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

study id #: NCT04179409

condition: Duchenne Muscular Dystrophy

status: not yet recruiting

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.

intervention: Casimersen, Eteplirsen, Golodirsen

mechanism of action: Exon-skipping to promote dystrophin production

results: https://clinicaltrials.gov/ct2/show/results/NCT04179409

last updated: December 04, 2019

start date: January 1, 2020

estimated completion: September 15, 2021

phase of development: Phase 2

size / enrollment: 6

study 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.

primary outcomes:

• 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.
  
• 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 outcomes:

• 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

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.

sponsor: Kevin Flanigan

contacts: Lauren Bird, 614-722-2699, lauren.bird@nationwidechildrens.org

investigators: Kevin Flanigan, MD

• United States, Ohio
  Nationwide Children’s Hospital