Vyondys 53 (golodirsen) / Sarepta Therap - LARVOL DELTA

An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases. (PubMed, Methods Mol Biol) - "The US Food and Drug Administration (FDA) has granted accelerated approval for four AONs to skip a single DMD exon for treating patients with DMD: eteplirsen for exon 51 skipping, golodirsen and viltolarsen for exon 53 skipping, and casimersen for exon 45 skipping. Splice-modulating AONs have also been extensively tested in other inherited diseases, such as Usher syndrome, dystrophic epidermolysis bullosa (DEB), fibrodysplasia ossificans progressiva (FOP), and allergic diseases. This chapter will introduce the developmental status of exon skipping and splice-modulating therapies for genetic diseases."

Journal • Allergy • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Inherited Retinal Dystrophy • Muscular Dystrophy • Myositis • Myotonic Dystrophy • Ophthalmology

Tips to Design Effective Splice-Switching Antisense Oligonucleotides for Exon Skipping and Exon Inclusion. (PubMed, Methods Mol Biol) - "The approval of Exondys 51 (eteplirsen) and Spinraza (nusinersen) for the treatment of patients with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) was the most noteworthy accomplishment in 2016...The mechanism of mRNA splicing is highly complex, and the efficacy of AONs are often unpredictable. We will discuss the design of effective AONs for exon skipping and exon inclusion in this chapter."

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

Direct Reprogramming of Human DMD Fibroblasts into Myotubes for In Vitro Evaluation of Antisense-Mediated Exon Skipping and Exons 45-55 Skipping Accompanied by Rescue of Dystrophin Expression. (PubMed, Methods Mol Biol) - "To overcome these challenges, researchers can generate myofibers from patient fibroblast cells by transducing the cells with a viral vector containing MyoD, a myogenic regulatory factor. Here, we describe a methodology for assessing dystrophin exons 45-55 multiple skipping efficiency using antisense oligonucleotides in human muscle cells derived from DMD patient fibroblast cells."

Journal • Preclinical • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Creation of DMD Muscle Cell Model Using CRISPR-Cas9 Genome Editing to Test the Efficacy of Antisense-Mediated Exon Skipping. (PubMed, Methods Mol Biol) - "The approval of Exondys 51 (eteplirsen) targeting exon 51 was the most noteworthy accomplishment in 2016...Furthermore, many DMD mutations are very rare and it is hard to find a patient with a specific mutation for muscle biopsy in many cases. Here, we describe a novel approach to create an immortalized muscle cell line with a DMD deletion mutation using the human rhabdomyosarcoma (RD) cell line and the CRISPR/Cas9 system that can be used to test the efficacy of exon skipping."

Journal • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor

In Vivo Evaluation of Multiple Exon Skipping with Peptide-PMOs in Cardiac and Skeletal Muscles in Dystrophic Dogs. (PubMed, Methods Mol Biol) - "The FDA conditionally approved the first exon skipping AON, called eteplirsen (brand name ExonDys51), targeting exon 51 of the DMD gene, in late 2016...Although the success of multiple exon skipping in a DMD dog model has made a significant impact on the development of therapeutics for DMD, unmodified AONs such as phosphorodiamidate morpholino oligomers (PMOs) have little efficacy in cardiac muscles. Here, we describe the systemic delivery of a cocktail of peptide-conjugated PMOs (PPMOs) to skip multiple exons in both skeletal and cardiac muscles in dystrophic dogs and the evaluation of the efficacies and toxicity in vivo."

Journal • Preclinical • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Patient With Duchenne Muscular Dystrophy Who Tolerated Viltolarsen After Prior Anaphylaxis to Golodirsen. (PubMed, Muscle Nerve) - No abstract available

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Systemic Injection of Peptide-PMOs into Humanized DMD Mice and Detection by RT-PCR and ELISA. (PubMed, Methods Mol Biol) - "Researchers have previously relied on high-performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC/MS) methods for detecting PPMO uptake, but an enzyme-linked immunosorbent assay (ELISA) has been shown to have greater sensitivity. Here, we present methodologies to determine the uptake efficiency of a PPMO into the heart and efficacy of exon 51 skipping by a PPMO injected retro-orbitally into a humanized DMD mouse model via ELISA and RT-PCR, respectively."

Journal • Preclinical • Becker Muscular Dystrophy • Cardiovascular • Congestive Heart Failure • Duchenne Muscular Dystrophy • Genetic Disorders • Heart Failure • Muscular Dystrophy • Respiratory Diseases

Quantitative Evaluation of Exon Skipping in Immortalized Muscle Cells in Vitro. (PubMed, Methods Mol Biol) - "This is the case with eteplirsen, an exon 51-skipping AO that is the first and only FDA-approved drug for DMD to date...Aside from allowing for the quantitative evaluation of candidate AOs based on their exon skipping efficiency and dystrophin protein rescue levels, these immortalized cells are stable, pure, easy to grow, and not subject to confounding by senescence-related issues. This procedure enables a more reliable screening of AOs prior to their entry in clinical trials and greatly facilitates the search for more efficacious candidate exon skipping AOs for DMD treatment."

Journal • Preclinical • Becker Muscular Dystrophy • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Evolution and Breakthroughs in Exon Skipping and Splice Modulation: From Inception to Clinical Success. (PubMed, Methods Mol Biol) - "The FDA has approved several AO therapies using exon skipping, including eteplirsen, viltolarsen, casimersen, and golodirsen for DMD and nusinersen for SMA. This chapter explores the early history, evolution, and clinical applications of AO-based splice modulation therapies, focusing on exon skipping, one of the most developed strategies."

Journal • Developmental Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Rare Diseases

Real-world phosphorodiamidate morpholino oligomer treatment patterns in Duchenne muscular dystrophy: a claims-based analysis. (PubMed, J Comp Eff Res) - "Male patients with ≥1 claim for a PMO approved for DMD in the US (eteplirsen, casimersen, golodirsen and viltolarsen) were included. In an analysis of administrative claims data, adherence to PMO treatment for DMD was high. For patients with a gap in PMO claims, most subsequently re-initiated treatment, indicating lower discontinuation rates than previously reported."

Journal • Real-world evidence • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Clinical applications of exon skipping antisense oligonucleotides in neuromuscular diseases. (PubMed, Mol Ther) - "Four exon skipping antisense oligonucleotides (ASOs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Duchenne muscular dystrophy (DMD), including eteplirsen, golodirsen, viltolarsen and casimersen. Many of these newly developed exon skipping ASOs have been studied in clinical trials in DMD patients, and early findings suggest clear improvements in molecular efficacy compared to the earlier version of ASOs, although the safety track record may not be the same as the first generation compounds. Here, we summarise the recent preclinical and clinical developments of ASOs and discuss the future challenges of exon skipping therapies for DMD and other neuromuscular diseases."

Journal • Review • CNS Disorders • Duchenne Muscular Dystrophy • 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

Golodirsen restores DMD transcript imbalance in Duchenne Muscular Dystrophy patient muscle cells. (PubMed, Skelet Muscle) - "All these findings suggest challenges other than AON delivery for high level of protein restoration in DMD, highlighting the importance of investigating the biological mechanisms upstream of protein production to further enhance the efficiency of any AON treatment in this condition."

Journal • 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

ESSENCE: Study of SRP-4045 (Casimersen) and SRP-4053 (Golodirsen) in Participants With Duchenne Muscular Dystrophy (DMD) (clinicaltrials.gov) - P3 | N=228 | Active, not recruiting | Sponsor: Sarepta Therapeutics, Inc. | Trial primary completion date: Oct 2025 ➔ Nov 2024

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

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

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

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

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

Increase in Full-Length Dystrophin by Exon Skipping in Duchenne Muscular Dystrophy Patients with Single Exon Duplications: An Open-label Study. (PubMed, J Neuromuscul Dis) - "We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications."

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

Six-Year Long-Term Safety and Efficacy of Golodirsen in Patients With DMD vs Mutation-Matched External Controls (MDA 2024) - P1/2, P3 | "Overall, golodirsen treatment up to ~6 years demonstrates a favorable, consistent safety profile and supports its long-term efficacy vs mutation-matched ECs. This is the longest follow-up of safety and functional benefit of golodirsen in a declining DMD population."

Clinical • Duchenne Muscular Dystrophy • Genetic Disorders • Infectious Disease • Muscular Dystrophy

Characteristics of Patients Receiving Novel Muscular Dystrophy Drugs in Trials vs Routine Care. (PubMed, JAMA Netw Open) - "This cross-sectional study collected data on patients who initiated 1 of 4 novel DMD treatments (eteplirsen, golodirsen, viltolarsen, and casimersen) using national claims databases of commercially insured (Merative MarketScan and Optum's Clinformatics Data Mart Database [CDM]) and Medicaid patients between September 19, 2016, and March 31, 2022. These findings raise questions about the translation of DMD drug trial findings to routine care settings, with patients in routine care discontinuing the treatment within 1 year and payers incurring substantial expenses for these medications. More data are needed on whether these high costs are accompanied by corresponding clinical benefits."

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Advances in Dystrophinopathy Diagnosis and Therapy. (PubMed, Biomolecules) - "Pharmacological therapy for dystrophinopathies comprises glucocorticoids (prednisone, prednisolone, and deflazacort), vamorolone, and ataluren...Eteplirsen, an antisense-oligonucleotide drug for skipping exon 51 from the Dystrophin gene, is available on the market, which may help up to 14% of Duchenne muscular dystrophy patients. There are various FDA-approved exon skipping drugs including ExonDys-51 for exon 51, VyonDys-53 and Viltolarsen for exon 53 and AmonDys-45 for exon 45 skipping. Other antisense oligonucleotide drugs in the pipeline include casimersen for exon 45, suvodirsen for exon 51, and golodirsen for exon 53 skipping. Advances in the diagnosis and therapy of dystrophinopathies offer new perspectives for their early discovery and care."

Journal • Review • Becker Muscular Dystrophy • Cardiomyopathy • Cardiovascular • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy • Osteoporosis • Rheumatology