Study of ARO-DM1 in Subjects With Type 1 Myotonic Dystrophy

Study Overview
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Brief Summary
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This is a Phase 1/2a double-blinded, placebo-controlled, dose-escalating study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple ascending doses of ARO-DM1 compared to placebo in male and female subjects with Type 1 Myotonic Dystrophy (DM1). Participants who have provided written informed consent and met all protocol eligibility requirements will be randomized to receive single (Part 1) or multiple (Part 2) doses of ARO-DM1 or placebo.

Official Title
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A Phase 1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ARO-DM1 in Subjects With Type 1 Myotonic Dystrophy Who Are ≥18 to ≤ 65 Years

Conditions
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Myotonic Dystrophy 1

Intervention / Treatment
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* Drug: ARO-DM1 for Injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Genetically confirmed diagnosis of DM1 Clinician-assessed signed of DM1 including clinically apparent myotonia Onset of DM1 symptoms occurred after the age of 12 years Walk for at least 10 meters independently at Screening Subjects of childbearing potential must agree to use highly effective contraception in addition to a condom during the study and for at least 90 days following the end of study or last dose of study drug, whichever is later. Subjects must not donate sperm or eggs during the study and for at least 90 days following the end of study or last dose of study drug whichever is later. Exclusion Criteria: Inadequately controlled diabetes Confirmed diagnosis of congenital DM1 Uncontrolled hypertension History of Tibialis Anterior (TA) biopsy within 3 months of Day 1 or planning to undergo TA biopsies during the study period Clinically significant cardiac, liver or renal disease HIV infection (seropositive) at Screening Seropositive for hepatitis B (HBV) or hepatitis C (HCV) at screening Untreated or poorly controlled epilepsy Treatment with anti-myotonia medication within a period of 5 half-lives of the medication prior to Screening. Note: Additional inclusion/exclusion criteria may apply per protocol

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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-DM1<br>ARO-DM1 for Injection | Drug: ARO-DM1 for Injection<br>* single or multiple doses of ARO-DM1 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 (Part 1): Up to Day 90; Multiple dose phase (Part 2): Up to Day 180 or Day 360 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of ARO-DM1: Maximum Observed Plasma Concentration (Cmax) |  | Single dose phase (Part 1): Up 24 hours post-dose; Multiple dose phase (Part 2): Through 24 hours post first and second dose | 
| PK of ARO-DM1: Time to Maximum Observed Plasma Concentration (Tmax) |  | Single dose phase (Part 1): Up 24 hours post-dose; Multiple dose phase (Part 2): Through 24 hours post first and second dose | 
| PK of ARO-DM1: Area Under the Plasma Concentration Versus Time Curve from Zero to 24 Hours (AUC0-24) |  | Single dose phase (Part 1): Up 24 hours post-dose; Multiple dose phase (Part 2): Through 24 hours post first and second dose | 
| PK of ARO-DM1: Area Under the Plasma Concentration Versus Time Curve from Zero to the Last Quantifiable Plasma Concentration (AUClast) |  | Single dose phase (Part 1): Up 24 hours post-dose; Multiple dose phase (Part 2): Through 24 hours post first and second dose | 
| PK of ARO-DM1: Area Under the Plasma Concentration Versus Time Curve from Zero to Infinity (AUCinf) |  | Single dose phase (Part 1): Up 24 hours post-dose; Multiple dose phase (Part 2): Through 24 hours post first and second dose | 
| PK of ARO-DM1: Elimination half-life (t1/2) |  | Single dose phase (Part 1): Up 24 hours post-dose; Multiple dose phase (Part 2): Through 24 hours post first and second dose | 
| PK of ARO-DM1: Apparent Systemic Clearance (CL/F) |  | Single dose phase (Part 1): Up 24 hours post-dose; Multiple dose phase (Part 2): Through 24 hours post first and second dose | 
| PK of ARO-DM1:m Apparent Terminal-phase Volume of Distribution (Vz/F) |  | Single dose phase (Part 1): Up 24 hours post-dose; Multiple dose phase (Part 2): Through 24 hours post first and second dose |