Study of ARO-DUX4 in Adult Patients With Facioscapulohumeral Muscular Dystrophy Type 1

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ARO-DUX4 in participants with facioscapulohumeral muscular dystrophy Type 1 (FSHD1). In Part 1 of the study, participants will receive a single dose of ARO-DUX4 or placebo. In Part 2 of the study, participants will receive 2 or 4 doses of ARO-DUX4 or placebo. Participants who complete Part 1 will have the option to re-screen and re-randomize into Part 2. All participants will undergo pre- and post-dose MRI-guided muscle biopsies (a total of 2 biopsies). Participants who complete Part 1 and enroll in Part 2 will be required to undergo an additional screening biopsy. Participants completing Part 1 or Part 2 may have the option to continue to receive drug in an open-label extension study or may be eligible to participate in later-stage clinical studies.

Official Title
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A Phase1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ARO-DUX4 in Adult Patients With Facioscapulohumeral Muscular Dystrophy Type 1

Conditions
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Facio-Scapulo-Humeral Dystrophy

Intervention / Treatment
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* Drug: ARO-DUX4 for Injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Genetically confirmed FSHD1 based on Screening evaluation or source verifiable medical record Clinical severity score between 3 and 8 (scale, 0 to 10) Must have eligible lower extremity muscle for biopsy as determined from MRI by a central reader A 12-lead electrocardiogram (ECG) at Screening with no abnormalities that may compromise participant's safety in the study Participants of childbearing potential and their partners must use highly effective contraception during the study and for at least 12 weeks following the end of study or last dose of study medication, whichever is later. Males must not donate sperm during the study from Day 1 until at least 12weeks following the end of study or last dose of study medication, whichever is later. Exclusion Criteria: Human Immunodeficiency Virus (HIV) infection as shown by presence of anti-HIV antibody (seropositive) at Screening Seropositive for hepatitis B (HBV) or hepatitis C (HCV) at Screening Uncontrolled hypertension Severe cardiovascular disease History of thrombolic eve4nts Platelet count less that the lower limit of normal at Screening History or presence of: a hypercoagulable state, nephrotic range proteinuria, antiphospholipid antibody syndrome, myeloproliferative disease, inability to ambulate, use of hormone-based contraceptives. Any contraindication to muscle biopsy or MRI Note: additional inclusion/exclusion criteria may apply per protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

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: ARO-DUX4<br>ARO-DUX4 for Injection | Drug: ARO-DUX4 for Injection<br>* single or multiple doses of ARO-DUX4 by intravenous (IV) infusion<br>|
| Placebo Comparator: Placebo<br>(0.9%NaCl) | Drug: Placebo<br>* calculated volume to match active treatment by IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Over Time Through End of Study (EOS) |  | Single dose phase: Up to Day 90; multiple dose phase: Up to Day 360 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of ARO-DUX4: Maximum Observed Plasma Concentration (Cmax) |  | Single dose phase: through 48 hours post-dose, Multiple dose phase: through 24 hours post first and second dose | 
| PK of ARO-DUX4: Area Under the Plasma Concentration Versus Time Curve from Zero to 24 Hours (AUC0-24) |  | Single dose phase: through 48 hours post-dose, Multiple dose phase: through 24 hours post first and second dose | 
| PK of ARO-DUX4: Area Under the Plasma Concentration Versus Time Curve from Zero to the Last Quantifiable Plasma Concentration (AUClast) |  | Single dose phase: through 48 hours post-dose, Multiple dose phase: through 24 hours post first and second dose | 
| PK of ARO-DUX4: Area Under the Plasma Concentration Versus Time from Zero to Infinity ( | AUCinf) | Single dose phase: through 48 hours post-dose, Multiple dose phase: through 24 hours post first and second dose | 
| PK of ARO-DUX4: Terminal Elimination Half-Life (t1/2) |  | Single dose phase: through 48 hours post-dose, Multiple dose phase: through 24 hours post first and second dose | 
| PK of ARO-DUX4: Systemic Clearance (CL) |  | Single dose phase: through 48 hours post-dose, Multiple dose phase: through 24 hours post first and second dose | 
| PK of ARO-DUX4: Volume of Distribution (Vss) |  | Single dose phase: through 48 hours post-dose, Multiple dose phase: through 24 hours post first and second dose | 
| PK of ARO-DUX4: Recovery of Unchanged Drug in Urine Over 0-24 Hours (Amount Excreted: Ae) |  | Single dose phase: through 48 hours post-dose, Multiple dose phase: through 24 hours post first and second dose | 
| PK of ARO-DUX4: Fraction of Drug Excreted in Urine as Percent of Intravenous (IV) Dose (Fe) |  | Single dose phase: through 48 hours post-dose, Multiple dose phase: through 24 hours post first and second dose | 
| PK of ARO-DUX4: Renal Clearance (CLr) |  | Single dose phase: through 48 hours post-dose, Multiple dose phase: through 24 hours post first and second dose |