Duchenne Muscular Dystrophy
Conditions
Keywords
DMD, Exon Skipping
Brief 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.
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 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.
Interventions
DRUGAmondys 45
This drug is used to target skipping of exon 45 of the dystrophin gene.
DRUGExondys 51
This drug is used to target skipping of exon 51 of the dystrophin gene.
DRUGVyondys 53
This drug is used to target skipping of exon 53 of the dystrophin gene.
Sponsors
Sarepta Therapeutics, Inc.
Kevin Flanigan
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
6 Months to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Dystrophin Expression From Baseline Following Treatment With Either AMONDYS 45 (Previously Casimersen), EXONDYS 51 (Previously Eteplirsen ), or VYONDYS 53 (Previously Golodirsen) | Baseline, 1 year | 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. |
| Monitoring for the Development of Unacceptable Toxicity. | 1 year | This will be measured by capturing and reviewing Adverse Events as defined by CTCAE v4.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Dystrophin Expression From Baseline Following Treatment With Either AMONDYS 45 (Previously Casimersen), EXONDYS 51 (Previously Eteplirsen ), or VYONDYS 53 (Previously Golodirsen). | 1 year | This will be assessed by the comparison of immunofluorescent staining in muscle biopsy tissue from baseline to 1 year post-initiation of treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AMONDYS 45 This arm will involve the treatment of boys with DMD who have a duplication of exon 45, for which AMONDYS 45 will target skipping of this exon.
AMONDYS 45: This drug is used to target skipping of exon 45 of the dystrophin gene. | 2 |
| EXONDYS 51 This arm will involve the treatment of boys with DMD who have a duplication of exon 51, for which EXONDYS 51 will target skipping of this exon.
EXONDYS 51: This drug is used to target skipping of exon 51 of the dystrophin gene. | 0 |
| VYONDYS 53 This arm will involve the treatment of boys with DMD who have a duplication of exon 53, for which VYONDYS 53 will target skipping of this exon.
VYONDYS 53: This drug is used to target skipping of exon 53 of the dystrophin gene. | 1 |
| Total | 3 |
Baseline characteristics
| Characteristic | AMONDYS 45 | Total | VYONDYS 53 |
|---|---|---|---|
| Age, Customized Age | 12 Years STANDARD_DEVIATION 6 | 16 Years STANDARD_DEVIATION 7 | 23 Years STANDARD_DEVIATION 0 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 1 Participants |
| Region of Enrollment United States | 2 participants | 3 participants | 1 participants |
| Sex/Gender, Customized Female | 0 Participants | 0 Participants | 0 Participants |
| Sex/Gender, Customized Male | 2 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 0 | 0 / 1 |
| other Total, other adverse events | 2 / 2 | 0 / 0 | 1 / 1 |
| serious Total, serious adverse events | 0 / 2 | 0 / 0 | 0 / 1 |
Outcome results
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.
Time frame: Baseline, 1 year
Population: We did not enroll any participants in the EXONDYS 51 treatment arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMONDYS 45 | Change in Dystrophin Expression From Baseline Following Treatment With Either AMONDYS 45 (Previously Casimersen), EXONDYS 51 (Previously Eteplirsen ), or VYONDYS 53 (Previously Golodirsen) | 3.1 Percent of Healthy Control | Standard Deviation 1.8 |
| VYONDYS 53 | Change in Dystrophin Expression From Baseline Following Treatment With Either AMONDYS 45 (Previously Casimersen), EXONDYS 51 (Previously Eteplirsen ), or VYONDYS 53 (Previously Golodirsen) | 6.1 Percent of Healthy Control | Standard Deviation 0 |
Primary
Monitoring for the Development of Unacceptable Toxicity.
This will be measured by capturing and reviewing Adverse Events as defined by CTCAE v4.0.
Time frame: 1 year
Population: We did not enroll any participants in the EXONDYS 51 treatment arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AMONDYS 45 | Monitoring for the Development of Unacceptable Toxicity. | 17 Events |
| VYONDYS 53 | Monitoring for the Development of Unacceptable Toxicity. | 11 Events |
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.
Time frame: 1 year
Population: We did not enroll any participants in the EXONDYS 51 treatment arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMONDYS 45 | Change in Dystrophin Expression From Baseline Following Treatment With Either AMONDYS 45 (Previously Casimersen), EXONDYS 51 (Previously Eteplirsen ), or VYONDYS 53 (Previously Golodirsen). | 38 % Dystrophin Postive Fibers | Standard Deviation 25 |
| VYONDYS 53 | Change in Dystrophin Expression From Baseline Following Treatment With Either AMONDYS 45 (Previously Casimersen), EXONDYS 51 (Previously Eteplirsen ), or VYONDYS 53 (Previously Golodirsen). | 30.8 % Dystrophin Postive Fibers | Standard Deviation 0 |