- |||||||||| Journal: Characteristics of Patients Receiving Novel Muscular Dystrophy Drugs in Trials vs Routine Care. (Pubmed Central) - Jan 24, 2024
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.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Amondys 45 (casimersen) / Sarepta Therap
Trial completion: 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) - Oct 12, 2023
P2, N=3, Completed,
More data are needed on whether these high costs are accompanied by corresponding clinical benefits. Active, not recruiting --> Completed
- |||||||||| Review, Journal: Advances in Dystrophinopathy Diagnosis and Therapy. (Pubmed Central) - Oct 4, 2023
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.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Amondys 45 (casimersen) / Sarepta Therap
Enrollment change, Trial completion date, Trial termination, Trial primary completion date: An Extension Study to Evaluate Casimersen or Golodirsen in Patients With Duchenne Muscular Dystrophy (clinicaltrials.gov) - Aug 21, 2023
P3, N=171, Terminated,
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.
- |||||||||| Review, Journal: The potential role and mechanism of circRNA/miRNA axis in cholesterol synthesis. (Pubmed Central) - Jun 20, 2023
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.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Exondys 51 (eteplirsen) / Sarepta Therap, Viltepso (viltolarsen) / Nippon Shinyaku
Preclinical, Journal: In Vivo Evaluation of Exon 51 Skipping in hDMD/Dmd-null Mice. (Pubmed Central) - Apr 4, 2023
A solution to this issue is to use double mutant hDMD/Dmd-null mice, which only carry the human DMD sequence and are null for the mouse Dmd sequence. Here, we describe intramuscular and intravenous injections of an ASO to skip exon 51 in hDMD/Dmd-null mice, and the evaluation of its efficacy in vivo.
- |||||||||| Review, Journal: Recent Trends in Antisense Therapies for Duchenne Muscular Dystrophy. (Pubmed Central) - Mar 30, 2023
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.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Amondys 45 (casimersen) / Sarepta Therap
Trial completion date, Trial primary completion date: ESSENCE: Study of SRP-4045 (Casimersen) and SRP-4053 (Golodirsen) in Participants With Duchenne Muscular Dystrophy (DMD) (clinicaltrials.gov) - Feb 21, 2023
P3, N=229, Active, not recruiting,
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. Trial completion date: Apr 2024 --> Oct 2025 | Trial primary completion date: Apr 2024 --> Oct 2025
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Amondys 45 (casimersen) / Sarepta Therap
Trial completion date: 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) - Nov 29, 2022
P2, N=3, Active, not recruiting,
Recruiting --> Active, not recruiting Trial completion date: Sep 2022 --> Sep 2023
- |||||||||| Journal: Restoring Dystrophin Expression by Skipping Exons 6 and 8 in Neonatal Dystrophic Dogs. (Pubmed Central) - Nov 20, 2022
In this chapter, we describe the systemic delivery of a cocktail of four PMOs that can successfully induce multiple exon skipping (exons 6-9) in neonatal dystrophic dogs. We also describe the procedures to evaluate the efficacy and toxicity, including clinical grading of dystrophic dogs, ELISA-based quantification of PMOs, histology, RT-PCR, and western blotting.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, NS-089/NCNP-02 / Nippon Shinyaku, National Center of Neurology and Psychiatry, Viltepso (viltolarsen) / Nippon Shinyaku
Journal: Restoring Dystrophin Expression with Exon 44 and 53 Skipping in the DMD Gene in Immortalized Myotubes. (Pubmed Central) - Nov 20, 2022
Two exon 53 skipping PMOs, golodirsen and viltolarsen, have received conditional approval for treating patients due to their ability to restore dystrophin protein expression...We introduce how to quantify exon-skipping efficiencies and dystrophin rescue levels represented by RT-PCR and western blotting, respectively. The screening methods using immortalized patient myotubes can serve to find exon-skipping PMO drug candidates.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Exondys 51 (eteplirsen) / Sarepta Therap, Amondys 45 (casimersen) / Sarepta Therap
Interim analysis of EVOLVE: a long-term observational study evaluating Eteplirsen, Golodirsen, or Casimersen in routine clinical practice (Virtual platform and E-Posters only) - Nov 5, 2022 - Abstract #WMS2022WMS_519;
Median age at LOA for eteplirsen-treated patients is 15.3 years, consistent with prior clinical trial post-hoc results; small sample size to date precludes analysis of age at LOA for golodirsen or casimersen. 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.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap
Golodirsen induced DMD transcripts localization and dystrophin production in MyoD-converted fibroblasts from 4053-101 clinical trial patients (Poster area - Ballroom B1-B2) - Aug 20, 2022 - Abstract #WMS2022WMS_311;
Next, we used an in-situ RNA hybridization technique, BaseScope, to investigate the sub-cellular localization of the DMD transcript in treated and non-treated differentiated patient-derived myogenic cells in vitro, which allowed us to assess the ratio of skipped and unskipped products. Our study provides additional information on the dynamics of DMD mRNA in patients and may help to better understand the biological reasons underpinning variability in dystrophin restoration that can be seen in AON clinical trials.
- |||||||||| FDA event, Journal: Absorption, distribution, metabolism, and excretion of FDA-approved antisense oligonucleotide drugs. (Pubmed Central) - Jun 25, 2022
Significance Statement Through a systematic analysis of the existing information of ADME parameters for ten FDA-approved ASO drugs, this review provides an overall view of the unique ADME characteristics of ASO drugs, which are distinct from small chemical drug ADME. This knowledge is useful for discovery and development of new ASO drugs as well as clinical use of current FDA-approved ASO drugs.
- |||||||||| FDA event, Journal, Adverse drug reaction: Adverse Drug Reactions and Toxicity of the FDA-approved Antisense Oligonucleotide Drugs. (Pubmed Central) - Jun 25, 2022
Significance Statement The current review provides a comprehensive analysis of unique and common ADRs and the toxicity of FDA-approved ASO drugs. The information can help better manage the risk of severe hepatotoxicity, kidney toxicity, and hypersensitivity reactions in the usage of currently approved ASO drugs and the discovery and development of new and safer ASO drugs.
- |||||||||| FDA event, Journal: Absorption, Distribution, Metabolism, and Excretion of FDA-approved Antisense Oligonucleotide Drugs. (Pubmed Central) - May 14, 2022
The summarized information provides the most updated knowledge of ADME characteristics of these ASO drugs, leading to a better understanding of their therapeutic efficacy and potential ADRs and toxicity. Numerous knowledge gaps, particularly on cellular uptake and subcellular trafficking and distributions are identified and future perspective and directions are discussed.
- |||||||||| Journal: Evaluation of DNA segments in 2'-modified RNA sequences in designing efficient splice switching antisense oligonucleotides. (Pubmed Central) - Apr 19, 2022
Although systemic delivery of PMOs has displayed a good safety profile even at high doses, the 2'-O-methyl phosphorothioate modified (2'-OMe PS) ASO drug candidate (drisapersen) failed due to safety issues...Our results demonstrated that 2'-modified RNA PS ASOs containing four or less PS DNA nucleotides at the 3'-end yielded improved exon 23 skipping efficacy in line with fully modified ASO controls. Based on these results, we firmly believe that the present study opens new avenues towards designing splice modulating ASOs with limited chemical modifications for enhanced safety and therapeutic efficacy.
- |||||||||| Preclinical, Journal: Evaluation of Exon Skipping and Dystrophin Restoration in In Vitro Models of Duchenne Muscular Dystrophy. (Pubmed Central) - Mar 4, 2022
Preclinical screening of the new oligonucleotide sequences is routinely performed using patient-derived cell cultures, and evaluation of their efficacy may be performed at RNA and/or protein level. While several methods to assess exon skipping and dystrophin expression in cell culture have been developed, the choice of methodology often depends on the availability of specific research equipment.In this chapter, we describe and indicate the relevant bibliography of all the methods that may be used in this evaluation and describe in detail the protocols routinely followed at our institution, one to evaluate the efficacy of skipping at RNA level (nested PCR) and the other the restoration of protein expression (myoblot ), which provide good results using equipment largely available to most research laboratories.
- |||||||||| Review, Journal: Deliver the promise: RNAs as a new class of molecular entities for therapy and vaccination. (Pubmed Central) - Feb 12, 2022
By overviewing individual RNA medications and vaccines approved by the FDA and some agents under development, we illustrate the unique compositions and pharmacological actions of RNA products. A new era of RNA research and development will likely lead to commercialization of more RNA agents for medical use, expanding the range of therapeutic targets and increasing the diversity of molecular modalities.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Viltepso (viltolarsen) / Nippon Shinyaku
Journal: Emerging Oligonucleotide Therapeutics for Rare Neuromuscular Diseases. (Pubmed Central) - Feb 4, 2022
Very recently, golodirsen and viltolarsen, for treatment of DMD patients amenable to skipping exon 53, have been approved by regulatory agencies in the USA and Japan, respectively. Here, we review scientific and clinical progress in developing new oligonucleotide therapeutics for selected rare neuromuscular diseases, discussing their efficacy and limitations.
- |||||||||| Journal: Interrogation of Dystrophin and Dystroglycan Complex Protein Turnover After Exon Skipping Therapy. (Pubmed Central) - Dec 21, 2021
In contrast, DGC proteins show constant turnover attributable to myofiber degeneration and dysregulation of the extracellular matrix (ECM) in dystrophic muscle. Based on our results, we demonstrate the use of targeted mass spectrometry to evaluate the suitability and functionality of restored dystrophin isoforms in the context of disease and propose its use to optimize alternative gene correction strategies in development for DMD.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Amondys 45 (casimersen) / Sarepta Therap
Enrollment closed: 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) - Oct 12, 2021
P2, N=3, Active, not recruiting,
Our results provide, for the first time, evidence of functionality of induced dystrophin following successful therapeutic intervention in the human. Enrolling by invitation --> Active, not recruiting
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Exondys 51 (eteplirsen) / Sarepta Therap, Viltepso (viltolarsen) / Nippon Shinyaku
Review, Journal: Optimization of antisense-mediated exon skipping for Duchenne muscular dystrophy. (Pubmed Central) - Aug 20, 2021
Viltolarsen, an AON for DMD exon 53 skipping, was approved in Japan earlier this year...This article reviews and discusses exon skipping and the current advances being made in the field, on drugs, multi-exon skipping, sequence design, and applicability. We also discuss challenges and future directions that will facilitate the development of exon skipping therapy.
- |||||||||| Amondys 45 (casimersen) / Sarepta Therap
Journal: Casimersen (Amondys 45) for Duchenne muscular dystrophy. (Pubmed Central) - Jul 14, 2021
In light of promising functional improvements, antisense and gene therapies stand poised to elevate the lives of patients with DMD and SMA. No abstract available
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap
Trial completion date, Trial termination, Trial primary completion date: An Open-Label Study of Golodirsen in Non-Ambulant Patients With Duchenne Muscular Dystrophy (clinicaltrials.gov) - May 17, 2021
P4, N=2, Terminated,
In this review, we summarize the possible therapeutic options and describe the current status of various, still imperfect, strategies used for attenuating the disease progression. Trial completion date: Oct 2023 --> May 2021 | Active, not recruiting --> Terminated | Trial primary completion date: Oct 2023 --> May 2021; The Sponsor has decided to focus their resources on other areas of therapy.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Translarna (ataluren) / PTC Therap, Exondys 51 (eteplirsen) / Sarepta Therap
Review, Journal: Is it the right time for an infant screening for Duchenne muscular dystrophy? (Pubmed Central) - May 15, 2021
Five to eight DMD subjects are believed to be diagnosed. The pilot project would give the opportunity to test in a small population the feasibility of an infant screening programme, which in the near future could be applicable to an entire country.
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