Vyondys 53 (golodirsen) / Sarepta Therapeutics - LARVOL DELTA

EXPERT CONSENSUS ON TREATMENT GUIDANCE FOR FDA-APPROVED AND SECOND-GENERATION EXON-SKIPPING THERAPIES IN DUCHENE MUSCULAR DYSTROPHY (DMD): A RAND/UCLA MODIFIED DELPHI PANEL (ISPOR 2026) - "We aimed to characterize the current therapeutic landscape for DMD, including exon-skipping therapies, gene therapy, and givinostat, as well as emerging second-generation exon-skipping agents. Using the RAND/UCLA modified Delphi panel method, nine US experts (seven pediatric neurologists, two physical therapists) rated the likelihood of recommending FDA-approved therapies (eteplirsen, golodirsen, viltolarsen, casimersen, GT, givinostat) and the anticipated clinical value of investigational therapies with Phase 1/2 data (delpacibart zotadirsen, DYNE-251, WVE-N531, and NS-089/NCNP-02)... The panel reached consensus that approved exon-skipping therapies provide modest benefit, particularly in earlier stages, while early data suggest that second-generation exon-skippers may have the potential to offer greater functional improvement. However, trials remain in early stages, and the full risks and benefits of these therapies are not yet known. The findings highlight the rapidly..."

Duchenne Muscular Dystrophy • Gene Therapies • 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=99 | Not yet recruiting | Sponsor: Sarepta Therapeutics | Initiation date: Feb 2016 ➔ Jun 2016

Trial initiation date • 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=99 | Not yet recruiting | Sponsor: Sarepta Therapeutics | Trial primary completion date: Apr 2018 ➔ Sep 2019

Trial primary completion date • 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=99 | Not yet recruiting | Sponsor: Sarepta Therapeutics

New P3 trial • 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=222 | Active, not recruiting | Sponsor: Sarepta Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Duchenne Muscular Dystrophy • Muscular Dystrophy

ESSENCE: Study of SRP-4045 (Casimersen) and SRP-4053 (Golodirsen) in Participants With Duchenne Muscular Dystrophy (DMD) (clinicaltrials.gov) - P3 | N=222 | Recruiting | Sponsor: Sarepta Therapeutics | N=126 ➔ 222 | Trial completion date: Jun 2021 ➔ Jun 2023 | Trial primary completion date: Sep 2019 ➔ Jun 2022

Enrollment change • Trial completion date • Trial primary completion date • Duchenne Muscular Dystrophy • Muscular Dystrophy

ESSENCE: Study of SRP-4045 (Casimersen) and SRP-4053 (Golodirsen) in Participants With Duchenne Muscular Dystrophy (DMD) (clinicaltrials.gov) - P3 | N=222 | Recruiting | Sponsor: Sarepta Therapeutics | Active, not recruiting ➔ Recruiting

Enrollment open • 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=126 | Recruiting | Sponsor: Sarepta Therapeutics | N=99 ➔ 126

Enrollment change • 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=99 | Recruiting | Sponsor: Sarepta Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open • 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

ESSENCE: Study of SRP-4045 (Casimersen) and SRP-4053 (Golodirsen) in Participants With Duchenne Muscular Dystrophy (DMD) (clinicaltrials.gov) - P3 | N=229 | Active, not recruiting | Sponsor: Sarepta Therapeutics, Inc. | Trial completion date: Apr 2024 ➔ Oct 2025 | Trial primary completion date: Apr 2024 ➔ Oct 2025

Trial completion date • Trial primary completion date • 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=229 | Active, not recruiting | Sponsor: Sarepta Therapeutics, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • 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=222 | Recruiting | Sponsor: Sarepta Therapeutics, Inc. | Trial completion date: May 2023 ➔ Apr 2024 | Trial primary completion date: May 2022 ➔ Apr 2024

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

Small RNA or oligonucleotide drugs and challenges in evaluating drug-drug interactions. (PubMed, Front Pharmacol) - "Widespread adoption of these strategies has further enabled the application of oligonucleotides as viable drugs and expanded the class of RNA therapeutics, with thirteen antisense oligonucleotides (ASOs) (fomiversen, mipomersen, nusinersen, inotersen, eteplirsen, golodirsen, casimersen, viltolarsen, tofersen, eplontersen, olezarsen, and donidalorsen), seven small interfering RNAs (siRNAs) (patisiran, givosiran, lumasiran, inclisiran, vutrisiran, nedosiran, and fitusiran), and two aptamers (pegaptanib and avacincaptad pegol) that have been approved by the United States Food and Drug Administration (FDA). This article provides an overview of FDA-approved oligonucleotide therapies, emphasizing chemical modifications, molecular targets for mechanistic actions, and available ADME and PK/PD properties, followed by the discussion of critical needs for risk assessment strategies suited for this unique modality that focuses on possible DDIs with concomitant drugs. The latter may..."

Journal • Review

Anti-PF4 antibodies are a potential mediator of antisense oligonucleotide (ASO)-induced thrombocytopenia. (ASH 2025) - "Twelve ASOs, Inotersen, Eplontersen,Olezarsen, Fomivirsen, Mipomersen, Tofersen, Nusinersen, Eteplirsen, Golodirsen, Viltolarsen,Casimersen (all FDA approved) and Volanesorsen (EMA approved) were evaluated in this study. With two ASOs, Fomivirsen and Eteplirsen, direct activation of platelets was noted. Studieswith additional ASOs revealed a novel immune mechanism involving ASO-PF4 complex formation andanti-PF4 antibody recognition that can plausibly mediate ASO-induced thrombocytopenia. These findingshighlight the key role PS linkages may play in ASO immunogenicity and provide a mechanistic frameworkfor risk mitigation in ASO drug design, supporting the safer development and broader application of ASOtherapeutics."

Hematological Disorders • Thrombocytopenia

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

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

Nephrotoxicity of Antisense Oligonucleotide Therapies in Duchenne Muscular Dystrophy: A Warning or a Challenge? (ISPOR-EU 2025) - "In the US Golodirsen, Viltolarsen, Eteplirsen and Casimersen are approved (conditionally) to treat DMD...Specific cases include: i) Drisapersen, terminated due to a poor benefit-risk profile, with notable renal toxicity, ii) Vesleteplirsen, associated with severe hypomagnesemia and hypokalemia... Patients with DMD treated with ONA require vigilant renal monitoring. Recommendations include regular assessment of renal biomarkers (e.g., proteinuria, creatinine), adjustment of corticosteroids, and preference for inactivated or conjugated vaccines."

Duchenne Muscular Dystrophy • Genetic Disorders • Inflammation • Muscular Dystrophy • Nephrology • Rare Diseases • Renal Disease

The Utilization, Reimbursement, and Cost of Targeted Therapies for Duchenne Muscular Dystrophy (DMD) in US Medicaid Programs: A Descriptive Trend Analysis from 2017 to 2022. (PubMed, Pharmaceut Med) - "The considerable rise in the utilization and spending of novel DMD drugs has imposed a significant burden on the Medicaid budget, underlining the need for policy measures to manage rising costs and maintain equal access to treatment."

Journal • Reimbursement • US reimbursement • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

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