Study of an Investigational Drug, RO7239361 (BMS-986089), in Ambulatory Boys With DMD

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and tolerability of RO7239361 in boys with Duchenne Muscular Dystrophy with any genetic mutation.

Official Title
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A Multi-Site, Randomized, Placebo-Controlled, Double-Blind, Multiple Ascending Subcutaneous Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of RO7239361 (BMS-986089) in Ambulatory Boys With Duchenne Muscular Dystrophy

Conditions
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Muscular Dystrophy (DMD)

Intervention / Treatment
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* Drug: RO7239361
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with DMD Able to walk without assistance Able to walk up 4 stairs in 8 seconds or less Weigh at least 15 kg Taking corticosteroids for DMD Exclusion Criteria: Ejection fraction < 55% on echocardiogram, based on central read Any behavior or mental issue that will affect the ability to complete the required study procedures Previously or currently taking medications like androgens or human growth hormone Use of a ventilator during the day Unable to have blood samples collected or receive an injection under the skin Treatment with exon skipping therapies 6 months prior to study start Treatment with ataluren or any investigational drug currently or within 5 half-lives prior to study start

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 10 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RO7239361<br>RO7239361 subcutaneous injections on specified days | Drug: RO7239361<br>* Colorless to slightly yellow, clear to opalescent solution, essentially free of particulate matter packaged in a 1 cc glass syringe equipped with a safety syringe device.<br>* Other names: taldefgrobep alfa;|
| Placebo Comparator: Placebo<br>Placebo subcutaneous injections on specified days | Drug: Placebo<br>* Colorless to slightly yellow, clear to opalescent solution, essentially free of particulate matter packaged in a 1 cc glass syringe equipped with a safety syringe device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Summary for the 24 Week Double-Blind Phase | Percentage of participants with fatalities, adverse event (AEs) and serious adverse events (SAEs) up to Week 24. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Baseline to Week 24 | 
| Safety Summary up to Week 72 | Percentage of participants with fatalities, adverse event (AEs) and serious adverse events (SAEs) up to Week 72. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Baseline to Week 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentrations (Cmax) of RO7239361 at Steady State for 4 mg QW, 12.5 mg QW and 35 mg QW Doses. | PK parameter estimates at steady state. Steady state was achieved following approximately 12 weeks QW administration. Panel: 1 = 4mg QW, 2 = 12.5mg QW, 3 = 35mg QW Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. No participants received the Panel 2 20mg dose. | Day 1: predose, 3, 6, 72 and 96 hours (h) postdose; Days 8, 15 and 22: predose; Day 29: predose and 96 h postdose; Weeks 12 and 24: predose | 
| Maximum Observed Serum Concentrations (Cmax) of RO7239361 at Steady State for 50 mg QW Dose. | PK parameter estimates at steady state following approximately 12 weeks QW administration. Panel 3 = 50 mg QW Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Day 1: predose, 3, 6, 72 and 96 h postdose; Days 8, 15 and 22: predose; Day 29: predose and 96 h postdose; Weeks 12 and 24: predose | 
| Time of Maximum Observed Serum Concentrations (Tmax) of RO7239361 at Steady State for 4 mg QW, 12.5 mg QW and 35 mg QW Doses. | PK parameter estimates at steady state. Steady state was achieved following approximately 12 weeks QW administration. Panel: 1 = 4mg QW, 2 = 12.5mg QW, 3 = 35mg QW. Results for the Panel 3 50mg QW dose level are represented in Outcome Measure 6. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Day 1: predose, 3, 6, 72 and 96 h postdose; Days 8, 15 and 22: predose; Day 29: predose and 96 h postdose; Weeks 12 and 24: predose | 
| Time of Maximum Observed Serum Concentrations (Tmax) of RO7239361 at Steady State for 50 mg QW Dose. | PK parameter estimates at steady state following approximately 12 weeks QW administration. Panel 3 = 50 mg QW Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Day 1: predose, 3, 6, 72 and 96 h postdose; Days 8, 15 and 22: predose; Day 29: predose and 96 h postdose; Weeks 12 and 24: predose | 
| Area Under the Concentration-Time Curve From Time Zero to Time of Next Dosing (AUCtau) of RO7239361 at Steady State for 4 mg QW, 12.5 mg QW and 35 mg QW Doses. | PK parameter estimates at steady state. Steady state was achieved following approximately 12 weeks QW administration. Panel: 1 = 4mg QW, 2 = 12.5mg QW, 3 = 35mg QW Results for the Panel 3 50mg QW dose level are represented in Outcome Measure 8. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Day 1: predose, 3, 6, 72 and 96 h postdose; Days 8, 15 and 22: predose; Day 29: predose and 96 h postdose; Weeks 12 and 24: predose | 
| Area Under the Concentration-Time Curve From Time Zero to Time of Next Dosing (AUCtau) of RO7239361 at Steady State for 50 mg QW Dose. | PK parameter estimates at steady state following approximately 12 weeks QW administration. Panel 3 = 50 mg QW Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Day 1: predose, 3, 6, 72 and 96 h postdose; Days 8, 15 and 22: predose; Day 29: predose and 96 h postdose; Weeks 12 and 24: predose | 
| RO7239361 Trough Concentrations | Trough concentrations of RO7239361 at different dose levels. Panel 1 = 4mg, Panel 2 = 12.5mg and 20mg, Panel 3 = 35mg, Expansion Panels = 35mg and 50mg. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Day 1: predose, 3, 6, 72 and 96 h postdose; Days 8, 15 and 22: predose; Day 29: predose and 96 h postdose; Weeks 12 and 24: predose | 
| Percentage of Participants With Positive Anti-RO7239361 Antibodies (ADA) Assessment, Double-Blind Phase | A positive ADA sample is defined as one in which the presence of detectable ADAs is confirmed to be specific to RO7239361. A participant is considered as ADA positive if, after initiation of treatment, they have an ADA positive relative to baseline sample. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Day 8 through Week 24, baseline and on-study information represented in table. | 
| Percentage of Participants With Positive Anti-RO7239361 Antibodies (ADA) Assessment up to Week 72 | A positive ADA sample is defined as one in which the presence of detectable ADAs is confirmed to be specific to RO7239361. A participant is considered as ADA positive if, after initiation of treatment, they have an ADA positive relative to baseline sample. Double-blind phase data for placebo participants is not included. Placebo participants in each arm moved on to RO7239361 upon entering the open label phase. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Day 8 through Week 72, baseline and on-study information represented in table. | 
| Serum Concentration of Free Myostatin in the Double-Blind Phase | Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Baseline through Week 24 | 
| Percent Inhibition of Free Myostatin in the Double-Blind Phase | Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Baseline through Week 24 | 
| Serum Concentration of Drug-Myostatin Complex in the Double-Blind Phase | Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Baseline through Week 24 | 
| Fold Change From Baseline in Contractile Versus Non-contractile Content for Muscles in the Right Thigh in the Double-Blind Phase | Ratio of contractile vs non-contractile content is contractile content / non-contractile content. Fold change from baseline of the ratio is defined as the ratio of fold change from baseline of contractile content vs fold change from baseline of non-contractile content. Right thigh measurements. W12 = Week 12, W24 = Week 24. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Baseline through Week 24 | 
| Change From Baseline in Thigh Muscle Maximal Cross Sectional Area (CSAmax) in the Double-Blind Phase | Right thigh measurements. W12 = Week 12, W24 = Week 24. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Baseline through Week 24 | 
| Percentage of Participants With Positive Anti-RO7239361 Antibodies (ADA) Assessment, Whole Study | A positive ADA sample is defined as one in which the presence of detectable ADAs is confirmed to be specific to RO7239361. A participant is considered as ADA positive if, after initiation of treatment, they have an ADA positive relative to baseline sample. Double-blind phase data for placebo participants are not included in this Whole Study outcome measure, but are reported in the outcome measure specific to the double-blind period. At the end of the double-blind period participants in the placebo arm switched to one of the RO7239361 arms upon entering the open label phase. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Day 8 through Week 228, baseline and on-study information represented in table. | 
| Serum Concentration of Free Myostatin, Whole Study | Double-blind phase data for placebo participants are not included in this Whole Study outcome measure, but are reported in the outcome measure specific to the double-blind period. At the end of the double-blind period participants in the placebo arm switched to one of the RO7239361 arms upon entering the open label phase. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Baseline through Week 252 | 
| Percent Inhibition of Free Myostatin, Whole Study | Double-blind phase data for placebo participants are not included in this Whole Study outcome measure, but are reported in the outcome measure specific to the double-blind period. At the end of the double-blind period participants in the placebo arm switched to one of the RO7239361 arms upon entering the open label phase. Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Baseline through Week 252 | 
| Serum Concentration of Drug-Myostatin Complex, Whole Study | Participants in the Placebo arm received placebo during the double-blind (DB) period (up to Week 24) and received RO7239361 during the open label (OL) phase. PFS in table row title indicates when study drug was changed from vial to prefilled syringe (PFS). Participants in Panel 1 received 4 mg RO7239361; participants in Panel 2 received either 12.5 mg (weight between 15 and 45 kg) or 20 mg (weight >45 kg) RO7239361, and participants in Panel 3 and the Expansion Panel received either 35 mg (weight between 15 and 45 kg) or 50 mg (weight >45 kg) RO7239361. | Baseline through Week 252 |