Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients

Study Overview
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Brief Summary
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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
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Primary outcome is safety, tolerability and dose selection for future studies.

Official Title
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Clinical Study to Assess the Safety fo AVI-4658 in Subjects With Duchenne Muscular Dystrophy Due to a Frame-shift Mutation Amenable to Correction by Skipping Exon 51.

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Drug: AVI-4658 for Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has provided written informed assent (as required by EC) and parents/guardians have provided written informed consent. Has an out-of-frame deletion(s) that could be corrected by skipping exon 51 based on DNA sequencing data from the candidate. Is male and between the ages of ≥ 5 years and ≤ 15 years. Has a muscle biopsy analysis showing < 5% revertant fibres present at baseline. 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. Intact right and left bicep muscles or alternative arm muscle group. Is able to walk independently at least 25 meters. Has a forced vital capacity (FVC) ≥ 50% of predicted and does not require ventilatory support or supplemental oxygen. Receives the standard of care for DMD as recommended by the DMD care recommendations from the North Star UK and TREAT-NMD. The parent(s) or legal guardian and Subject have undergone counselling about the expectations of this protocol and agree to participate. The parent(s) or legal guardian and Subject intend to comply with all study evaluations and return for all study activities. Exclusion Criteria: A DNA polymorphism within exon 51 that may compromise PMO duplex formation. Known antibodies to dystrophin. Lacks intact right and left bicep muscles or alternative arm muscle group. A calculated creatinine clearance less than 70% of predicted normal for age based on the Cockcroft and Gault Formula. A left ventricular ejection fraction (EF) of < 35% and/or fractional shortening of <25% based on echocardiography (ECHO)during screening. A history of respiratory insufficiency as defined by need for intermittent or continuous supplemental oxygen. A severe cognitive dysfunction rendering the potential subject unable to understand and comply with the study protocol. Any known immune deficiency or autoimmune disease. A known bleeding disorder or has received chronic anticoagulant treatment within three months of study entry. 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). Surgery within 3 months of study entry or planned for anytime during the duration of the study. Another clinically significant illness at time of study entry. 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. 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.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - 0.5 mg/kg/wk<br>Subjects in this group will receive 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 | Drug: AVI-4658 for Injection<br>* 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.<br>* Other names: Eteplirsen;|
| Experimental: Cohort 2 - 1.0 mg/kg/wk<br>Subjects in this group will receive 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 | Drug: AVI-4658 for Injection<br>* 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.<br>* Other names: Eteplirsen;|
| Experimental: Cohort 3 - 2.0 mg/kg/wk<br>Subjects in this group will receive 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 | Drug: AVI-4658 for Injection<br>* 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.<br>* Other names: Eteplirsen;|
| Experimental: Cohort 4 - 4.0 mg/kg/wk<br>Subjects in this group will receive 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 | Drug: AVI-4658 for Injection<br>* 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.<br>* Other names: Eteplirsen;|
| Experimental: Cohort 5 - 10.0 mg/kg/wk<br>Subjects in this group will receive 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 | Drug: AVI-4658 for Injection<br>* 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.<br>* Other names: Eteplirsen;|
| Experimental: Cohort 6 - 20.0 mg/kg/wk<br>Subjects in this group will receive 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 | Drug: AVI-4658 for Injection<br>* 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.<br>* Other names: Eteplirsen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | Number of subjects with 1 or more Treatment Emergent Adverse Event that are possibly related to the investigational drug | Baseline to 6 months | 
| Treatment Emergent Adverse Events | Number of Patients with Treatment Emergent Adverse Events | from Baseline to Follow up (27 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - Mean Peak Plasma Concentration of AVI-4658 After Administration | Standard Pharmacokinetic parameters estimated using non-compartmental modeling of plasma concentration data. | 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 | 
| 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. | Biopsies were taken at Baseline and Week 14 |