Exploratory Study of NS-089/NCNP-02 in DMD

Study Overview
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Brief Summary
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This study is designed to assess the safety, tolerability, efficacy and pharmacokinetics (PK) of NS-089/NCNP-02 in subjects diagnosed with Duchenne muscular dystrophy (DMD), and to determine the dosage for subsequent studies.

Official Title
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Exploratory Study of NS-089/NCNP-02 in Duchenne Muscular Dystrophy

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Drug: NS-089/NCNP-02


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has an out of frame deletion(s) that could be corrected by skipping exon 44 as confirmed by any of methodology at the time of visit 1. If not confirmed by any of methodology that evaluates the relative copy number of all exons (i.e. MLPA etc), must be confirmed through these techniques by the time of visit 3. DNA sequencing of exon 44 confirms that no DNA polymorphisms occur that could compromise duplex formation between NS-089/NCNP-02 and pre-mRNA. Male and >= 8 years and < 17 years of age at the time of obtaining informed consent and/or assent. Subjects aged >= 4 years and < 8 years can be enrolled according to the circumstances. Able to give informed consent in writing signed by parent(s) or legal guardian who is able to understand all of the study procedure requirements. If applicable, able to give informed assent in writing signed by the subject. Life expectancy of at least 1 year Able to ambulate. Non-ambulant subject can be enrolled according to the circumstances. Have intact muscles, which have adequate quality for biopsy. (No lacks or severe atrophy of biceps brachii or tibialis anterior muscle) QTc <450 msec (based on 12-lead ECGs), or <480 msec for subject with Bundle Branch Block. Glucocorticoid-naive patients, or patients who have used systemic 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: Has participated in other pharmacological clinical trial that might recover dystrophin protein by the readthrough or the exon-skipping therapy, and/or upregulate the dystrophin-associated proteins such as utrophin. A forced vital capacity (FVC) < 50% of predicted. Continuous use of artificial respirator (except for use of NPPV while sleeping) A left ventricular ejection fraction (EF) < 40% or fractional shortening (FS) < 25% based on echocardiogram (ECHO). Surgery within the last 3 months prior to the first anticipated administration of study medication or planned for anytime between visit 1 of Part 1 and the last visit of Part 2. Positive hepatitis B surface antigen (HbsAg), hepatitis C antibody test (HCV), or human immunodeficiency virus (HIV) test at screening. Current diagnosis of any immune deficiency or autoimmune disease. Current diagnosis of any active or uncontrolled infection, cardiomyopathy, or liver or renal disease. Use of any other investigational agents and/or experimental agents within 3 months prior to the first anticipated administration of study medication. History of any severe drug allergy.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 17 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NS-089/NCNP-02<br>NS-089/NCNP-02 | Drug: NS-089/NCNP-02<br>* NS-089/NCNP-02 for Infusion is packaged as 50 mg/mL with 3 mL per vial. Study dosages will be infused over a 1 hour period at the following dose levels. [Part 1] NS-089/NCNP-02 is administered at dose levels 1 and 3 in Cohort 1 and at dose levels 2 and 4 in Cohort 2. Dose level 1: 1.62 mg/kg once weekly for 2 weeks; Dose level 2: 10 mg/kg once weekly for 2 weeks; Dose level 3: 40 mg/kg once weekly for 2 weeks; Dose level 4: 80 mg/kg once weekly for 2 weeks [Part 2] Based on the results from Part 1, two dosages are selected as study dosages in Part 2. Each selected dose are administered once a week for 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse event and adverse drug reaction [Safety and Tolerability] | adverse event and adverse drug reaction | At the end of Part 2 (24 weeks treatment period and 12 weeks follow up period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression of dystrophin protein | Expression of dystrophin protein | At the end of the treatment period (24 weeks) of Part 2 | 
| NSAA | North Star Ambulatory Assessment | At the end of the treatment period (24 weeks) of Part 2 | 
| TTSTAND | Time to Stand Test | At the end of the treatment period (24 weeks) of Part 2 | 
| TTRW | Time to Run/Walk 10 Meters test | At the end of the treatment period (24 weeks) of Part 2 | 
| 6MWT and 2MWT | Six-Minute Walk Test (6MWT) and Two-Minute Walk Test (2MWT) | At the end of the treatment period (24 weeks) of Part 2 | 
| TUG | Timed Up & Go (TUG) test | At the end of the treatment period (24 weeks) of Part 2 | 
| PUL | Performance of Upper Limb test | At the end of the treatment period (24 weeks) of Part 2 | 
| Detection of exon 44-skipped mRNA of dystrophin in muscle tissue | Detection of exon 44-skipped mRNA of dystrophin in muscle tissue | At the end of the treatment period (24 weeks) of Part 2 | 
| NS-089/NCNP-02 concentration of the blood plasma | NS-089/NCNP-02 concentration of the blood plasma | At the end of Part 2 (24 weeks treatment period and 12 weeks follow up period) | 
| Serum Creatine kinase concentration | Serum Creatine kinase concentration | At the end of Part 2 (24 weeks treatment period and 12 weeks follow up period) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Duchenne Muscular Dystrophy