for progressive neuromuscular diseases."

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

A Population Pharmacokinetic Model to Inform Extension of the Eteplirsen Dosing Regimen Across the Broad DMD Population. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Simulations showed similar exposures for eteplirsen (30 mg/kg intravenously once weekly) across different age groups (0.5 to < 2, 2 to < 4, 4 to < 7, and 7 to ≤ 16 years). These findings support the existing eteplirsen dosing paradigm of uniform weight-based dosing at 30 mg/kg/week across the broad age range of the target DMD population (6 months to adolescence)."

Journal • PK/PD data • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • Pediatrics • Respiratory Diseases

Two Novel Mouse Models of Duchenne Muscular Dystrophy with Similar Dmd Exon 51 Frameshift Mutations and Varied Phenotype Severity. (PubMed, Int J Mol Sci) - "Moreover, an increase in full-length isoform mRNA was detected in diaphragms of insG line mice. Although further work is needed to qualify these mutations as sole origins of dissimilarity, both genetically modified mouse lines are suitable models of DMD and can be used to test gene therapy based on alternative splicing."

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

Antisense oligonucleotide as novel therapies for neurogenetic disorders (PubMed, Zhonghua Yi Xue Yi Chuan Xue Za Zhi) - "Some of these therapeutics, including eteplirsen, golodirsen, viltolarsen, nusinersen and inotersen, have been approved by the Food and Drug Administration (FDA) and begun to draw the public's attention as an effective therapeutic approach. This review has elaborated the mechanism of ASO therapies, including basic rationales, modifications, side effects and delivery routes. It also systemically summarized the FDA-approved ASO therapeutics and their applications for various neurological disorders, and discussed the limitations and challenges the real-world market may face and issues genetic counselor should take into consideration in the near future."

Journal • Review • CNS Disorders • Genetic Disorders

A Study to Compare Safety and Efficacy of High Doses of Eteplirsen in Participants With Duchenne Muscular Dystrophy (DMD) (MIS51ON) (clinicaltrials.gov) - P3 | N=160 | Active, not recruiting | Sponsor: Sarepta Therapeutics, Inc. | Trial completion date: Nov 2024 ➔ Oct 2026 | Trial primary completion date: Nov 2024 ➔ Oct 2026

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

Characterization of Nonclinical Drug Metabolism and Pharmacokinetic Properties of Phosphorodiamidate Morpholino Oligonucleotides, A Novel Drug Class for Duchenne Muscular Dystrophy. (PubMed, Drug Metab Dispos) - "Eteplirsen, golodirsen, and casimersen are phosphorodiamidate morpholino oligomers (PMOs) that are approved in the United States for the treatment of patients with Duchenne muscular dystrophy (DMD) with mutations in the DMD gene that are amenable to exon 51, 53, and 45 skipping, respectively. A PMO drug class may support a platform approach to enhance understanding of the pharmacokinetic and pharmacodynamic behavior of these molecules. The grouping of novel agent series into platforms could be beneficial in the development of drug candidates for populations in which traditional clinical trials are not feasible."

Journal • PK/PD data • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Assessment of Phosphorodiamidate Morpholino Oligomer Treatment Patterns for Patients with Duchenne Muscular Dystrophy: A MarketScan Claims Analysis. (PubMed, Adv Ther) - "Understanding treatment patterns is important for characterizing real-world utilization of precision genetic medicines. This study observed a high PDC for PMO treatments for DMD. Most patients had continuous PMO claims coverage, and most patients with a gap in PMO claims had a subsequent PMO claim. Nonetheless, the observed persistence may have been underestimated given shortcomings of claims data and payer coverage considerations. Caution should be exercised when inferring treatment effectiveness or tolerability based on observed treatment patterns from claims data alone for weight-based, infused PMO treatments."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

An Accurate and Fast 31P qNMR Assay Method for Oligonucleotide Therapeutics. (PubMed, Anal Chem) - "The 31P qNMR method showed 7 ± 2%, 8 ± 1%, and 12 ± 1% lower concentration values compared with drug product labels for eteplirsen, inotersen, and inclisiran, respectively. The underestimate of UV results for eteplirsen, which has a phosphorodiamidate morpholino oligomer (PMO) structure, suggests that the UV-260 nm extinction coefficient may need to be re-established for the PMO based oligonucleotide. Therefore, the 31P qNMR method could be a primary assay method for the oligonucleotide drug and reference standard."

Journal

EVOLVE: A Long-term Observational Study Evaluating Eteplirsen, Golodirsen, or Casimersen in Routine Clinical Practice (clinicaltrials.gov) - P=N/A | N=300 | Enrolling by invitation | Sponsor: Sarepta Therapeutics, Inc.

New trial • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Impact of Disease-modifying Therapies on Respiratory Function in People with Neuromuscular Disorders. (PubMed, Sleep Med Clin) - "The paradigm of care is changing as new disease-modifying therapies are altering disease trajectory, outcomes, expectations, as well as patient and caregiver experiences. This article provides an overview on therapeutic advances for SMA and DMD in the last 10 years, with a focus on the effects of disease-modifying therapies on respiratory function."

Journal • Review • CNS Disorders • Cough • Duchenne Muscular Dystrophy • Genetic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Pulmonary Disease • Rare Diseases • Respiratory Diseases • Sleep Disorder

Adverse events associated with eteplirsen: A disproportionality analysis using the 2016-2023 FAERS data. (PubMed, Heliyon) - "This has contributed to a deeper understanding of the complex interrelations between adverse reactions and the use of eteplirsen. The findings underscore the critical importance of ongoing monitoring and sustained observation to promptly detect and effectively manage AEs, thereby enhancing the overall safety and well-being of patients treated with eteplirsen for DMD."

Adverse events • Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Infectious Disease • Muscular Dystrophy

Comprehensive review of adverse reactions and toxicology in ASO-based therapies for Duchenne Muscular Dystrophy: From FDA-approved drugs to peptide-conjugated ASO. (PubMed, Curr Res Toxicol) - "This article provides a comprehensive review and discussion of the available data pertaining to adverse reactions and toxicology associated with FDA-approved ASO drugs for DMD. Furthermore, it offers insights into the emerging category of peptide-conjugated ASO drugs those are clinical and preclinical trials, shedding light on their potential benefits and challenges."

FDA event • Journal • Review • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Eteplirsen Treatment for Duchenne Muscular Dystrophy: A Qualitative Patient Experience Study. (PubMed, Adv Ther) - "This exploratory study indicated that most caregivers perceived improvements or maintenances in aspects of their child's physical functioning, ADLs, and HRQoL since eteplirsen initiation, which they perceived to be a positive outcome."

Journal • Duchenne Muscular Dystrophy • Fatigue • Genetic Disorders • Muscular Dystrophy • Pain

Mechanisms of Action of the US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs. (PubMed, BioDrugs) - "RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.]."

FDA event • Journal • Review • Amyloidosis • Amyotrophic Lateral Sclerosis • Cardiac Amyloidosis • CNS Disorders • Cytomegalovirus Infection • Duchenne Muscular Dystrophy • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Infectious Disease • Metabolic Disorders • Movement Disorders • Muscular Dystrophy • Rare Diseases

Cas12 DNA editing restores dystrophin expression and muscle function in mouse model of Duchenne muscular dystrophy and demonstrates high editing efficiency in NHPs (ESGCT 2023) - "Here, we generated a novel humanized DMD mouse model harboring human DMD exon51, which exhibited highly similar phenotypes in patients with DMD...In addition, no in vivo toxicities were observed, including nerve, liver, and kidney injury, in the humanized DMD mice and WT NHPs. Unlike antisense-oligonucleotide-based exon skipping therapy administering throughout a patient's lifetime or AAV gene replacement therapy expressing micro-dystrophins for partial dystrophin functionality, our innovative CRISPR-based hfCas12Max-mediated single-cut approach modifying genomic DNA offers a promising, long-lasting, and "one-and-done" new treatment modality that targets the underlying cause of DMD."

Preclinical • Cardiomyopathy • Cardiovascular • Duchenne Muscular Dystrophy • Fibrosis • Genetic Disorders • Immunology • Muscular Dystrophy • Renal Disease

Survival in eteplirsen-treated Duchenne Muscular Dystrophy patients: Are there benefits beyond steroids? (PubMed, Muscle Nerve) - No abstract available

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Inhibition of survivin by 2'-O-methyl phosphorothioate-modified steric-blocking antisense oligonucleotides. (PubMed, RSC Adv) - "To date, ten ASO drugs, which are capable of either inducing mRNA degradation via RNase H recruitment (fomivirsen, mipomersen, inotersen, volanesorsen and tofersen) or splice modulation (eteplirsen, nusinersen, golodirsen, viltolarsen and casimersen), have been approved by the regulatory agencies for market entry. Furthermore, western blot analysis confirmed that ASO-7 could significantly repress survivin production on protein level. Based on our preliminary results, we believe that ASO-7 could be a useful BIRC5 inhibitor for both research purpose and therapeutic development."

Journal • Oncology • BIRC5

Predictors of Loss of Ambulation in Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis. (PubMed, J Neuromuscul Dis) - "Glucocorticoid therapy was associated with delayed loss of ambulation (overall meta-analysis HR deflazacort/prednisone/prednisolone: 0.44 [95% CI: 0.40-0.48]) (n = 25 studies)...Treatment with ataluren (n = 2 studies) and eteplirsen (n = 3 studies) were associated with prolonged ambulation...In total, 33% of studies exhibited some risk of bias. Our synthesis of predictors of loss of ambulation in DMD contributes to the understanding the natural history of disease and informs the design of new trials of novel therapies targeting this heavily burdened patient population."

IO biomarker • Journal • Retrospective data • Review • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • CD40 • SPP1

Development of hfCas12Max-Based Single-Cut Gene Editing Therapy for Duchenne Muscular Dystrophy (ASGCT 2024) - "Thus far, the antisense oligonucleotide (ASO) medicine, known as eteplirsen or casimersen, has been approved to treat DMD patients with particular mutations in the exon 45-55 hotspot regions. Our innovative CRISPR-based therapeutic, utilizing hfCas12Max for a precise single-cut modification of genomic DNA, presents a captivating new treatment paradigm, which offers a promising, long-lasting, and "one-and-done" new treatment modality that targets the underlying cause of DMD."

CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Adenine Base Editing Mediated Exon Skipping Restores Dystrophin Expression in a Humanized Mouse Model of Duchenne Muscular Dystrophy (ASGCT 2024) - "Correction of the DMD exon 51 deletion mutation by skipping exon 50 can therapeutically benefit ~3.8% of DMD patients... This distinctive DMD mouse model, which harbors the human genomic sequence, enables the in vivo evaluation of clinically relevant ABE gene editing strategies and other therapeutic interventions, signifying a substantial advancement towards the clinical application of adenine base editing for the correction of DMD in patients."

Preclinical • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Inflammation • Muscular Dystrophy

Survival among patients receiving eteplirsen for up to 8 years for the treatment of Duchenne muscular dystrophy and contextualization with natural history controls. (PubMed, Muscle Nerve) - "Data suggest eteplirsen may prolong survival in patients with DMD across a wide age range. As more data become available, the impact of eteplirsen on survival will be further elucidated."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Delayed Pulmonary Progression in Golodirsen-Treated Patients With Duchenne Muscular Dystrophy vs Mutation-Matched External Controls (MDA 2024) - P=N/A, P1/2, P3 | "A previously published analysis of eteplirsen vs mutation-matched ECs demonstrated similar rates of FVC%p decline. The estimated delay in time to reach cough-assist and to reach nighttime ventilation for golodirsen-treated patients vs ECs was 5.6 (~14 vs 19) and 7.5 (~16 vs 23) years, respectively. In conclusion, golodirsen treatment was associated with significant attenuation of pulmonary decline based on FVC%p."

Clinical • Cough • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • Respiratory Diseases

Exon skipping therapies in Duchenne muscular dystrophy: a case series of children who initiated before 3 years of age (MDA 2024) - "Patient 1 was diagnosed at 4 months, initiated eteplirsen at 10 months and corticosteroids at 3 years, and transitioned to viltolarsen at 3 years; he is currently 4 years. Patient 2 was diagnosed prenatally, initiated casimersen at 14 months; he is currently 40 months. Patient 3 was diagnosed at 2 months, initiated casimersen at 7 months; he is currently 25 months."

Clinical • Developmental Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy