A Phase 1/2 of NS-050/NCNP-03 in Boys With DMD (Meteor50)

Study Overview
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Brief Summary
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This is a Phase 1/2 study of Multiple-Ascending Dose (MAD) levels for 12 weeks of treatment followed by 24 weeks of open-label treatment with a selected dose of NS-050/NCNP-03 administered once weekly to ambulant boys with DMD, who have a DMD mutation amenable to exon 50 skipping.

Official Title
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A Phase 1/2, First in Human, Multiple-dose, 2-part Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NS-050/NCNP-03 in Boys With Duchenne Muscular Dystrophy (DMD)

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Drug: NS-050/NCNP-03
* Drug: Placebo


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 50 to restore the dystrophin mRNA reading frame; Able to walk independently without assistive devices; Able 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., oxendolone, oxandrolone) or products containing resveratrol or adenosine triphosphate within 3 months prior to first dose of study drug; Currently taking another investigational drug or has taken another investigational drug within 3 months prior to the first dose of study drug; Surgery within the 3 months prior to the first dose of study drug or planned during the study duration; Having taken any gene therapy. 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: NS-050/NCNP-03<br>Participants will be randomized and receive NS-050/NCNP-03 intravenous (IV) infusions once weekly for 2 weeks at each of MAD levels (1.95, 5, 10, 20, 40, and 80 mg/kg). | Drug: NS-050/NCNP-03<br>* NS-050/NCNP-03 solution for IV infusion.<br>|
| Placebo Comparator: Part 1: Placebo<br>Participants will be randomized and receive NS-050/NCNP-03 placebo-matching IV infusions once weekly for 2 weeks at each of MAD levels. | Drug: Placebo<br>* NS-050/NCNP-03 placebo-matching solution for IV infusion.<br>|
| Experimental: Part 2: NS-050/NCNP-03<br>Participants will receive NS-050/NCNP-03 IV infusions once weekly for 24 weeks at the dosage selected by the Data and Safety Monitoring Board (DSMB) at the conclusion of Part 1. | Drug: NS-050/NCNP-03<br>* NS-050/NCNP-03 solution for IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Overall Summary of Treatment-emergent Adverse Events (TEAEs) | TEAEs will be summarized both at the patient level for number of TEAEs, highest severity, relationship, action, and outcome, and at the TEAE level (summarizing events) by system organ class (SOC) and preferred term (PT) as well as severity, relationship, action, and outcome. The most recent version of the Medical Dictionary for Regulatory Activities (MedDRA) will be used for coding TEAEs. | Baseline up to Week 24 | 
| Part 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of NS-050/NCNP-03 | Blood samples will be collected at the designated time frame. Pharmacokinetic (PK) parameters of NS-050/NCNP-03 will be calculated using non-compartmental methods. | Day 1 (1st dose) for each dose level | 
| Part 1: Amount of Drug Excreted in Urine of NS-050/NCNP-03 | Urine samples will be collected at the designated time frame. PK parameters of NS-050/NCNP-03 will be calculated using non-compartmental methods. | Day 1 (1st dose) for each dose level | 
| Part 2: Change from baseline in skeletal muscle dystrophin protein by immunoblot (Western blot) |  | Baseline, Week25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Change from baseline in skeletal muscle dystrophin protein by mass spectrometry |  | Baseline, Week25 | 
| Part 2: Change from baseline in skeletal muscle dystrophin protein levels by immunofluorescence staining |  | Baseline, Week25 | 
| Part 2: Change from baseline in percentage of exon 50-skipped mRNA of skeletal muscle dystrophin |  | Baseline, Week25 | 
| Part 2: 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 | 
| Part 2: Time to Stand (TTSTAND) |  | Baseline, Week13, Week25 | 
| Part 2: Time to Run/Walk 10 Meters (TTRW) |  | Baseline, Week13, Week25 | 
| Part 2: Time to Climb 4 Stairs (TTCLIMB) |  | Baseline, Week13, Week25 | 
| Part 2: Total distance of 6 Minute Walk Test (6MWT) |  | Baseline, Week13, Week25 | 
| Part 2: Muscle strength measured by Quantitative Muscle Testing (QMT) |  | Baseline, Week13, Week25 | 
| Part 2: Grip and Pinch strength |  | Baseline, Week13, Week25 | 
| Part 2: 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 |