Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial

Servais, Laurent; Mercuri, Eugenio; Straub, Volker; Guglieri, Michela; Seferian, Andrei; Scoto, Mariacristina; Leone, Daniela; Koenig, E.; Khan, Navid; Dugar, Ashish; Wang, Xiaodong; Han, Baoqin; Wang, Dan; Muntoni, Francesco; Brusa, Chiara; Antonaci, Laura; Brogna, Claudia; Merli, Laura; Monforte, Mauro; Norcia, Giulia; Pane, Marika; Ferrantini, Gloria; Dickson, George; Morgan, Jennifer E.; Sardone, Valentina; Akana, Cody; Charleston, Jay S.; Desjardins, Cody A.; El-Husayni, Saleh; Frank, Diane E.; Schnell, Frederick J.

doi:10.1089/nat.2021.0043

Cited by 77 publications

(46 citation statements)

References 43 publications

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“…DMD is a rare disease, and only 8%-10% of DMD patients have a variant amenable to exon 53 skipping [3]. While the small sample size (N = 16) represents a limitation of this study, both the study design and sample size are consistent with other studies investigating potential approaches to treatment for this patient population [21][22][23][24]. An additional limitation is the use of an historical control group (group-level matched) in this study, rather than a placebo arm.…”

Section: Limitationssupporting

confidence: 57%

“…Long-term data on the use of FDA-approved DMD therapies are beginning to emerge. A recent paper by Servais and colleagues found that golodirsen treatment in DMD patients (n = 25, mean age 8.4 years) amenable to exon 53 skipping did not significantly reduce loss of ambulation, 6MWT, or forced vital capacity evaluations at 3 years relative to external controls [21]. Viltolarsen (presented here) and golodirsen target the same DMD gene exon 53.…”

Section: Discussionmentioning

confidence: 58%

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Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy

Clemens

Rao

Connolly

et al. 2022

JND

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Background: Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused by mutations in the DMD gene resulting in an absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes in viltolarsen treated patients were compared to a matched historical control group. Objective: To evaluate long-term efficacy and safety of the anti-sense oligonucleotide viltolarsen in the treatment of patients with DMD amenable to exon 53 skipping therapy. Methods: This trial (NCT03167255) is the extension of a previously published 24-week trial in North America (NCT02740972) that examined dystrophin levels, timed function tests compared to a matched historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study, CINRG DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53 skipping who were treated with viltolarsen. Both groups were treated with glucocorticoids. All 16 participants elected to enroll in this long-term trial (up to 192 weeks) to continue evaluation of motor function and safety. Results: Time to stand from supine and time to run/walk 10 meters showed stabilization from baseline through week 109 for viltolarsen-treated participants whereas the historical control group showed decline (statistically significant differences for multiple timepoints). Safety was similar to that observed in the previous 24-week trial, which was predominantly mild. There have been no treatment-related serious adverse events and no discontinuations. Conclusions: Based on these results at over 2 years, viltolarsen can be a new treatment option for patients with DMD amenable to exon 53 skipping.

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Section: Limitationssupporting

confidence: 57%

Section: Discussionmentioning

confidence: 58%

Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy

Clemens

Rao

Connolly

et al. 2022

JND

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“…The long-term clinical efficacy of these therapies has been confirmed in recent reports (Nelson et al 2019;Servais et al 2022;Xu et al 2019), however the risks associated with off-target mutations and tumorigenicity still raise significant safety concerns.…”

Section: Introductionmentioning

confidence: 98%

Long-Term Biodistribution and Safety of Human Dystrophin Expressing Chimeric Cell Therapy After Systemic-Intraosseous Administration to Duchenne Muscular Dystrophy Model

Siemionow

Brodowska

Langa

et al. 2022

Arch. Immunol. Ther. Exp.

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Duchenne muscular dystrophy (DMD) is a lethal disease caused by X-linked mutations in the dystrophin gene. Dystrophin deficiency results in progressive degeneration of cardiac, respiratory and skeletal muscles leading to premature death due to cardiopulmonary complications. Currently, no cure exists for DMD. Based on our previous reports confirming a protective effect of human dystrophin expressing chimeric (DEC) cell therapy on cardiac, respiratory, and skeletal muscle function after intraosseous administration, now we assessed long-term safety and biodistribution of human DEC therapy for potential clinical applications in DMD patients. Safety of different DEC doses (1 × 106 and 5 × 106) was assessed at 180 days after systemic-intraosseous administration to mdx/scid mice, a model of DMD. Assessments included: single cell gel electrophoresis assay (COMET assay) to confirm lack of genetic toxicology, magnetic resonance imaging (MRI) for tumorigenicity, and body, muscle and organ weights. Human DEC biodistribution to the target (heart, diaphragm, gastrocnemius muscle) and non-target (blood, bone marrow, lung, liver, spleen) organs was detected by flow cytometry assessment of HLA-ABC markers. Human origin of dystrophin was verified by co-localization of dystrophin and human spectrin by immunofluorescence. No complications were observed after intraosseous transplant of human DEC. COMET assay of donors and fused DEC cells confirmed lack of DNA damage. Biodistribution analysis of HLA-ABC expression revealed dose-dependent presence of human DEC cells in target organs, whereas negligible presence was detected in non-target organs. Human origin of dystrophin in the heart, diaphragm and gastrocnemius muscle was confirmed by co-localization of dystrophin expression with human spectrin. MRI revealed no evidence of tumor formation. Body mass and muscle and organ weights were stable and comparable to vehicle controls, further confirming DEC safety at 180 days post- transplant. This preclinical study confirmed long-term local and systemic safety of human DEC therapy at 180 days after intraosseous administration. Thus, DEC can be considered as a novel myoblast based advanced therapy medicinal product for DMD patients.

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“…Golodirsen was first tested in a 24-week placebo-controlled, dose-escalation study of 12 participants [ 36 ]. Thirty-nine participants were then enrolled in a long-term extension study (NCT02310906).…”

Section: Exon Skippingmentioning

confidence: 99%

Current Outline of Exon Skipping Trials in Duchenne Muscular Dystrophy

Eser

Topaloǧlu

2022

Genes

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Molecular treatments for Duchenne muscular dystrophy (DMD) are already in clinical practice. One particular means is exon skipping, an approach which has more than 15 years of background. There are several promising clinical trials based on earlier works. The aim is to be able to initiate the production of enough dystrophin to change the rate of progression and create a clinical shift towards the better. Some of these molecules already have received at least conditional approval by health authorities; however, we still need new accumulating data.

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Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial

Cited by 77 publications

References 43 publications

Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy

Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy

Long-Term Biodistribution and Safety of Human Dystrophin Expressing Chimeric Cell Therapy After Systemic-Intraosseous Administration to Duchenne Muscular Dystrophy Model

Current Outline of Exon Skipping Trials in Duchenne Muscular Dystrophy

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