- |||||||||| SRP-4055 / Sarepta Therap
Journal: Identification of immune-related features involved in Duchenne muscular dystrophy: A bidirectional transcriptome and proteome-driven analysis. (Pubmed Central) - Dec 10, 2022
In addition, three genes (ATP6AP2, CTSS, and VIM) showed excellent diagnostic performance on discriminating DMD in GSE1004, GSE3307, GSE6011 and GSE38417 datasets (all AUC > 0.8), which is validated in patients (10 DMD vs. 10 controls), DMD with exon 55 mutations, mdx mouse, and nomogram model. Taken together, ATP6AP2, CTSS, and VIM play important roles in the inflammatory response in DMD, which may serve as diagnostic biomarkers and therapeutic targets.
- |||||||||| 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,
Taken together, ATP6AP2, CTSS, and VIM play important roles in the inflammatory response in DMD, which may serve as diagnostic biomarkers and therapeutic targets. 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.
- |||||||||| Idefirix (imlifidase) / Hansa Biopharma, Sarepta Therap, Rituxan (rituximab) / Biogen, Zenyaku Kogyo, Roche
Successful Desensitization of Severe Alloimmune Platelet Refractoriness and Provision of Permissive Platelet Transfusions with a Novel IgG-Targeted Enzyme Therapeutic (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_5639;
PATIENT CASE A 43-year-old woman with AML treated with cytarabine and daunorubicin was referred for matched-unrelated donor allogeneic hematopoietic progenitor cell transplantation...STUDY DESIGN With IRB approval, the number of predicted clinically significant alloantibodies (antibodies with = 3000 mean fluorescence intensity, MFI) and PRA (LABScreen single antigen and PRA Class I, One Lambda/ThermoFisher, West Hills, California) were compared at baseline, after rituximab/TPE, and after imlifidase administration...Our limited data suggest a potentially novel application of imlifidase for desensitization of highly platelet allo-refractory patients requiring multiple platelet transfusions over a short period. We will perform western blot analysis of antibodies from in vivo samples collected over the treatment course to compare antibody fragmentation over time, as partially cleaved immunoglobulin detected by our microbead-based assays may not be pathologic.2 Additionally, as the patient’s initial antibody levels exceeded the range of linearity of the bead-based assay, serial dilution studies of patient serum over the treatment course will more precisely semi-quantitate the true peak antibody levels.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Journal: Gene editing of Duchenne muscular dystrophy using biomineralization-based spCas9 variant nanoparticles. (Pubmed Central) - Oct 16, 2022
We evaluated multiple target regions with different PAMs for the DMD exon 51 splice acceptor site through Bm-SpRY NPs method and found that the target region with TAG PAM has the highest editing efficiency and significant preferential mutation...Here, the present study provides a biomineralized PAM Less Cas9 (SpRY) variant nanoparticles (Bm-SpRY NPs) for DMD gene editing in vitro and in vivo. This study may extend the application of CRISPR system for DMD gene therapy.
- |||||||||| Galgt2 gene therapy / Nationwide Children's, Sarepta Therap
P1/2 data, Journal: A first-in-human phase I/IIa gene transfer clinical trial for Duchenne muscular dystrophy using rAAVrh74.MCK.GALGT2. (Pubmed Central) - Oct 4, 2022
Subject 2, treated at a younger age and at a higher dose, demonstrated an improvement over 24 months in NSAA score (from 20 to 23 points), an increase in 6MWT distance (from 405 to 478 m), and only a minimal increase in 100 m time (45.6-48.4 s). These data suggest preliminary safety at a dose of 1 × 10 vg/kg and functional stabilization in one patient.
- |||||||||| Idefirix (imlifidase) / Hansa Biopharma, Sarepta Therap
Erythrocyte Targeted Ides Selectively Cleaves RBC-Bound Antibodies and Protects Against IgG Mediated Hemolysis (Orange County Convention Center - Tangerine Ballroom 1) - Sep 26, 2022 - Abstract #AABB2022AABB_505;
Fab-IdeS fusion proteins bind to the erythrocyte surface improving pharmacokinetics, enhancing selectivity for RBC-bound IgG, and increasing potency in a murine passive immunization model. Further investigation is warranted to determine their potential as translational therapeutics for treatment of IgG-mediated hemolysis in clinical settings.
- |||||||||| Review, Journal: Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets. (Pubmed Central) - Sep 3, 2022
In this last case, the use of ASOs permits modifying the expression of specific proteins by modulating splicing of specific pre-RNAs (e.g., Nusinersen acts on the splicing of exon 7 in SMN2 mRNA normally not expressed; it is used for spinal muscular atrophy) or by downregulation of transcript levels (e.g., Inotersen acts on the transthryretin mRNA to reduce its expression; it is prescribed for the treatment of hereditary transthyretin amyloidosis) in order to restore the biochemical/physiological condition and ameliorate quality of life...In this review, we summarize the main transcriptional therapeutic drugs approved to date for the treatment of genetic diseases by principal regulatory government agencies and recent clinical trials aimed at the treatment of cancer. Their mechanism of action, chemical structure, administration, and biomedical performance are predominantly discussed.
- |||||||||| Exondys 51 (eteplirsen) / Sarepta Therap
Journal: Delays in pulmonary decline in eteplirsen-treated patients with Duchenne muscular dystrophy. (Pubmed Central) - Aug 24, 2022
Their mechanism of action, chemical structure, administration, and biomedical performance are predominantly discussed. The attenuation of FVC%p decline suggests that eteplirsen-treated patients had statistically significant and clinically meaningful attenuations in pulmonary decline compared with SoC patients.
- |||||||||| Idefirix (imlifidase) / Hansa Biopharma, Sarepta Therap
Trial completion date, Trial initiation date, Trial primary completion date: A Study to Investigate DSA Rebound in Patients Treated with Imlifidase Prior to Transplantation (clinicaltrials.gov) - Aug 24, 2022
P2, N=12, Not yet recruiting,
The attenuation of FVC%p decline suggests that eteplirsen-treated patients had statistically significant and clinically meaningful attenuations in pulmonary decline compared with SoC patients. Trial completion date: Jun 2023 --> Jun 2024 | Initiation date: Oct 2021 --> Oct 2022 | Trial primary completion date: Mar 2023 --> Mar 2024
- |||||||||| SRP-4055 / Sarepta Therap
Review, Journal, Tumor Mutational Burden: Transformation from polycythemia vera to acute promyelocytic leukemia: Case report and literature review. (Pubmed Central) - Aug 22, 2022
Trial completion date: Jun 2023 --> Jun 2024 | Initiation date: Oct 2021 --> Oct 2022 | Trial primary completion date: Mar 2023 --> Mar 2024 Polycythemia vera can transform into acute promyelocytic leukemia; therefore, it is important to review bone aspiration and other tests to perform a comprehensive assessment and monitor the disease status, to detect disease progression and intervene early when it transforms into acute promyelocytic leukemia.
- |||||||||| delandistrogene moxeparvovec (SRP-9001) / Sarepta Therap, Roche
PK/PD modelling to inform clinical development of an adeno-associated virus gene transfer therapy for Duchenne muscular dystrophy (Poster area - Ballroom B1-B2) - Aug 20, 2022 - Abstract #WMS2022WMS_428;
For the first time, biodistribution, biomarker, and functional efficacy data were used to quantify and demonstrate PK/PD relationships for an adeno-associated virus (AAV)-based gene transfer therapy in a DMD animal model. The results continue to support the expected therapeutic benefit and clinical dose of delandistrogene moxeparvovec, an AAV-based gene transfer therapy.
- |||||||||| delandistrogene moxeparvovec (SRP-9001) / Sarepta Therap, Roche
Evaluating pharmacology and efficacy of delandistrogene moxeparvovec in young and aged DMDMDX rats (Poster area - Ballroom B1-B2) - Aug 20, 2022 - Abstract #WMS2022WMS_424;
Taken together, these findings confirm expression in cardiac muscle, as expected, and support the myocardial efficacy and safety of delandistrogene moxeparvovec. Further evaluation of cardiac disease phenotypes at 12 and 24 weeks post-systemic delivery utilising several indicators of cardiac function will also be presented.
- |||||||||| 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.
- |||||||||| delandistrogene moxeparvovec (SRP-9001) / Sarepta Therap, Roche
Phase 1/2a trial of delandistrogene moxeparvovec in patients with DMD: 4-year update (Poster area - Ballroom B1-B2) - Aug 20, 2022 - Abstract #WMS2022WMS_310;
P1/2
The observed safety profile and the enduring response following treatment provide proof of concept for continuation of clinical trials assessing delandistrogene moxeparvovec using single-dose gene therapy in patients with DMD. We present the latest long-term (4-year) safety and functional data from this study.
- |||||||||| Building a FORCETM platform-based DMD franchise for the treatment of individuals with mutations amenable to exon skipping (Poster area - Ballroom B1-B2) - Aug 20, 2022 - Abstract #WMS2022WMS_306;
FORCE-M23D is a mouse-specific Fab-PMO conjugate designed to target TfR1 and skip exon 23 of the murine Dmd transcript to restore dystrophin expression in the mdx mouse model of DMD...Additionally, Dyne's clinical candidate, DYNE-251, a Fab-conjugated PMO designed to skip DMD exon 51, was evaluated in non-human primates (NHPs)...Lastly, we have begun development of FORCE conjugates for the treatment of exon 53 and exon 45 skipping amenable patients...This conjugate resulted in superior skipping of exon 53 compared to unconjugated PMO. Collectively, these data support utilizing the FORCE platform for the development of therapies for individuals with DMD mutations amenable to exon skipping.
- |||||||||| delandistrogene moxeparvovec (SRP-9001) / Sarepta Therap, Roche
One-year data from ENDEAVOR, a phase 1b trial of delandistrogene moxeparvovec in boys with DMD (Poster area - Ballroom B1-B2) - Aug 20, 2022 - Abstract #WMS2022WMS_304;
P1
Exploratory functional endpoints include the North Star Ambulatory Assessment and timed function tests (Cohorts 1, 2 and 4) and performance of the upper limb and pulmonary function tests (Cohorts 2 and 3). We present 1-year safety and functional data and 12-week expression data following treatment with commercially representative delandistrogene moxeparvovec material.
- |||||||||| delandistrogene moxeparvovec (SRP-9001) / Sarepta Therap, Roche
Integrated analyses of data from clinical trials of delandistrogene moxeparvovec in DMD (Poster area - Ballroom B1-B2) - Aug 20, 2022 - Abstract #WMS2022WMS_303;
P1, P1/2,
In this analysis, data from all treated patients will be compared with propensity score-weighted EC cohort to contextualise the results of the three ongoing delandistrogene moxeparvovec clinical studies in patients with DMD. Collective safety data (as of the latest data-cut) from all patients (all cohorts in studies 101 and studies 102 and endeavor) will be presented.
- |||||||||| delandistrogene moxeparvovec (SRP-9001) / Sarepta Therap, Roche
Validity of remote evaluation of the North Star Ambulatory Assessment in patients with Duchenne muscular dystrophy (Poster area - Ballroom B1-B2) - Aug 20, 2022 - Abstract #WMS2022WMS_138;
These findings suggest that remote functional assessment of patients with DMD is not statistically different from in-person assessment and has comparable clinical meaningfulness, validating its use in clinical trials of delandistrogene moxeparvovec. Given the burden that treatment and monitoring place on patients with DMD and their caregivers, remote assessment may be beneficial in future research, clinical trials, and clinical settings.
- |||||||||| Galgt2 gene therapy / Nationwide Children's, Sarepta Therap
Trial completion date: Gene Transfer Clinical Trial to Deliver rAAVrh74.MCK.GALGT2 for Duchenne Muscular Dystrophy (clinicaltrials.gov) - Jul 29, 2022
P1/2, N=2, Active, not recruiting,
Additionally, the introduction of Fmoc chemistry into PMOs opens up the possibility for PMO synthesis in commercial peptide synthesizers for future development. Trial completion date: Jun 2022 --> Oct 2023
- |||||||||| Exon 43 / Sarepta Therap
Journal: Two novel CACNA1F gene mutations cause two different phenotypes: Aland Eye Disease and incomplete Congenital Stationary Night Blindness. (Pubmed Central) - Jul 15, 2022
In Patient 2 variant c.5156G > C localized in the donor's splicing site of exon 43 was identified...Clinical spectrum is more severe and resembles the AIED phenotype when the mutation affects the first part of the protein, while it is more similar to CSNB2 if the mutation is localized at the end of the protein. Genetic testing results to be an essential tool to provide more accurate diagnosis and prognosis in patients with inherited retinal degenerative disorders and could help, in the future, to develop more specific therapeutic strategies.
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