NS-089/NCNP-02-201 in Boys With Duchenne Muscular Dystrophy (DMD)

Study Overview
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Brief Summary
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This is a Phase 2, open-label, multi-center, 2-part study of NS-089/NCNP-02 administered by weekly IV infusion to ambulant boys aged ≥4 to <15 years with DMD due to mutations amenable to exon 44 skipping. Participants will receive a selected dose of NS-089/NCNP-02 administered once weekly. The study consists of 2 parts: Part 1 and Part 2. Six participants (Cohort 1) will participate in both Part 1 and Part 2, and 14 participants (Cohort 2) will be added for Part 2.

Official Title
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A Phase 2 Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of NS-089/NCNP-02 in Boys With Duchenne Muscular Dystrophy (DMD)

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: Male ≥ 4 years and <15 years of age Confirmed DMD mutation(s) in the dystrophin gene that is amenable to skipping of exon 44 to restore the dystrophin mRNA reading frame Able to walk independently without assistive devices Ability to complete the TTSTAND without assistance in <7 seconds Stable dose of glucocorticoid for at least 3 months and the dose is expected to remain on a stable dose for the duration of the study. Other inclusion criteria may apply. Exclusion Criteria: Evidence of symptomatic cardiomyopathy Current or previous treatment with anabolic steroids (e.g., oxandrolone) or products containing resveratrol or adenosine triphosphate within 3 months prior to first dose of study drug Current or previous treatment with any other investigational drug within 3 months prior to the first dose of study drug or within 5 times the half-life of a medication, whichever is longer Surgery within the 3 months prior to the first dose of study drug or planned during the study duration Previously treated in an interventional study of NS-089/NCNP-02 Having taken any gene therapy or other exon-skipping oligonucleotide Other exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 14 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NS-089/NCNP-02<br>Experimental: NS-089/NCNP-02 NS-089/NCNP-02 solution for infusion (Cohort 1) NS-089/NCNP-02 solution for infusion (Cohort 2) | Drug: NS-089/NCNP-02<br>* Cohort 1: Part 1 Dose Level 1-3: a 4-week Treatment Phase at each treatment dose level Part 2 Single Dose Level: a 24-week Treatment Phase at the MTD of Part 1 Cohort 2: Part 2 Single Dose Level: a 24-week Treatment Phase at the MTD of Part 1<br>* Other names: Brogidirsen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event and Adverse Drug Reaction |  | through study completion, up to follow-up phone call for Part 2 | 
| Plasma pharmacokinetic (PK) parameters |  | Day1, Week4 for each dose for Part 1, Day1 and Week24 for Part 2] Maximum plasma concentration (Cmax) of NS-089/NCNP-02 | 
| Plasma pharmacokinetic (PK) parameters |  | Day1, Week4 for each dose for Part 1, Day1 and Week24 for Part 2] Time of the maximum plasma concentration （Tmax） of NS-089/NCNP-02 | 
| Plasma pharmacokinetic (PK) parameters |  | Day1, Week4 for each dose for Part 1, Day1 and Week24 for Part 2] Terminal half-life (T1/2) of NS-089/NCNP-02 | 
| Plasma pharmacokinetic (PK) parameters |  | Day1, Week4 for each dose for Part 1, Day1 and Week24 for Part 2] Area under the concentration-time curve from time 0 to the last time point (AUC0-t) of NS-089/NCNP-02 | 
| Plasma pharmacokinetic (PK) parameters |  | Day1, Week4 for each dose for Part 1, Day1 and Week24 for Part 2] Area under the concentration-time curve from time 0 to infinity (AUC0-∞) of NS-089/NCNP-02 | 
| Plasma pharmacokinetic (PK) parameters |  | [Time Frame: Day1, Week4 for each dose for Part 1, Day1 and Week24 for Part 2] Total body clearance (CLtot) of NS-089/NCNP-02 | 
| Plasma pharmacokinetic (PK) parameters |  | Day1, Week4 for each dose for Part 1, Day1 and Week24 for Part 2] The steady-state volume of distribution (Vdss) of NS-089/NCNP-02 | 
| Urine pharmacokinetic parameters |  | Day1, Week4 for each dose for Part 1, Day1 and Week24 for Part 2] Urinary excretion of NS-089/NCNP-02 | 
| Change from baseline in skeletal muscle dystrophin protein by immunoblot (Western blot). |  | Baseline, Week25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in skeletal muscle dystrophin protein by mass spectrometry. |  | Baseline, Week25 | 
| Change from baseline in skeletal muscle dystrophin protein levels by immunofluorescence staining. |  | Baseline, Week25 | 
| Change from baseline in percentage of exon 44-skipped mRNA of skeletal muscle dystrophin |  | Baseline, Week25 | 
| North Star Ambulatory Assessment (NSAA) score | The NSAA is a functional scale devised for use in ambulant children with Duchenne muscular dystrophy (DMD). It consists of 17 activities graded 0 (unable to perform), 1 (performs with modifications), 2 (normal movement). It assesses abilities necessary to remain ambulant that have been found to progressively deteriorate in untreated DMD patients, as well as in other muscular dystrophies such as Becker Muscular Dystrophy. NSAA Total Score ranges from 0 to 34, with a score of 34 implying normal function. | Baseline, Week13, Week25 | 
| Time to Run/Walk 10 Meters (TTRW) |  | Baseline, Week13, Week25 | 
| Time to Stand (TTSTAND) |  | Baseline, Week13, Week25 | 
| Total distance of 6 Minute Walk Test (6MWT) |  | Baseline, Week13, Week25 | 
| Time to Climb 4 Stairs (TTCLIMB) |  | Baseline, Week13, Week25 | 
| Muscle strength measured by Quantitative Muscle Testing (QMT) |  | Baseline, Week13, Week25 | 
| Grip and pinch strength |  | Baseline, Week13, Week25 | 
| Performance of Upper Limb (PUL) 2.0. score | The PUL 2.0 provides both a total score and sub-scores for the 3 domains (shoulder, middle, and distal) that in DMD are progressively involved with a proximal to distal gradient. The PUL includes 22 items with an entry item to define the starting functional level. The 22 items are subdivided into the high-level shoulder dimension (6 items), middle level elbow dimension (9 items), and distal wrist and hand dimension (7 items). For weaker patients, a low score on the entry item (0-2) means high level items do not need to be performed. Scoring options vary across the scale between 0-1 and 0-2 according to performance. Each dimension can be scored separately with a maximum score of 12 for the high-level shoulder dimension, 17 for the middle level elbow dimension, and 13 for the distal wrist and hand dimension. A total score can be achieved by adding the 3 level scores (maximum total score of 42). | Baseline, Week13, Week25 |