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.

Duchenne Muscular Dystrophy Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04179409
• Other study ID #: SRPT-Dup-US-001
• Status: Completed
• Phase: Phase 2
• Start date: February 18, 2020
• Est. completion date: September 1, 2023

Study information

• Verified date: October 2023
• Source: Nationwide Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an 48-week open-label study to determine the efficacy and safety of AMONDYS 45, EXONDYS 51, VYONDYS 53 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.

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 AMONDYS 45, EXONDYS 51, VYONDYS 53 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. AMONDYS 45, EXONDYS 51, VYONDYS 53 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 EXONDYS 51 suggests that PMOs are well tolerated in the non-clinical setting. Moreover, treatment with EXONDYS 51(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 AMONDYS 45, EXONDYS 51, VYONDYS 53 and the urgent medical need for a treatment for this subject population support the conclusion that the potential benefits of exposing subjects to AMONDYS 45, EXONDYS 51, VYONDYS 53 outweigh the potential risks.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3
• Est. completion date: September 1, 2023
• Est. primary completion date: September 1, 2021
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 6 Months and older

Eligibility

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

Related Conditions & MeSH terms

• Duchenne Muscular Dystrophy
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

Drug:
• Amondys 45
This drug is used to target skipping of exon 45 of the dystrophin gene.
• Exondys 51
This drug is used to target skipping of exon 51 of the dystrophin gene.
• Vyondys 53
This drug is used to target skipping of exon 53 of the dystrophin gene.

Locations

Country	Name	City	State
United States	Nationwide Children's Hospital	Columbus	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Kevin Flanigan	Sarepta Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (4)

Aartsma-Rus A, Fokkema I, Verschuuren J, Ginjaar I, van Deutekom J, van Ommen GJ, den Dunnen JT. Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat. 2009 Mar;30(3):293-9. doi: 10.1002/humu.20918. — View Citation

Greer KL, Lochmuller H, Flanigan K, Fletcher S, Wilton SD. Targeted exon skipping to correct exon duplications in the dystrophin gene. Mol Ther Nucleic Acids. 2014 Mar 18;3(3):e155. doi: 10.1038/mtna.2014.8. — View Citation

Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, Kaye EM, Mercuri E; Eteplirsen Study Group and Telethon Foundation DMD Italian Network. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016 Feb;79(2):257-71. doi: 10.1002/ana.24555. Epub 2016 Jan 8. — View Citation

Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Kota J, Malik V, Shontz K, Walker CM, Flanigan KM, Corridore M, Kean JR, Allen HD, Shilling C, Melia KR, Sazani P, Saoud JB, Kaye EM; Eteplirsen Study Group. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013 Nov;74(5):637-47. doi: 10.1002/ana.23982. Epub 2013 Sep 10. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Dystrophin Expression From Baseline Following Treatment With Either AMONDYS 45 (Previously Casimersen), EXONDYS 51 (Previously Eteplirsen ), or VYONDYS 53 (Previously Golodirsen)	This will be assessed by the comparison of quantification of protein in muscle biopsy tissue by western blot from baseline to 1 year post-initiation of treatment.	Baseline, 1 year
Primary	Monitoring for the Development of Unacceptable Toxicity.	This will be measured by capturing and reviewing Adverse Events as defined by CTCAE v4.0.	1 year
Secondary	Change in Dystrophin Expression From Baseline Following Treatment With Either AMONDYS 45 (Previously Casimersen), EXONDYS 51 (Previously Eteplirsen ), or VYONDYS 53 (Previously Golodirsen).	This will be assessed by the comparison of immunofluorescent staining in muscle biopsy tissue from baseline to 1 year post-initiation of treatment.	1 year