- |||||||||| vesleteplirsen (SRP-5051) / Sarepta Therap, Exondys 51 (eteplirsen) / Sarepta Therap
Enrollment change, Trial completion date, Trial primary completion date: MOMENTUM: Two-Part Study for Dose Determination of Vesleteplirsen (SRP-5051) (Part A), Then Dose Efficacy (Part B) in Participants With Duchenne Muscular Dystrophy Amenable to Exon 51-Skipping Treatment (clinicaltrials.gov) - Jan 7, 2021
P2, N=70, Recruiting,
Furthermore, other reported AhR antagonists also upregulate utrophin, showing that this pathway, which is currently being explored in other clinical applications including oncology and rheumatoid arthritis, could also be exploited in future DMD therapies. N=45 --> 70 | Trial completion date: Aug 2021 --> May 2022 | Trial primary completion date: Aug 2021 --> May 2022
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap, Calcort (deflazacort) / Sanofi
Journal: Medical management of muscle weakness in Duchenne muscular dystrophy. (Pubmed Central) - Dec 20, 2020
The options available for medical management of the motor symptoms of DMD are expanding rapidly. The choice of medical therapies should balance expected benefit with side effects.
- |||||||||| ezutromid (SMT C1100) / Sarepta Therap
Journal: Decreasing HepG2 Cytotoxicity by Lowering the Lipophilicity of Benzo[d]oxazolephosphinate Ester Utrophin Modulators. (Pubmed Central) - Dec 19, 2020
To improve the suboptimal profile of ezutromid, the first-in-class clinical candidate, a second generation of utrophin modulators bearing a phosphinate ester moiety was developed...Notably, ClogP was found to directly correlate with pIC in HepG2 cells, hence leading to a potentially safer toxicological profiles in this series. Compound 21 showed a balanced profile (H2K EC: 4.17 μM, solubility: 477 μM, mouse hepatocyte T > 240 min) and increased utrophin protein 1.6-fold in a Western blot assay.
- |||||||||| Idefirix (imlifidase) / Hansa Biopharma, Sarepta Therap
Enrollment closed: A Follow up Study of Patients Treated With Imlifidase Prior to Kidney Transplantation (clinicaltrials.gov) - Dec 17, 2020
P=N/A, N=39, Active, not recruiting,
Compound 21 showed a balanced profile (H2K EC: 4.17 μM, solubility: 477 μM, mouse hepatocyte T > 240 min) and increased utrophin protein 1.6-fold in a Western blot assay. Recruiting --> Active, not recruiting
- |||||||||| ezutromid (SMT C1100) / Sarepta Therap
Journal: 2-Arylbenzo[d]oxazole phosphinate esters as second-generation modulators of utrophin for the treatment of Duchenne Muscular Dystrophy. (Pubmed Central) - Dec 16, 2020
The improved physicochemical and ADME properties, further reflected in the enhanced pharmacokinetic profile of the most advanced compounds, 30 and 27, led to significantly better in vivo exposure compared to ezutromid, and alleviation of the dystrophic phenotype in mdx mice. While 30 was found to have dose-limiting hepatotoxicity, 27 and its enantiomers exhibited limited off-target effects, resulting in a safe profile and highlighting their potential utility as next generation utrophin modulators suitable for progression towards a future DMD therapy.
- |||||||||| Viltepso (viltolarsen) / Nippon Shinyaku, SRP-4052 / Sarepta Therap
Clinical, Journal: Characterizing Exon Skipping Efficiency in DMD Patient Samples in Clinical Trials of Antisense Oligonucleotides. (Pubmed Central) - Dec 16, 2020
In this methods article, we present the molecular characterization of dystrophin expression using Sanger sequencing, RT-PCR, and western blotting in the clinical trial. The characterization of dystrophin expression was fundamental in the study for showing the efficacy since no functional outcome tests were performed.
- |||||||||| Idefirix (imlifidase) / Hansa Biopharma, Sarepta Therap
Trial completion date, Trial primary completion date: A Study of Imlifidase in Patients With Guillain-Barré Syndrome (clinicaltrials.gov) - Dec 10, 2020
P2, N=30, Recruiting,
The characterization of dystrophin expression was fundamental in the study for showing the efficacy since no functional outcome tests were performed. Trial completion date: Sep 2021 --> Dec 2022 | Trial primary completion date: Sep 2021 --> Dec 2022
- |||||||||| SRP-4055 / Sarepta Therap, DMD exon 55 skipping program / Wave Life Sciences
Journal: Morpholino Oligomer-Induced Dystrophin Isoforms to Map the Functional Domains in the Dystrophin Protein. (Pubmed Central) - Nov 27, 2020
Here, we induced "Becker muscular dystrophy-like" in-frame dystrophin isoforms in vivo by intraperitoneal injection of peptide-conjugated phosphorodiamidate morpholino oligomers targeting selected exons. The dystrophin isoform encoded by the transcript lacking exons 56+57 appears to be more functional than that encoded by the 58+59-deleted transcript, as determined by higher dystrophin expression, stabilized β-dystroglycan, and less severe dystrophic pathology, indicating some potential for the strategy to address Duchenne-causing mutations affecting these exons.
- |||||||||| scAAV1.tMCK.NTF3 / Sarepta Therap
Enrollment open: Phase I/IIa Trial of scAAV1.tMCK.NTF3 for Treatment of CMT1A (clinicaltrials.gov) - Nov 19, 2020
P1/2, N=3, Recruiting,
The dystrophin isoform encoded by the transcript lacking exons 56+57 appears to be more functional than that encoded by the 58+59-deleted transcript, as determined by higher dystrophin expression, stabilized β-dystroglycan, and less severe dystrophic pathology, indicating some potential for the strategy to address Duchenne-causing mutations affecting these exons. Not yet recruiting --> Recruiting
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap
Journal: Golodirsen for Duchenne muscular dystrophy. (Pubmed Central) - Oct 8, 2020
This article summarizes golodirsen's pharmacology, efficacy and safety information. It also discusses some controversies that golodirsen met after the approval.
- |||||||||| [VIRTUAL] FUNCTIONAL CORRECTION OF W1282X-CFTR THROUGH EXON 23 SKIPPING AND PHARMACOLOGICAL MODULATION () - Oct 7, 2020 - Abstract #NACFC2020NACFC_414;
Duchenne muscular dystrophy patients with certain mutations can be treated with the drug eteplirsen, which achieves exon skipping with antisense oligonucleotides (ASOs)...Most notably, these exon 23 skipped cell lines had 0-2% of wild-type (WT) CFTR function, which could be boosted to ~15% when treated with CFTR modulators (24-hour VX-661/VX-445 and acute VX-770)...An additional 14 other known CF-causing CFTR mutations in exon 23 (CFTR2 database) may also benefit from this approach. Characterization of the results of exon 24 skipping, within the context of the CF-causing CFTR variant N1303K, are ongoing.
- |||||||||| DMD exon 52 skipping program / Wave Life Sciences, SRP-4052 / Sarepta Therap
[VIRTUAL] DEVELOPING AN EFFECTIVE EXONS 45-55 SKIPPING THERAPY FOR DUCHENNE MUSCULAR DYSTROPHY (Live + Q&A) - Oct 4, 2020 - Abstract #CCCCanada2020CCC_Canada_114;
We developed an exons 45-55 skipping cocktail effective in restoring dystrophin synthesis in patient-derived myotubes, and have identified a peptide to enhance the in vivo efficacy of this cocktail. Future work will test the effects of this DG9-conjugated cocktail on a novel DMD mouse model we are currently characterizing.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap
Review, Journal: Golodirsen: First Approval. (Pubmed Central) - Oct 3, 2020
Golodirsen is in phase III clinical development for the treatment of DMD worldwide. This article summarizes the milestones in the development of golodirsen leading to this first approval for DMD.
- |||||||||| Review, Journal: RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges. (Pubmed Central) - Oct 2, 2020
A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets...Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials...SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.
- |||||||||| Elevidys (delandistrogene moxeparvovec) / Sarepta Therap, Roche
Trial completion date, Trial primary completion date: A Randomized, Double-blind, Placebo-controlled Study of Delandistrogene Moxeparvovec (SRP-9001) for Duchenne Muscular Dystrophy (DMD) (clinicaltrials.gov) - Oct 1, 2020
P2, N=41, Active, not recruiting,
This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges. Trial completion date: Oct 2022 --> Apr 2026 | Trial primary completion date: Oct 2022 --> Dec 2020
- |||||||||| Idefirix (imlifidase) / Hansa Biopharma, Sarepta Therap
Trial completion, Trial completion date, Trial primary completion date: GOOD-IDES: Open-Label Phase II Study to Evaluate the Efficacy and Safety of IdeS in Anti-GBM Disease (clinicaltrials.gov) - Sep 24, 2020
P2, N=15, Completed,
We describe the rare case of a 13-year-old patient who was non-ambulatory for 18 months and receiving eteplirsen, an exon-skipping drug (Sarepta Therapeutics, Inc., Cambridge, MA), who regained household and classroom ambulation following surgical management of his equinus contractures. Recruiting --> Completed | Trial completion date: Mar 2019 --> Jul 2020 | Trial primary completion date: Mar 2019 --> Jul 2020
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap
Clinical, Journal: Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy. (Pubmed Central) - Sep 23, 2020
P1/2
Recruiting --> Completed | Trial completion date: Mar 2019 --> Jul 2020 | Trial primary completion date: Mar 2019 --> Jul 2020 Golodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Exondys 51 (eteplirsen) / Sarepta Therap, Viltepso (viltolarsen) / Nippon Shinyaku
Journal: Molecular Diagnosis and Novel Therapies for Neuromuscular Diseases. (Pubmed Central) - Sep 22, 2020
Personalized genetic medicine for neuromuscular diseases faces several key challenges, including the difficulty of obtaining appropriate cell and animal models and limited its applicability. This Special Issue "Molecular Diagnosis and Novel Therapies for Neuromuscular/Musculoskeletal Diseases" highlights key areas of research progress that improve our understanding and the therapeutic outcomes of neuromuscular diseases in the personalized medicine era.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap
Journal: Golodirsen (Vyondys 53) for Duchenne muscular dystrophy. (Pubmed Central) - Sep 20, 2020
This Special Issue "Molecular Diagnosis and Novel Therapies for Neuromuscular/Musculoskeletal Diseases" highlights key areas of research progress that improve our understanding and the therapeutic outcomes of neuromuscular diseases in the personalized medicine era. No abstract available
- |||||||||| SRP-4052 / Sarepta Therap
Journal: Dominant collagen XII mutations cause a distal myopathy. (Pubmed Central) - Sep 8, 2020
This study characterizes a distal myopathy phenotype in adults with dominant COL12A1 pathogenic variants, further defining the phenotypic spectrum and natural history of COL12A1-related myopathies. This work also provides proof of concept of a precision medicine treatment approach by proposing and validating allele-specific knockdown using siRNAs specifically designed to target a patient's dominant COL12A1 disease allele.
- |||||||||| Translarna (ataluren) / PTC Therapeutics, Sanofi, Exondys 51 (eteplirsen) / Sarepta Therap
Review, Journal: Therapies that are available and under development for Duchenne muscular dystrophy: What about lung function? (Pubmed Central) - Sep 5, 2020
With regard to new therapeutic agents, initial study results are encouraging. However, larger clinical trials are needed that minimize the risk of study bias, optimize the comparability of treatment groups, examine clinically meaningful pulmonary outcome measures, and include long-term follow up.
- |||||||||| ezutromid (SMT C1100) / Sarepta Therap
Journal: Isolation, structural identification, synthesis, and pharmacological profiling of 1,2-trans-dihydro-1,2-diol metabolites of the utrophin modulator ezutromid. (Pubmed Central) - Sep 1, 2020
Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis and their production in in vitro systems. We further elucidate the likely metabolic pathway and CYP450 isoforms responsible for DHD1 and DHD3 production and characterise their physicochemical, ADME, pharmacological properties and preliminary toxicological profile.
|
