- |||||||||| ezutromid (SMT C1100) / Sarepta Therap
Clinical, P1 data, PK/PD data, Journal: A Phase 1b Trial to Assess the Pharmacokinetics of Ezutromid in Pediatric Duchenne Muscular Dystrophy Patients on a Balanced Diet. (Pubmed Central) - Aug 5, 2020
No severe or serious adverse events and no study discontinuations due to adverse events were reported. This study provides assurance that, with the formulation tested (F3) and instructions regarding food (balanced diet and whole-fat milk), 2500 mg BID of ezutromid achieves plasma concentrations that, based on preclinical studies, should be able to modulate utrophin expression in future clinical trials.
- |||||||||| ezutromid (SMT C1100) / Sarepta Therap
Preclinical, Journal: Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model. (Pubmed Central) - Jul 28, 2020
Following on from ezutromid, the first-in-class benzoxazole utrophin modulator that progressed to Phase 2 clinical trials for the treatment of Duchenne muscular dystrophy, a new chemotype was designed to optimise its physicochemical and ADME profile...The pharmacological properties of both enantiomers were evaluated in vitro and in vivo. No significant difference in the activity or efficacy was observed between the two enantiomers; activity was found to be comparable to the racemic mixture.
- |||||||||| SRP-4044 / Sarepta Therap
Journal: Repurposing Pathogenic Variants of DMD Gene and its Isoforms for DMD Exon Skipping Intervention. (Pubmed Central) - Jul 15, 2020
Exon 44/45 variations were found to be the most prominent among single exon variations, whereas exon 49/50 was found to be the most frequently mutated locations in single/multiple exon variations...A major proportion of DMD subjects (80%) could be diagnosed by the MLPA technique. The data generated from our study may be beneficial for strengthening of mutation database in the North Indian population.
- |||||||||| Journal: Therapeutic Oligonucleotides: State of the Art. (Pubmed Central) - Jul 9, 2020
Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Journal: New and emerging pharmacotherapy for duchenne muscular dystrophy: a focus on synthetic therapeutics. (Pubmed Central) - Jun 8, 2020
Many trials have identified cohorts who responded more favorably to medications, despite a lack of significance in the overall intent-to-treat populations. This indicates that more medication screening and personalized treatment with patient-specific targeting might deliver more clinically significant results.
- |||||||||| Idefirix (imlifidase) / Hansa Biopharma
[VIRTUAL] In-Vivo Application of Ides (Imlifidase) in Nonhuman Primates Results in Xenoreactive Desensitization: A Novel Anti-Humoral Therapy (Virtual) - May 29, 2020 - Abstract #ATC2020ATC_1772;
Both in-vitro and in-vivo IdeS administration demonstrates a reduction in IgG binding and complement-dependent cytotoxicity, with effects within 30 minutes of IdeS treatment and lasting up to 14 days. In-vivo administration of IdeS demonstrates substantial effect in xenoreactive IgG reduction, representing a promising target for xenotransplant applications, including the ability to transiently desensitize a highly xenoreactive NHP recipient as part of a pretransplant induction strategy or as rescue therapy for IgG-mediated xenograft rejection.
- |||||||||| Idefirix (imlifidase) / Hansa Biopharma
[VIRTUAL] Anti-HLA IgM Antibodies are Unaffected by Imlifidase (IdeS) Treatment (Virtual) - May 29, 2020 - Abstract #ATC2020ATC_507;
P2
The reduction of anti-HLA IgM signals, which was noted after imlifidase treatment in some patients, was not observed in IgG-depleted sera. The high anti-HLA IgM signals are likely to be an artefact of IgG-complexed IgM on the surface of HLA beads.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap, AT702 / Astellas
Preclinical, Journal: Long-Term Efficacy of AAV9-U7snRNA-Mediated Exon 51 Skipping in mdx52 Mice. (Pubmed Central) - May 29, 2020
A single injection of AAV9-U7 exon 51 (U7ex51) induces widespread and sustained levels of exon 51 skipping, leading to significant restoration of dystrophin and improvement of the dystrophic phenotype in the mdx52 mouse...Additionally, while low levels of exon skipping were measured in the brain, the dystrophin protein could not be detected, in line with a lack of improvement of their abnormal behavioral fear response. These results thus confirm the high therapeutic potential of the AAV-mediated exon-skipping approach, yet the apparent discrepancies between exon skipping and protein restoration levels suggest some limitations of this experimental model.
- |||||||||| Vyondys 53 (golodirsen) / Sarepta Therap, Exondys 51 (eteplirsen) / Sarepta Therap, Viltepso (viltolarsen) / Nippon Shinyaku
Journal: Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies. (Pubmed Central) - May 19, 2020
Recent advances in exon skipping have yielded promising results; the US Food and Drug Administration (FDA) approved eteplirsen (Exondys51) as the first exon-skipping drug for the treatment of Duchenne muscular dystrophy, and in vivo exon skipping has been demonstrated in animal models of dysferlinopathy, limb-girdle muscular dystrophy type 2C and congenital muscular dystrophy type 1A...Challenges remain as exon-skipping agents can have deleterious non-specific effects and different in-frame deletions show phenotypic variance. This article reviews the state of the art of exon skipping for treating muscular dystrophy and discusses challenges and future prospects.
- |||||||||| SRP-4052 / Sarepta Therap
Journal: Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy. (Pubmed Central) - Apr 23, 2020
Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model...Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Journal: Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy. (Pubmed Central) - Mar 29, 2020
Eteplirsen induced skipping of exon 51 is applicable to 12.4% of local patients...Mutation screening is crucial for providing insights into the underlying genetic signature of the disease in the local population and contributes toward existing information on DMD mutations in Asia and globally. This will guide future targeted drug development and clinical trial planning for this disease.
- |||||||||| SAF-301 / Lysogene, Alcyone, LYS-SAF302 / Lysogene, Sarepta Therap
Preclinical, Journal: An improved AAV vector for neurological correction of the mouse model of Mucopolysaccharidosis IIIA. (Pubmed Central) - Mar 14, 2020
Biodistribution of SAF302 was further assessed using GFP (SAF302GFP), indicating that vector spread was limited to the area around the injection tract. Further modification of the injection strategy to a single depth with higher injection volume increased vector distribution leading to more widespread GFP distribution and sustained expression, suggesting this approach should be adopted in future trials.
- |||||||||| Review, Journal: 2019 FDA TIDES (Peptides and Oligonucleotides) Harvest. (Pubmed Central) - Mar 11, 2020
This means a consolidation of these kinds of drugs in the pharmaceutical arena, paving the way in the coming years for the approval of others for diverse medical indications. Here the TIDES approved in 2019 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects.
- |||||||||| scAAV1.tMCK.NTF3 / Sarepta Therap
Trial completion date, Trial primary completion date: Phase I/IIa Trial of scAAV1.tMCK.NTF3 for Treatment of CMT1A (clinicaltrials.gov) - Feb 19, 2020
P1/2, N=9, Not yet recruiting,
Not yet recruiting --> Enrolling by invitation Trial completion date: Apr 2020 --> Jul 2023 | Trial primary completion date: Apr 2020 --> Mar 2023
- |||||||||| SRP-4044 / Sarepta Therap
Journal: Cardiopulmonary phenotypic discordance is common in Duchenne muscular dystrophy. (Pubmed Central) - Jan 29, 2020
In our cohort of DMD patients, discordant cardiopulmonary function was common (present in one-third of our patients), and the dystrophin genotype did not reliably predict a patient's cardiopulmonary phenotype. If confirmed by larger, multi-center studies, our findings have significant implications for predicting patient prognosis, evaluating DMD therapies, and designing new DMD therapies.
- |||||||||| Exon 43 / Sarepta Therap
Journal: Fusion of the COL1A1 and FYN Genes in Epithelioid Osteoblastoma. (Pubmed Central) - Jan 28, 2020
A COL1A1-FYN fusion gene was found in an epithelioid osteoblastoma resulting in deregulation of FYN. Whether COL1A1-FYN represents a consistent genetic feature of epithelioid osteoblastomas, remains to be seen.
- |||||||||| Elevidys (delandistrogene moxeparvovec) / Sarepta Therap, Roche
Enrollment closed: A Randomized, Double-blind, Placebo-controlled Study of Delandistrogene Moxeparvovec (SRP-9001) for Duchenne Muscular Dystrophy (DMD) (clinicaltrials.gov) - Jan 27, 2020
P2, N=41, Active, not recruiting,
Whether COL1A1-FYN represents a consistent genetic feature of epithelioid osteoblastomas, remains to be seen. Recruiting --> Active, not recruiting
- |||||||||| LYS-SAF302 / Lysogene, Sarepta Therap
Preclinical, Journal: AAVrh10 Vector Corrects Disease Pathology in MPS IIIA Mice and Achieves Widespread Distribution of SGSH in Large Animal Brains. (Pubmed Central) - Jan 10, 2020
The ability of the vector adeno-associated virus (AAV)rh.10-CAG-SGSH (LYS-SAF302) to correct disease pathology was evaluated in a mouse model for MPS IIIA...Increases of SGSH enzyme activity of at least 20% above endogenous levels were detected in 78% (dogs 4 weeks after injection) and 97% (monkeys 6 weeks after injection) of the total brain volume. Taken together, these data validate intraparenchymal AAV administration as a promising method to achieve widespread enzyme distribution and correction of disease pathology in MPS IIIA.
- |||||||||| Galgt2 gene therapy / Nationwide Children's, Sarepta Therap
Journal: rAAVrh74.MCK.GALGT2 Demonstrates Safety and Widespread Muscle Glycosylation after Intravenous Delivery in C57BL/6J Mice. (Pubmed Central) - Jan 1, 2020
Using intramuscular delivery, GALGT2-induced muscle glycosylation was increased in Cmah-deficient mice, which have a humanized sialoglycome, relative to wild-type mice, suggesting that use of mice may underestimate GALGT2 activity in human muscle. These data demonstrate safety and high transduction of muscles throughout the body plan with i.v. delivery of rAAVrh74.MCK.GALGT2.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Journal: Identifying and Avoiding tcDNA-ASO Sequence-Specific Toxicity for the Development of DMD Exon 51 Skipping Therapy. (Pubmed Central) - Dec 28, 2019
Modification of the H51-PS-tcDNA sequence, while maintaining target specificity through wobble pairing, abolished the observed toxicity by preventing homodimer formation. The resulting detoxified wobble-tcDNA candidate did not affect coagulation or complement pathways any longer nor activated platelets in vitro and was well tolerated in vivo in mice, confirming the possibility to detoxify specific tcDNA-ASO candidates successfully.
- |||||||||| Journal: Therapeutic Antisense Oligonucleotides Are Coming of Age. (Pubmed Central) - Dec 21, 2019
In addition, advances in understanding human disease, including the genetic basis for most monogenic diseases and the availability of the full human genome sequence, have created numerous therapeutic applications for the technology. I summarize the state of the technology and highlight how advances in the technology position ASOs to be an important contributor to future medicines.
- |||||||||| Galgt2 gene therapy / Nationwide Children's, Sarepta Therap
Preclinical, Journal: rAAVrh74.MCK.GALGT2 Protects against Loss of Hemodynamic Function in the Aging mdx Mouse Heart. (Pubmed Central) - Dec 21, 2019
rAAVrh74.MCK.GALGT2 treatment of mdx heart correlated with increased glycosylation of α-dystroglycan with the CT glycan and increased utrophin protein expression. These data provide the first demonstration that GALGT2 overexpression can inhibit the loss of cardiac function in the dystrophin-deficient heart and, thus, may benefit both cardiac and skeletal muscles in DMD patients.
|
