Duchenne Muscular Dystrophy
Conditions
Brief summary
The specific aim of this Phase I/II study is to assess the safety of intravenous administered Morpholino oligomer directed against exon 51 (AVI-4658 PMO).
Detailed description
Primary outcome is safety, tolerability and dose selection for future studies.
Interventions
DRUGAVI-4658 for Injection
AVI-4658 for Injection, is packaged as 100 mg/mL in phosphate buffered saline with 1 mL per vial. Study dosages will be infused over a 1 hour period with Normal saline in 6 dose cohorts.
Sponsors
British Medical Research Council
Sarepta Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
5 Years to 15 Years
Healthy volunteers
No
Inclusion criteria
1. Has provided written informed assent (as required by EC) and parents/guardians have provided written informed consent. 2. Has an out-of-frame deletion(s) that could be corrected by skipping exon 51 based on DNA sequencing data from the candidate. 3. Is male and between the ages of ≥ 5 years and ≤ 15 years. 4. Has a muscle biopsy analysis showing \< 5% revertant fibres present at baseline. 5. DNA sequencing of the candidate's dystrophin exon 51 confirms that no DNA polymorphisms are present that could compromise PMO duplex formation or there is confirmation of in vitro dystrophin production after AVI-4658 exposure to fibroblast or myoblast in vitro cultures. 6. Intact right and left bicep muscles or alternative arm muscle group. 7. Is able to walk independently at least 25 meters. 8. Has a forced vital capacity (FVC) ≥ 50% of predicted and does not require ventilatory support or supplemental oxygen. 9. Receives the standard of care for DMD as recommended by the DMD care recommendations from the North Star UK and TREAT-NMD. 10. The parent(s) or legal guardian and Subject have undergone counselling about the expectations of this protocol and agree to participate. 11. The parent(s) or legal guardian and Subject intend to comply with all study evaluations and return for all study activities.
Exclusion criteria
1. A DNA polymorphism within exon 51 that may compromise PMO duplex formation. 2. Known antibodies to dystrophin. 3. Lacks intact right and left bicep muscles or alternative arm muscle group. 4. A calculated creatinine clearance less than 70% of predicted normal for age based on the Cockcroft and Gault Formula. 5. A left ventricular ejection fraction (EF) of \< 35% and/or fractional shortening of \<25% based on echocardiography (ECHO)during screening. 6. A history of respiratory insufficiency as defined by need for intermittent or continuous supplemental oxygen. 7. A severe cognitive dysfunction rendering the potential subject unable to understand and comply with the study protocol. 8. Any known immune deficiency or autoimmune disease. 9. A known bleeding disorder or has received chronic anticoagulant treatment within three months of study entry. 10. Receipt of pharmacologic treatment, apart from corticosteroids, that might affect muscle strength or function within 8 weeks of study entry (viz., growth hormone, anabolic steroids). 11. Surgery within 3 months of study entry or planned for anytime during the duration of the study. 12. Another clinically significant illness at time of study entry. 13. Subject or parent has active psychiatric disorder, has adverse psychosocial circumstances,recent significant emotional loss, and/or history of depressive or anxiety disorder that might interfere with protocol compliance. 14. Use of any experimental treatments, has participated in any DMD interventional clinical trial within 4 weeks of study entry or participated in the AVI-4658-33 intramuscular (i.m.) trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | Baseline to 6 months | Number of subjects with 1 or more Treatment Emergent Adverse Event that are possibly related to the investigational drug |
| Treatment Emergent Adverse Events | from Baseline to Follow up (27 weeks) | Number of Patients with Treatment Emergent Adverse Events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics - Mean Peak Plasma Concentration of AVI-4658 After Administration | Samples were taken: 30 minutes pre dose; and at 5 (±1), 15 (±2), 30 (±5), 60 (±5), and 90 (±5) minutes; and 2, 4, 6, 8, 12, and 24 hours (all ± 15 minutes) post dose at Weeks 1, 6, and 12 | Standard Pharmacokinetic parameters estimated using non-compartmental modeling of plasma concentration data. |
| Efficacy of Eteplirsen Over 12 Weeks of Dosing | Biopsies were taken at Baseline and Week 14 | Efficacy was defined as an estimated change in the percentage of dystrophin positive fibers (assessed by IHC) at Week 14 from Baseline after 12 weekly doses of eterplirsen. This outcome measure represents the number of patients to show an increase in the percentage of dystrophin-positive fibers. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - 0.5mg/kg/wk Subjects in this group received a 0.5 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period | 4 |
| Cohort 2 - 1.0mg/kg/wk Subjects in this group received a 1.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period | 2 |
| Cohort 3 - 2.0mg/kg/wk Subjects in this group received a 2.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period | 2 |
| Cohort 4 - 4.0mg/kg/wk Subjects in this group received a 4.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period | 3 |
| Cohort 5 - 10.0mg/kg/wk Subjects in this group received a 10.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period | 4 |
| Cohort 6 - 20.0mg/kg/wk Subjects in this group received a 20.0 mg/kg/wk dose of AVI-4658 over 12 weekly IV infusions in 50 mL of normal saline solution over a 60-minute period | 4 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 - 0.5mg/kg/wk | Cohort 2 - 1.0mg/kg/wk | Cohort 3 - 2.0mg/kg/wk | Cohort 4 - 4.0mg/kg/wk | Cohort 5 - 10.0mg/kg/wk | Cohort 6 - 20.0mg/kg/wk | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 8.3 years STANDARD_DEVIATION 0.5 | 6.0 years STANDARD_DEVIATION 0 | 11.0 years STANDARD_DEVIATION 2.83 | 9.7 years STANDARD_DEVIATION 0.58 | 8.8 years STANDARD_DEVIATION 2.75 | 8.8 years STANDARD_DEVIATION 1.26 | 8.7 years STANDARD_DEVIATION 1.91 |
| Body Weight | 33 kilograms STANDARD_DEVIATION 4.09 | 23.7 kilograms STANDARD_DEVIATION 3.46 | 42.6 kilograms STANDARD_DEVIATION 6.36 | 40.1 kilograms STANDARD_DEVIATION 19 | 34.6 kilograms STANDARD_DEVIATION 14.01 | 33.0 kilograms STANDARD_DEVIATION 8.71 | 34.5 kilograms STANDARD_DEVIATION 10.84 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 127.3 centimeters STANDARD_DEVIATION 5.05 | 110.7 centimeters STANDARD_DEVIATION 4.45 | 126.9 centimeters STANDARD_DEVIATION 5.09 | 126.9 centimeters STANDARD_DEVIATION 14.4 | 123.7 centimeters STANDARD_DEVIATION 10.04 | 126.5 centimeters STANDARD_DEVIATION 7.18 | 124.5 centimeters STANDARD_DEVIATION 8.99 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 1 Participants | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 18 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 2 / 2 | 2 / 2 | 3 / 3 | 4 / 4 | 4 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 2 | 1 / 2 | 1 / 3 | 0 / 4 | 0 / 4 |
Outcome results
Primary
Safety and Tolerability
Number of subjects with 1 or more Treatment Emergent Adverse Event that are possibly related to the investigational drug
Time frame: Baseline to 6 months
Population: Safety Population - Any patient who received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open Label Treatment Arm | Safety and Tolerability | 14 participants |
Primary
Treatment Emergent Adverse Events
Number of Patients with Treatment Emergent Adverse Events
Time frame: from Baseline to Follow up (27 weeks)
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open Label Treatment Arm | Treatment Emergent Adverse Events | 19 participants |
Secondary
Efficacy of Eteplirsen Over 12 Weeks of Dosing
Efficacy was defined as an estimated change in the percentage of dystrophin positive fibers (assessed by IHC) at Week 14 from Baseline after 12 weekly doses of eterplirsen. This outcome measure represents the number of patients to show an increase in the percentage of dystrophin-positive fibers.
Time frame: Biopsies were taken at Baseline and Week 14
Population: Per Protocol Population - Included all patients who received all 12 doses of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Open Label Treatment Arm | Efficacy of Eteplirsen Over 12 Weeks of Dosing | 11 participants |
Secondary
Pharmacokinetics - Mean Peak Plasma Concentration of AVI-4658 After Administration
Standard Pharmacokinetic parameters estimated using non-compartmental modeling of plasma concentration data.
Time frame: Samples were taken: 30 minutes pre dose; and at 5 (±1), 15 (±2), 30 (±5), 60 (±5), and 90 (±5) minutes; and 2, 4, 6, 8, 12, and 24 hours (all ± 15 minutes) post dose at Weeks 1, 6, and 12
Population: PK Evaluable Population: Included all patients who provided at least 1 PK sample. The reportable PK population included those patients with at least Cmax, Tmax, and AUC0-24 computed from 1 or more of the 3 sampling days (1st, 6th, 12th dose \[Weeks 1, 6, and 12\]).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Label Treatment Arm | Pharmacokinetics - Mean Peak Plasma Concentration of AVI-4658 After Administration | 39000 ng/mL | Standard Deviation 16900 |
Post Hoc
Adverse Events >15%
Adverse events that occurred in \>15% of overall patient population across dose level arms.
Time frame: 27 Weeks
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Open Label Treatment Arm | Adverse Events >15% | Myalgia | 1 Events |
| Open Label Treatment Arm | Adverse Events >15% | Abdominal Pain | 0 Events |
| Open Label Treatment Arm | Adverse Events >15% | Arthralgia | 1 Events |
| Open Label Treatment Arm | Adverse Events >15% | Vomiting | 0 Events |
| Open Label Treatment Arm | Adverse Events >15% | Cardiomyopathy | 0 Events |
| Open Label Treatment Arm | Adverse Events >15% | Upper respiratory tract infection | 2 Events |
| Open Label Treatment Arm | Adverse Events >15% | Dizziness | 0 Events |
| Open Label Treatment Arm | Adverse Events >15% | Nausea | 0 Events |
| Open Label Treatment Arm | Adverse Events >15% | Fall | 2 Events |
| Open Label Treatment Arm | Adverse Events >15% | Tachycardia | 0 Events |
| Open Label Treatment Arm | Adverse Events >15% | Rhinitis | 1 Events |
| Open Label Treatment Arm | Adverse Events >15% | Influenza like illness | 0 Events |
| Open Label Treatment Arm | Adverse Events >15% | Back Pain | 1 Events |
| Open Label Treatment Arm | Adverse Events >15% | Headache | 2 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Myalgia | 1 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Fall | 0 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Upper respiratory tract infection | 1 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Headache | 1 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Tachycardia | 0 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Arthralgia | 0 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Abdominal Pain | 1 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Dizziness | 0 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Nausea | 0 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Cardiomyopathy | 0 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Vomiting | 0 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Influenza like illness | 0 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Back Pain | 0 Events |
| Cohort 2 - 1.0 mg/kg/wk | Adverse Events >15% | Rhinitis | 0 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Upper respiratory tract infection | 0 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Vomiting | 1 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Cardiomyopathy | 0 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Dizziness | 1 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Back Pain | 1 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Tachycardia | 0 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Fall | 0 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Influenza like illness | 2 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Arthralgia | 1 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Nausea | 1 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Rhinitis | 0 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Myalgia | 1 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Headache | 2 Events |
| Cohort 3 - 2.0 mg/kg/wk | Adverse Events >15% | Abdominal Pain | 0 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Back Pain | 2 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Cardiomyopathy | 1 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Tachycardia | 1 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Abdominal Pain | 1 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Nausea | 1 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Vomiting | 1 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Influenza like illness | 0 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Rhinitis | 1 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Upper respiratory tract infection | 1 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Fall | 2 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Arthralgia | 1 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Myalgia | 0 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Dizziness | 1 Events |
| Cohort 4 - 4.0 mg/kg/wk | Adverse Events >15% | Headache | 0 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Fall | 0 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Cardiomyopathy | 0 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Influenza like illness | 1 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Arthralgia | 0 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Back Pain | 2 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Vomiting | 1 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Nausea | 0 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Myalgia | 1 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Abdominal Pain | 1 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Headache | 2 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Dizziness | 0 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Tachycardia | 0 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Upper respiratory tract infection | 2 Events |
| Cohort 5 - 10.0 mg/kg/wk | Adverse Events >15% | Rhinitis | 4 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Dizziness | 1 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Fall | 1 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Myalgia | 0 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Arthralgia | 0 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Influenza like illness | 0 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Abdominal Pain | 0 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Vomiting | 0 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Rhinitis | 1 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Tachycardia | 2 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Back Pain | 1 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Upper respiratory tract infection | 2 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Nausea | 1 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Cardiomyopathy | 2 Events |
| Cohort 6 - 20.0 mg/kg/wk | Adverse Events >15% | Headache | 1 Events |