Phase I/II Study of PRO044 in Duchenne Muscular Dystrophy (DMD)

Study Overview
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Brief Summary
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The purpose of this study is to see whether PRO044 is safe and effective to use as medication for DMD patients with a mutation around location 44 in the DNA for the dystrophin protein.

Detailed Description
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To assess the effect of PRO044 at different dose levels in subjects with Duchenne muscular dystrophy To assess the safety and tolerability of PRO044 at different dose levels in subjects with Duchenne muscular dystrophy To determine the pharmacokinetics of PRO044 at different dose levels after subcutaneous and intravenous administration in subjects with Duchenne muscular dystrophy.

Official Title
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A Phase I/IIa, Open Label, Escalating Dose, Pilot Study to Assess the Effect, Safety, Tolerability and Pharmacokinetics of Multiple Subcutaneous and Intravenous Doses of PRO044 in Patients With Duchenne Muscular Dystrophy

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Drug: PRO044 SC
* Drug: PRO044 IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Boys aged between 5 and 16 years inclusive. Duchenne muscular dystrophy resulting from a mutation correctable by treatment with PRO044. Life expectancy of at least 6 months. No previous treatment with investigational medicinal treatment within 6 months prior to the start of the (pre)-screening for the study. No previous treatment with idebenone within 6 months prior to the start of the (pre)-screening for the study. Willing and able to adhere to the study visit schedule and other protocol requirements. Written informed consent signed (by parent(s)/legal guardian and/or the patient, according to the local regulations). Glucocorticosteroids use which is stable for at least 2 months prior first drug administration. Exclusion Criteria: Aberrant RNA splicing and/or aberrant response to PRO044, detected by in vitro PRO044 assay during pre-screening. Known presence of dystrophin in ≥ 5% of fibers in a pre-study diagnostic muscle biopsy. Severe muscle abnormalities defined as increased signal intensity in >50% of the tibialis anterior muscle at MRI. FEV1 and/or FVC < 60% of predicted. Current or history of liver or renal disease. Acute illness within 4 weeks prior to treatment (Day 1) which may interfere with the measurements. Severe mental retardation which in the opinion of the investigator prohibits participation in this study. Severe cardiac myopathy which in the opinion of the investigator prohibits participation in this study. Need for mechanical ventilation. Creatinine concentration above 1.5 times the upper limit of normal (age corrected). Serum ASAT and/or ALAT concentration(s) which suggest hepatic impairment. Use of anticoagulants, antithrombotics or antiplatelet agents. Use of idebenone. Use of any investigational product within 6 months prior to the start of the (pre)-screening for the study. Subject has donated blood less than 90 days before the start of the (pre)-screening for the study. Current or history of drug and/or alcohol abuse. Participation in another trial with an investigational product.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 16 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PRO044, cohort 1<br>Subcutaneous injection of 0.5 mg/kg on day 1, 8, 15, 22 and 29. | Drug: PRO044 SC<br>* Subcutaneous injection, once a week, for five weeks<br>|
| Experimental: PRO044, cohort 2<br>Subcutaneous injection of maximally 1.5 mg/kg on day 1, 8, 15, 22 and 29. | Drug: PRO044 SC<br>* Subcutaneous injection, once a week, for five weeks<br>|
| Experimental: PRO044, cohort 3<br>Subcutaneous injection of maximally 5 mg/kg on day 1, 8, 15, 22 and 29. | Drug: PRO044 SC<br>* Subcutaneous injection, once a week, for five weeks<br>|
| Experimental: PRO044, cohort 4<br>Subcutaneous injection of maximally 8 mg/kg on day 1, 8, 15, 22 and 29. | Drug: PRO044 SC<br>* Subcutaneous injection, once a week, for five weeks<br>|
| Experimental: PRO044, cohort 5<br>Subcutaneous injection of maximally 10 mg/kg on day 1, 8, 15, 22 and 29 | Drug: PRO044 SC<br>* Subcutaneous injection, once a week, for five weeks<br>|
| Experimental: PRO044, cohort 6<br>Subcutaneous injection of maximally 12 mg/kg on day 1, 8, 15, 22 and 29 | Drug: PRO044 SC<br>* Subcutaneous injection, once a week, for five weeks<br>|
| Experimental: PRO044, cohort 7<br>Intravenous injection of maximally 1.5 mg/kg on day 1, 8, 15, 22 and 29 | Drug: PRO044 IV<br>* Intravenous injection, once a week, for five weeks<br>|
| Experimental: PRO044, cohort 8<br>Intravenous injection of maximally 5 mg/kg on day 1, 8, 15, 22 and 29 | Drug: PRO044 IV<br>* Intravenous injection, once a week, for five weeks<br>|
| Experimental: PRO044, cohort 9<br>Intravenous injection of maximally 8 mg/kg on day 1, 8, 15, 22 and 29 | Drug: PRO044 IV<br>* Intravenous injection, once a week, for five weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Increase in Dystrophin Expression in the Muscle Biopsies by Immunofluorescence Analyses of Cross-sections and by Western Blot Analyses of Total Protein Extracts |  | Within 13 weeks after 5 weeks of treatment | 
| Safety and Tolerability of PRO044 | number of subjects with 1 or more treatment emergent adverse events following SC or IV PRO044 | During the 5 weeks of treatment and during the 13 weeks after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PRO044 Pharmacokinetic Cmax (μg/mL) Following Subcutaneous Administration | Pharmacokinetic population evaluated for maximum plasma concentration (Cmax) | Week 1, Week 5 |