P24 Safety and tolerability of Eteplirsen in patients 6 –48 Months old with DMD amenable to exon 51 skipping: an open-label extension study
Eteplirsen is indicated for treatment of exon 51 skip-amenable patients with DMD. Study 4658-102 (NCT03218995), a phase 2, open-label, dose-escalation trial, showed that eteplirsen (30 mg/kg IV once weekly) was well tolerated in patients aged 24 to 48 months (cohort 1, n=9) and 6 to (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: E. Mercuri, A. Seferian, N. Deconinck, L. Orogun, X. Ni, W. Zhang, K. Drummond, I. Sehinovych, F. Muntoni Source Type: research
P25 Single- and repeat-dose nonclinical data for PGN-EDO51 demonstrate potential for the treatment of Duchenne muscular dystrophy (DMD)
PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. PGN-EDO51 is PepGen's clinical candidate for the treatment of people with DMD amenable to exon 51 skipping. In the mdx mouse model of DMD, a single intravenous (IV) dose of 30 or 60 mg/kg of mPGN EDO23 (mouse analogue of PGN-EDO51) resulted in exon skipping levels of 52.5% and 82.8% and dystrophin protein production of 22.5% and 51.7% in biceps. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: A. Holland, P. Lonkar, C. Sweeney, J. Gilbert, N. Svenstrup, J. Goyal Source Type: research
P26 CONNECT-EDO51: Trial designs to support the development of PGN-EDO51 for Duchenne Muscular dystrophy amenable to exon 51 skipping
PepGen's Enhanced Delivery Oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. The EDO PGN-EDO51 is being evaluated for the treatment of Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. Phase 1 single dose data in healthy volunteers demonstrated the highest levels of oligonucleotide delivery to biceps muscles at 15 mg/kg (up to 50 nM) and exon skipping (up to 2% skipping by ddPCR) that have been reported after a single dose in healthy volunteers. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: J. Larkindale, S. Vacca, J. Cormier, J. Shoskes, J. Goyal, A. Holland, P. Lonkar, J. Foy, M. Mellion Source Type: research
P27 Three novel enhanced delivery Oligonucleotide candidates for Duchenne muscular dystrophy mediate high levels of exon 53, 45, and 44 skipping
PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. PGN-EDO53, PGN-EDO45, and PGN-EDO44 are being evaluated for potential treatment of Duchenne muscular dystrophy (DMD) subpopulations amenable to exon 53, exon 45, or exon 44 skipping, respectively. Wild-type human myoblasts were dosed with PGN-EDO45 versus R6G-PMO45 (comparator PPMO), and with PGN-EDO44. High levels of exon skipping were seen for both EDO candidates. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: A. Holland, P. Lonkar, C. Sweeney, H. Zhang, N. Svenstrup, C. Gibbons, L. Xu, J. Foy, J. Goyal Source Type: research
P28 The antisense oligonucleotide BMN 351 durably ameliorates dystrophic phenotypes in a mouse model of exon 51 –skip-amenable Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is caused by mutation of the DMD gene. Exon skipping with antisense oligonucleotides (ASOs) can be used to restore the DMD open reading frame, enabling production of internally shortened —but still functional—dystrophin. BMN 351 is a next-generation 2’-O-methyl phosphorothioate ASO designed to induce efficient exon 51 skipping by targeting a novel alternative splicing enhancer site. It also contains a 5’ triethylene glycol modification and 5-methyl cytosines to improve ASO s tability and pharmacological characteristics. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: D. Porco, D. Neil, B. Crawford, C. O'Neill, Y. Qi, T. Oppeneer, K. Larimore, S. Gupta, F. Beretta Source Type: research
P29 DMD transcript imbalance and nuclear trafficking evaluation in muscle biopsies from baseline and golodirsen treated 4053-101 clinical trial patients
Duchenne muscular dystrophy (DMD) is an X-linked, rare, neuromuscular disease caused by mutations in the DMD gene affecting its reading frame. This results in a substantial reduction or absence of dystrophin protein and a non-uniform expression of the DMD transcript throughout its 14-kb length, the so-called transcript imbalance. Recent evidence has also found an impairment in the sub-cellular localization of the DMD transcript in mdx mice, demonstrating nuclear retention, compared to wild type. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: R. Rossi, S. Singh, S. Torelli, F. Catapano, D. Chambers, J. Morgan, J. Malhotra, F. Muntoni Source Type: research
P30 A phase 1b/2 open-label study of WVE-N531 in patients with Duchenne muscular dystrophy: part B study design and rationale
Duchenne muscular dystrophy (DMD) is the most common genetic muscular dystrophy caused by mutations in the gene encoding dystrophin. WVE-N531 is a stereopure antisense oligonucleotide, which contains phosphoryl guanidine (PN) chemistry. WVE-N531 was designed to induce exon 53 skipping and yield dystrophin protein production in patients with DMD amenable to exon 53 skipping. Part A of a Phase 1b/2 open-label study (NCT04906460) demonstrated that WVE-N531 was safe and well-tolerated, with a promising pharmacokinetic (PK) and pharmacodynamic (PD) profile in three ambulatory boys. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: M. Tillinger, M. Volpe, C. Casey, S. Lake, X. Hu, D. Xu, P. Narayanan, A. Hart, J. Haegele, S. Lamore, S. Bhatia, A. Li-Kwai-Cheung, L. Servais Source Type: research
P31 Interim analysis of EVOLVE: evaluating Eteplirsen, Golodirsen, or Casimersen treatment in patients < 7 years old in routine clinical practice
Current clinical recommendations for Duchenne muscular dystrophy (DMD) emphasize the importance of early diagnosis and treatment. Clinical trial 4658-102 (NCT03218995) demonstrated the safety and tolerability of eteplirsen in the youngest population of patients with DMD (6 to 48 months). Here, patients ’ ( (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: S. Grabich, S. Santra, M. Waldrop, K. Mathews, F. Abid, L. Ramos-Platt, R. Scharf, C. Zaidman, I. Sehinovych, C. McDonald Source Type: research
P32 Jak inhibitors Tofacitinib and Ruxolitinib do not improve functional deficits in dystrophin-deficient mdx mice
In this study, 6-week-old male C57BL/10 wildtype control (wt) and C57BL/10-mdx (mdx) mice were treated daily via oral gavage for 15 weeks across six groups (n=15 each): 1. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: C. Bosco, K. Uaesoontrachoon, S. Srinivassane, J. Rowsell, P. Elustondo, A. Mackinnon, K. Nagaraju, J. Peterson Source Type: research
P33 RKER-065 ameliorated muscle and bone loss in a progressive murine model of Duchenne muscular dystrophy
Patients with Duchenne muscular dystrophy (DMD) have reduced muscle mass and function. They also exhibit low bone strength leading to a higher risk of skeletal fractures. Minimal treatment options include the current standard of care long-term corticosteroids, which further reduce muscle and bone mass. The TGF- β superfamily of ligands, including myostatin and activins, signal through activin type II receptors (ActRII) and negatively regulate muscle and bone mass and function. KER-065 is an investigational, novel modified ActRII-Fc ligand trap designed to target these catabolic ligands. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: R. Nathan, M. Cahill, R. Todorova, S. Macaluso, C. Tseng, F. Fisher, L. Lerner, J. Seehra, J. Lachey Source Type: research
P34 RKER-065, a novel ActRII ligand trap, counteracted the negative impact of glucocorticoid treatment on bone and muscle
Glucocorticoids are the first-line medications for Duchenne muscular dystrophy. The adverse consequences of glucocorticoid treatment include growth retardation, poor bone health, and muscle atrophy. Transforming growth factor-beta family members, including activin A, activin B and myostatin, are potent negative regulators of musculoskeletal growth. RKER-065 is an investigational, modified type II activin receptor (ActRII) ligand trap designed to bind and inhibit these ligands. The goal of the present study is to determine if RKER-065 can prevent the negative effects of glucocorticoids on bone and muscle. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: G. Zhen, R. Nathan, M. Cahill, C. Materna, F. Fisher, L. Lerner, J. Lachey, J. Seehra Source Type: research
P35 Two-year clinical outcomes with fordadistrogene movaparvovec (FM) for Duchenne muscular dystrophy (DMD) and contextualization with external controls
We report the effect of FM on motor function at 2 y vs selected external control groups. Ambulatory subjects (n=16) with confirmed DMD received a single i.v. dose (2E14 vg/kg) of FM. An external control group was generated from a prediction model developed within the cTAP collaboration using large natural history databases. A second control group with similar baseline characteristics was constructed using 2-y data from subjects with at least 1 y of treatment in a recent null phase 2 trial. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: P. Shieh, R. Butterfield, F. Muntoni, E. Mercuri, J. Signorovitch, P. Schwartz, H. Li, M. Binks, T. McDonnell, K. Ryan, M. Delnomdedieu, Q. Shen, D. Levy, E. Smith Source Type: research
P36 Givinostat in Duchenne muscular dystrophy: effect on disease milestones
Givinostat is a novel orally active histone deacetylase inhibitor being developed for the treatment of Duchenne muscular dystrophy (DMD). Givinostat efficacy and safety were assessed in the Epidys Study, a randomized, double blind, placebo controlled, multicenter Phase 3 study in ambulant DMD patients (NCT02851797). Study DSC/14/2357/51 (NCT03373968) is an ongoing open label, long-term study of givinostat in 200 DMD male subjects previously enrolled in one of the other DMD givinostat studies who will receive treatment until givinostat marketing approval. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: C. McDonald, L. Servais, F. Munell, U. Schara-Schmidt, E. Bertini, G. Comi, A. Blaschek, S. Cazzaniga, P. Bettica, K. Vandenborne, E. Mercuri Source Type: research
P37 Givinostat in DMD: results of the Epidys Study with particular attention to NSAA
Givinostat is a novel orally active histone deacetylase (HDAC) inhibitor being developed for the treatment of DMD. The Epidys Study is a randomized, double blind, placebo controlled, multicenter Phase 3 study to evaluate the efficacy and safety of givinostat in ambulant patients with DMD (Clinicaltrials.gov ID: NCT02851797). One-hundred and seventy-nine boys aged ≥6 years at baseline affected by DMD were enrolled and 95% of them completed the study. The primary efficacy assessment was the time to climb 4 standard stairs (4SC). (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: E. Mercuri, C. Brogna, J. Mah, N. Goemans, E. Niks, S. Cazzaniga, P. Bettica, C. McDonald Source Type: research
VP38 Changes to glucocorticosteroid prescribing patterns in Duchenne muscular dystrophy in the UK over the last decade
This study aims to describe changes in UK prescribing patterns of GCs between 2012-2022 and differences in side effects between groups. The NorthStar database prospectively collects longitudinal data from all children with DMD followed in all 24 UK paediatric neuromuscular centres. Data on GC usage was available for 1096 patients, across 6521 observations; 800 patients (73%) were taking GCs. (Source: Neuromuscular Disorders)
Source: Neuromuscular Disorders - October 1, 2023 Category: Neurology Authors: G. Landon, G. Stimpson, A. Sarkozy, A. Manzur, M. Guglieri, F. Muntoni, G. Baranello Source Type: research
