Duchenne Muscular Dystrophy
Conditions
Keywords
Duchenne muscular dystrophy, DMD, Oligonucleotides, Antisense, Exon skipping
Brief summary
This is a phase I/II study to evaluate the safety, tolerability, efficacy, and pharmacokinetic (PK) profile of DS-5141b in patients with Duchenne muscular dystrophy (DMD) amenable to exon 45 skipping and to determine the dosage for subsequent studies.
Interventions
DRUGDS-5141b
DS-5141b, Subcutaneous injection
Sponsors
Daiichi Sankyo
Daiichi Sankyo Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
5 Years to 10 Years
Healthy volunteers
No
Inclusion criteria
* Confirmation of out-of-frame deletion(s) that could be corrected by dystrophin gene exon 45 skipping. * Intact muscles of adequate quality for biopsy to allow evaluation of the efficacy of the study drug. * Boys aged from 5 years to \<11 years. * Patients able to walk at least 325 meters in the 6-minutes walk test. * Glucocorticoid-naive patients, or patients who have used glucocorticoids for at least 6 months prior to enrollment in this study with no dose changes for at least 3 months prior to enrollment.
Exclusion criteria
* A genetic mutation that can not be expected the expression of dystrophin protein by dystrophin gene exon 45 skipping. * A concurrent illness other than DMD that can cause muscle weakness and/or impairment of motor function. * Current or history of severe disorder. * Left ventricular ejection fraction (LEVF) \<55%. * Corrected QT interval (QTc) \>0.45 sec.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameter Area Under the Curve (AUC) Tau of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy | Week 48 of Part 2-Extension-2 | Pharmacokinetic parameters were assessed using non-compartmental methods. |
| Number of Participants Reporting at Least One Treatment-emergent Adverse Event (TEAE) In Participants With Duchenne Muscular Dystrophy | 48 Weeks of Part 2-Extension-2 | A treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during treatment having been absent prior to treatment or reemerges during treatment or worsens in severity during treatment. |
| Pharmacokinetic Parameter Maximum Concentration (Cmax) of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy | Week 48 of Part 2-Extension-2 | Pharmacokinetic parameters were assessed using non-compartmental methods. |
| Mean Dystrophin Protein Expression in Muscle Tissue | Week 48 of Part 2-Extension-2 | — |
| Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy | Week 48 of Part 2-Extension-2 | Pharmacokinetic parameters were assessed using non-compartmental methods. |
| Pharmacokinetic Parameter Half-life (T1/2) of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Dystrophy | Week 48 of Part 2-Extension-2 | Pharmacokinetic parameters were assessed using non-compartmental methods. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants With Exon 45-skipped Dystrophin mRNA Expression in Muscle Tissue Posttreatment | Week 48 of Part 2-Extension-2 |
Countries
Japan
Participant flow
Recruitment details
A total of 12 participants were screened; 8 participants who met all inclusion criteria and no exclusion criteria were enrolled in the study at 2 clinic centers in Japan.
Participants by arm
| Arm | Count |
|---|---|
| DS-5141b 2.0 mg/kg All participants who received a subcutaneous injection of DS-5141b 2.0 mg/kg once a week. | 3 |
| DS-5141b 6.0 mg/kg All participants who received a subcutaneous injection of DS-5141b 6.0 mg/kg once a week. | 5 |
| Total | 8 |
Baseline characteristics
| Characteristic | DS-5141b 6.0 mg/kg | Total | DS-5141b 2.0 mg/kg |
|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 8 Participants | 3 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 7.2 years STANDARD_DEVIATION 1.9 | 6.9 years STANDARD_DEVIATION 1.7 | 6.3 years STANDARD_DEVIATION 1.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 8 Participants | 3 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 | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 5 participants | 8 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 5 |
| other Total, other adverse events | 3 / 3 | 5 / 5 |
| serious Total, serious adverse events | 0 / 3 | 1 / 5 |
Outcome results
Primary
Mean Dystrophin Protein Expression in Muscle Tissue
Time frame: Week 48 of Part 2-Extension-2
Population: Dystrophin protein expression was assessed in the Efficacy Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All: DS-5141b 2.0 mg/kg | Mean Dystrophin Protein Expression in Muscle Tissue | Baseline: Normalized by myosin heavy chain | 2.51 percent of normal protein expression | Standard Deviation 4.13 |
| All: DS-5141b 2.0 mg/kg | Mean Dystrophin Protein Expression in Muscle Tissue | Post Extension Treatment: Normalized by myosin heavy chain | 3.65 percent of normal protein expression | Standard Deviation 5.98 |
| All: DS-5141b 6.0 mg/kg | Mean Dystrophin Protein Expression in Muscle Tissue | Baseline: Normalized by myosin heavy chain | 1.86 percent of normal protein expression | Standard Deviation 1.95 |
| All: DS-5141b 6.0 mg/kg | Mean Dystrophin Protein Expression in Muscle Tissue | Post Extension Treatment: Normalized by myosin heavy chain | 2.43 percent of normal protein expression | Standard Deviation 2.42 |
Primary
Number of Participants Reporting at Least One Treatment-emergent Adverse Event (TEAE) In Participants With Duchenne Muscular Dystrophy
A treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during treatment having been absent prior to treatment or reemerges during treatment or worsens in severity during treatment.
Time frame: 48 Weeks of Part 2-Extension-2
Population: Safety events were assessed in the Safety Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All: DS-5141b 2.0 mg/kg | Number of Participants Reporting at Least One Treatment-emergent Adverse Event (TEAE) In Participants With Duchenne Muscular Dystrophy | 3 Participants |
| All: DS-5141b 6.0 mg/kg | Number of Participants Reporting at Least One Treatment-emergent Adverse Event (TEAE) In Participants With Duchenne Muscular Dystrophy | 5 Participants |
Primary
Pharmacokinetic Parameter Area Under the Curve (AUC) Tau of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy
Pharmacokinetic parameters were assessed using non-compartmental methods.
Time frame: Week 48 of Part 2-Extension-2
Population: Pharmacokinetic parameters were assessed in participants with available data in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All: DS-5141b 2.0 mg/kg | Pharmacokinetic Parameter Area Under the Curve (AUC) Tau of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy | 23100 ng*h/mL | Standard Deviation 5920 |
| All: DS-5141b 6.0 mg/kg | Pharmacokinetic Parameter Area Under the Curve (AUC) Tau of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy | 102000 ng*h/mL | Standard Deviation 45600 |
Primary
Pharmacokinetic Parameter Half-life (T1/2) of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Dystrophy
Pharmacokinetic parameters were assessed using non-compartmental methods.
Time frame: Week 48 of Part 2-Extension-2
Population: Pharmacokinetic parameters were assessed in participants with available data in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| All: DS-5141b 6.0 mg/kg | Pharmacokinetic Parameter Half-life (T1/2) of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Dystrophy | 32.4 hours |
Primary
Pharmacokinetic Parameter Maximum Concentration (Cmax) of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy
Pharmacokinetic parameters were assessed using non-compartmental methods.
Time frame: Week 48 of Part 2-Extension-2
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All: DS-5141b 2.0 mg/kg | Pharmacokinetic Parameter Maximum Concentration (Cmax) of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy | 1320 ng/mL | Standard Deviation 293 |
| All: DS-5141b 6.0 mg/kg | Pharmacokinetic Parameter Maximum Concentration (Cmax) of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy | 5190 ng/mL | Standard Deviation 2590 |
Primary
Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy
Pharmacokinetic parameters were assessed using non-compartmental methods.
Time frame: Week 48 of Part 2-Extension-2
Population: Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All: DS-5141b 2.0 mg/kg | Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy | 1.98 hours |
| All: DS-5141b 6.0 mg/kg | Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) of DS-5141a (Free Form of DS-5141b) in Participants With Duchenne Muscular Dystrophy | 4.07 hours |
Secondary
Number of Participants With Exon 45-skipped Dystrophin mRNA Expression in Muscle Tissue Posttreatment
Time frame: Week 48 of Part 2-Extension-2
Population: Dystrophin mRNA expression was assessed in the Efficacy Analysis Set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All: DS-5141b 2.0 mg/kg | Number of Participants With Exon 45-skipped Dystrophin mRNA Expression in Muscle Tissue Posttreatment | 3 Participants |
| All: DS-5141b 6.0 mg/kg | Number of Participants With Exon 45-skipped Dystrophin mRNA Expression in Muscle Tissue Posttreatment | 5 Participants |