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A 48-Week, Open Label, Study to Evaluate the Efficacy and Safety of Casimersen, Eteplirsen and Golodirsen in Subjects With Duchenne Muscular Dystrophy Carrying Eligible DMD Duplications

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ClinicalTrials.gov Identifier: NCT04179409
Recruitment Status : Enrolling by invitation
First Posted : November 27, 2019
Last Update Posted : February 20, 2020
Sponsor:
Collaborator:
Sarepta Therapeutics, Inc.
Information provided by (Responsible Party):
Kevin Flanigan, Nationwide Children's Hospital

Study Description
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Brief Summary:
This is an 48-week open-label study to determine the efficacy and safety of casimersen, eteplirsen, or golodirsen for the treatment of boys with duchenne muscular dystrophy who have a single exon duplication of either exon 45, 51 or 53, respectively. There will be weekly infusions and two muscle biopsies at baseline and at month 12.

Condition or disease Intervention/treatment Phase
Duchenne Muscular Dystrophy Drug: Casimersen Drug: Eteplirsen Drug: Golodirsen Phase 2

Detailed Description:

DMD is a rare, serious, debilitating, and ultimately fatal, disease for which there is an urgent need to develop safe and effective therapies. In order to efficiently meet this urgency and the needs of the subject community, the study evaluates the efficacy and safety of casimersen, eteplirsen, and of golodirsen administration over approximately 1 year in DMD subjects with duplication mutations amenable to treatment by exon 45, 51 or exon 53 skipping. Skipping of a single copy of the duplicated exon is expected to result in a wild-type (WT) DMD transcript allowing the expression of a WT, full length dystrophin protein. Successful skipping of a single copy of the duplicated exon in in vitro and in vivo models has been reported in the literature. Casimersen, eteplirsen, and golodirsen have the potential to be disease-modifying treatments for boys with DMD mutations amenable to exon 45, 51 and exon 53 skipping, respectively.

The totality of the non-clinical data with these PMOs as well as AVI-4225 (targeting exon 23) and eteplirsen suggests that PMOs are well tolerated in the non-clinical setting. Moreover, treatment with eteplirsen (at 30 mg/kg and 50 mg/kg) has been well-tolerated by boys with DMD deletion mutations amenable to skipping exon 51. The relatively low expected risk for subjects exposed to casimersen, eteplirsen, or golodirsen and the urgent medical need for a treatment for this subject population support the conclusion that the potential benefits of exposing subjects to casimersen, eteplirsen, or golodirsen outweigh the potential risks.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A 48-Week, Open Label, Study to Evaluate the Efficacy and Safety of Casimersen, Eteplirsen and Golodirsen in Subjects With Duchenne Muscular Dystrophy Carrying Eligible DMD Duplications
Actual Study Start Date : February 18, 2020
Estimated Primary Completion Date : September 15, 2021
Estimated Study Completion Date : September 15, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Eteplirsen

Arms and Interventions
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Arm Intervention/treatment
Experimental: Casimersen
This arm will involve the treatment of boys with DMD who have a duplication of exon 45, for which casimersen will target skipping of this exon.
 Drug: Casimersen
This drug is used to target skipping of exon 45 of the dystrophin gene.
Other Name: SRP-4045
Experimental: Eteplirsen
This arm will involve the treatment of boys with DMD who have a duplication of exon 51, for which eteplirsen will target skipping of this exon.
 Drug: Eteplirsen
This drug is used to target skipping of exon 51 of the dystrophin gene.
Other Names:
  • EXONDYS 51®
  • AVI-4658
Experimental: Golodirsen
This arm will involve the treatment of boys with DMD who have a duplication of exon 53, for which golodirsen will target skipping of this exon.
 Drug: Golodirsen
This drug is used to target skipping of exon 53 of the dystrophin gene.
Other Name: SRP-4053


Outcome Measures
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Primary Outcome Measures :
  1. Change in dystrophin expression from baseline following treatment with either casimersen (previously SRP-4045), eteplirsen (previously AVI-4658), or golodirsen (previously SRP-4053). [ Time Frame: 1 year ]
    This will be assessed by quantification of protein in muscle biopsy tissue by western blot.

  2. Monitoring for the development of unacceptable toxicity. [ Time Frame: 1 year ]
    This will be measured by capturing and reviewing Adverse Events ad defined by CTCAE v4.0.


Secondary Outcome Measures :
  1. Change in dystrophin expression from baseline following treatment with either casimersen (previously SRP-4045), eteplirsen (previously AVI-4658), or golodirsen (previously SRP-4053). [ Time Frame: 1 year ]
    Expression of dystrophin will be measured by immunofluorescent staining in muscle tissue sections in comparison to baseline values


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Is a male with DMD and has an out-of-frame duplication of either exon 45, 51, or 53, with a normal copy number of all other DMD exons.
  • Is above age 6 months of age.
  • Has sufficient muscle mass in a pair of bilateral muscles that will allow for pre- and post-treatment muscle biopsies per PI discretion.
  • If the subject is ambulant and 4 years old or greater and has been on a stable dose or dose equivalent of oral corticosteroids for at least 12 weeks prior to Week 1 the dose is expected to remain constant (except for modifications to accommodate changes in weight) throughout the study.

Exclusion Criteria:

  • Any additional missing exon for DMD that cannot be treated with study drugs.

Other inclusion/exclusion criteria apply

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04179409


Locations
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United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
Sponsors and Collaborators
Kevin Flanigan
Sarepta Therapeutics, Inc.
Investigators
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Principal Investigator: Kevin Flanigan, MD Nationwide Children's Hospital
More Information
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Publications:

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Responsible Party: Kevin Flanigan, Professor of Neurology, Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT04179409    
Other Study ID Numbers: SRPT-Dup-US-001
First Posted: November 27, 2019    Key Record Dates
Last Update Posted: February 20, 2020
Last Verified: February 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Kevin Flanigan, Nationwide Children's Hospital:
DMD
Exon Skipping
Additional relevant MeSH terms:
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Muscular Dystrophies
Muscular Dystrophy, Duchenne
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
 Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked