Amondys 45 (casimersen) / Sarepta Therap - LARVOL DELTA

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

Casimersen (AMONDYS 45™): An Antisense Oligonucleotide for Duchenne Muscular Dystrophy. (PubMed, Biomedicines) - "While casimersen is currently continuing in phase III of clinical trials in various countries, it was granted approval by the FDA under the accelerated approval program due to its observed increase in dystrophin production. This article discusses the pathophysiology of DMD, summarizes available treatments thus far, and provides a full drug review of casimersen (AMONDYS 45TM)."

Journal • Review • CNS Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

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

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

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

AMONDYS 45 (Casimersen), a Novel Antisense Phosphorodiamidate Morpholino Oligomer: Clinical Considerations for Treatment in Duchenne Muscular Dystrophy. (PubMed, Cureus) - "These collective findings indicate that casimersen has the potential to elicit functional changes in individuals with DMD, although further studies are necessary to comprehensively evaluate the specific functional improvements. Regardless, the FDA approval and ongoing clinic trials mark a significant milestone in the development of DMD treatments and offer hope for those affected by this debilitating disease."

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

A 48-Week, Open Label, Study to Evaluate the Efficacy and Safety of AMONDYS 45, EXONDYS 51, VYONDYS 53 in Subjects With DuchenneMuscular Dystrophy Carrying Eligible DMD Duplications. (clinicaltrials.gov) - P2 | N=3 | Completed | Sponsor: Kevin Flanigan | Active, not recruiting ➔ Completed

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

Delandistrogene moxeparvovec (Elevidys) for Duchenne muscular dystrophy. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

An Extension Study to Evaluate Casimersen or Golodirsen in Patients With Duchenne Muscular Dystrophy (clinicaltrials.gov) - P3 | N=171 | Terminated | Sponsor: Sarepta Therapeutics, Inc. | N=260 ➔ 171 | Trial completion date: Aug 2026 ➔ Jul 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Aug 2026 ➔ Jul 2023; Participants were either transitioned to a post-trial access program or another Sarepta study, or they declined further treatment. There were no safety concerns with this study.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Interim analysis of EVOLVE: evaluating Eteplirsen, Golodirsen, or Casimersen treatment in patients <7 years old in routine clinical practice (WMS 2023) - No abstract available

Clinical

An Extension Study to Evaluate Casimersen or Golodirsen in Patients With Duchenne Muscular Dystrophy (clinicaltrials.gov) - P3 | N=260 | Active, not recruiting | Sponsor: Sarepta Therapeutics, Inc. | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

The potential role and mechanism of circRNA/miRNA axis in cholesterol synthesis. (PubMed, Int J Biol Sci) - "Interestingly, many small nucleic acid drugs and vaccines were approved for the market, including Inclisiran, Patisiran, Inotersen, Givosiran, Lumasiran, Nusinersen, Volanesorsen, Eteplirsen, Golodirsen, Viltolarsen, Casimersen, Elasomeran, Tozinameran. Suppressing HMGCR, SQLE, and miR-122 with circRNA_ABCA1, circ-PRKCH, circEZH2, circRNA-SCAP, and circFOXO3 are the promising therapeutic target for drug development, specifically the circFOXO3. This review focuses on the role and mechanism of the circRNA/miRNA axis in cholesterol synthesis in the hope of providing knowledge to identify new targets."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • ABCA1 • DHCR7 • FDFT1 • FOXO3 • HMGCS1 • MIR122 • PRKCH • PTEN • SC5D • YWHAG

Interim Analysis of EVOLVE: A Long-term Observational Study Evaluating Eteplirsen, Golodirsen, or Casimersen in Routine Clinical Practice (EPNS 2023) - "These real-world data from the interim analysis of EVOLVE support the safety profiles and will continue to describe long-term clinical outcomes of eteplirsen, golodirsen, and casimersen."

Clinical • Observational data • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Recent Trends in Antisense Therapies for Duchenne Muscular Dystrophy. (PubMed, Pharmaceutics) - "These upcoming therapies often utilize novel drug chemistries to address limitations of existing therapies, and their development could herald the next generation of antisense therapy. This review article aims to summarize the current state of development for antisense-based therapies for the treatment of Duchenne muscular dystrophy, exploring candidates designed for both exon skipping and gene knockdown."

Journal • Review • 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

A 48-Week, Open Label, Study to Evaluate the Efficacy and Safety of Casimersen, Eteplirsen and Golodirsen in Subjects With Duchenne Muscular Dystrophy Carrying Eligible DMD Duplications (clinicaltrials.gov) - P2 | N=3 | Active, not recruiting | Sponsor: Kevin Flanigan | Trial completion date: Sep 2022 ➔ Sep 2023

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