Evaluation of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ARO-DUX4 in Adult Patients with Facioscapulohumeral Muscular Dystrophy Type 1

Trial ID: 2023-509748-89-00
Protocol: ARODUX4-1001
Sponsor: Sarepta Therapeutics Inc.

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Diseases & Conditions

Facioscapulohumeral muscular dystrophy

Objectives

The primary objective of this study is to evaluate the **safety**, **tolerability**, **pharmacokinetics** (PK), and **pharmacodynamics** (PD) of ARO-DUX4 in adult patients with **Facioscapulohumeral Muscular Dystrophy Type 1** (FSHD1). This is achieved through the administration of escalating single and multiple doses. The clinical relevance of this objective lies in determining the potential therapeutic benefits and safety profile of ARO-DUX4, which could lead to improved management of FSHD1, a progressive muscle disorder characterized by muscle weakness and atrophy.

Participants

The clinical trial involves a total of **26 participants** diagnosed with **facioscapulohumeral muscular dystrophy** Type 1 (FSHD1). The study population includes both male and female subjects aged between 18 and 70 years. Participants are required to have a genetically confirmed diagnosis of FSHD1, with a clinical severity score ranging from 3 to 8 on a scale of 0 to 10. The trial includes individuals with a body mass index (BMI) between 18.0 and 35.0 kg/m², although exceptions may be made at the principal investigator's discretion. Participants must be nonpregnant and nonlactating females or males, and they must agree to use highly effective contraception during the study and for a specified period afterward. The selection process ensures that participants are able and willing to comply with all study assessments and adhere to the protocol schedule. The trial does not exclude vulnerable populations, and participants must have no significant abnormalities on a 12-lead ECG that could compromise their safety during the study. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the **safety**, tolerability, pharmacokinetics, and pharmacodynamics of ARO-DUX4 in adult patients with **facioscapulohumeral muscular dystrophy** Type 1 (FSHD1). This study is structured as a Phase 1/2a, dose-escalating trial, employing a randomized, double-blind, and controlled methodology. The trial will involve the administration of ARO-DUX4, a **solution for injection**, via intravenous infusion, with sodium chloride serving as the placebo. The trial is expected to commence on July 1, 2024, and conclude by October 31, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as genetic confirmation of FSHD1, clinical severity score, and other health parameters. Following successful screening, participants will be randomized to receive either the investigational product or placebo. The trial will include multiple follow-up visits to monitor the incidence, frequency, and severity of treatment-emergent adverse events (TEAEs), as well as to assess the pharmacokinetic and pharmacodynamic profiles of ARO-DUX4. The primary endpoint will be evaluated over a period extending to Day 90 for Part 1 and Day 360 for Part 2 of the study. The end-of-study visit will mark the completion of the trial for each participant.

The expected duration of participant involvement will vary, with some participants completing the study by Day 90 and others by Day 360, depending on the part of the study they are enrolled in. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, non-compliance with study procedures, or withdrawal of consent. Participants are required to adhere to the protocol schedule and comply with all study assessments to ensure the integrity of the trial data.

Treatment

The clinical trial involves the administration of **ARO-DUX4**, an investigational medicinal product developed by Arrowhead Pharmaceuticals Inc. The active substance in ARO-DUX4 is **ADS-010**, which is a nucleic acid-based compound. ARO-DUX4 is formulated as a **solution for injection** and is administered via **intravenous infusion**. The study is designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-DUX4 in adult patients with **facioscapulohumeral muscular dystrophy Type 1** (FSHD1). The dosing regimen involves escalating single and multiple doses, although specific dosing schedules and maximum dose amounts are not provided in the available data.

In addition to the experimental treatment, the study utilizes **Sodium Chloride** as a comparator treatment, serving as a placebo. Sodium Chloride is also administered as an **injection** via **intravenous infusion**. It is a chemically derived substance and is used to ensure the blinding of the study. The use of Sodium Chloride as a placebo allows for the assessment of the effects of ARO-DUX4 in comparison to a standard inert solution. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

Efficacy

Efficacy in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the incidence, frequency, and severity of treatment-emergent adverse events (TEAEs) in subjects with **Facioscapulohumeral Muscular Dystrophy Type 1 (FSHD1)** over time, with evaluations conducted through the end of the study at Day 90 for Part 1 and Day 360 for Part 2. Secondary endpoints include the measurement of plasma pharmacokinetics (PK) and urinary excretion of ARO-DUX4 in subjects with FSHD1. These parameters will be collected and analyzed to determine the pharmacokinetic profile of the investigational product. The study will utilize validated laboratory tests and assessments to ensure accurate and reliable data collection. The schedule for these assessments will be aligned with the study protocol, ensuring systematic data collection at predefined timepoints throughout the trial duration.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Genetically confirmed FSHD1 (based on Screening evaluation or source verifiable medical record). If available, the number of repeats (1 to 10) via assessment of the size of the D4Z4 array on chromosome 4 should be provided. Confirmation must be obtained prior to the baseline muscle biopsy.
Clinical severity score (CSS) between 3 and 8 (scale, 0 to 10)
Must have an eligible lower extremity muscle for biopsy as determined from MRI by a central reader, with MFF ≥10% and less than approximately 40%.
Males or nonpregnant, nonlactating females ≥18 years of age who do not plan to become pregnant during the study, with an upper age limit of ≤70 years.
Able and willing to provide written informed consent prior to the performance of any study specific procedures.
Subjects with a body mass index (BMI) between 18.0 and 35.0 kg/m2, inclusive. A subject with FSHD1 and a BMI outside this range may be allowed into the study at the discretion of the PI.
A 12-lead ECG at Screening with no abnormalities that may compromise the subject’s safety in this study per PI discretion.
Subjects of childbearing potential and their partners must agree to use highly effective contraception during the study and for at least 9 months following the end of the study or last dose of IP, whichever is later. Males must not donate sperm during the study from Day 1 until at least 9 months following the end of the study or last dose of IP, whichever is later.
Must be willing and able to comply with all study assessments and adhere to the protocol schedule.

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Exclusion Criteria

Is unable to comply with the study requirements, including the number of required visits to the clinical site.
HIV infection, as shown by the presence of anti-HIV antibody (seropositive) at Screening.
Seropositive for hepatitis B (positive HBsAg at Screening) or hepatitis C (HCV) at Screening, (positive for anti-HCV antibody must be confirmed with positive HCV-RNA test for exclusion).
Uncontrolled hypertension (blood pressure >160/100 mmHg at Screening, confirmed by repeat).
A history of torsade de pointes, ventricular rhythm disturbances (eg, ventricular tachycardia or fibrillation), heart block (excluding first-degree block, being PR interval prolongation only), congenital long QT syndrome, new ST segment elevation or depression, or new Q wave on ECG. Subjects with a history of atrial arrhythmias should be discussed with the Medical Monitor.
Symptomatic heart failure (per New York Heart Association [NYHA] guidelines), unstable angina, myocardial infarction, peripheral vascular disease, atherosclerotic cardiovascular disease, severe cardiovascular disease (ejection fraction <20%, transient ischemic attack, or cerebrovascular accident within 6 months prior to Day 1) or history of active smoking (tobacco).
History of malignancy within the last 2 years except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Subjects with other curatively treated malignancies who have no evidence of metastatic disease and >2-year disease-free interval may be entered following approval by the Medical Monitor.
History of major surgery within 3 months of Screening.
Regular use of alcohol within 1 month prior to the Screening visit (ie, more than 14 units of alcohol per week [1 unit=150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]).
Use of an investigational agent or device within 30 days (or longer as per local regulations) prior to dosing or current participation in an investigational study.
Blood donation (500 mL) within 7 days prior to study treatment administration. Donation or loss of whole blood (excluding the volume of blood that will be drawn during the Screening procedures of this study) prior to administration of the study treatment as follows: 50 mL to 499 mL of whole blood within 30 days, or more than 499 mL of whole blood within 56 days prior to study treatment administration.
Any concomitant medical or psychiatric condition or social situation that would make it difficult to comply with protocol requirements or put the subject at additional safety risk.
Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 calculated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (CKD-EPI).
Current concomitant use of theophylline (including duration of study).
History of thromboembolic events including deep vein thrombosis, thrombotic stroke, pulmonary embolism, or atrial thrombi.
Thrombocytopenia (platelet count less than the lower limit of normal) at Screening.
History or presence of any of the following based on source verifiable medical record and physical exam or reported medical history when applicable: • a hypercoagulable state including factor V Leiden mutation, increased factor VIII, increased proteins C and S, and antithrombin deficiency • nephrotic range proteinuria • antiphospholipid antibody syndrome or myeloproliferative diseases (polycythemia vera and essential thrombocythemia) • inability to ambulate • use of hormone-based contraceptives (including oral, transdermal patch, vaginal ring, and injectables) ≤16 weeks prior to Day 1, peri- and postmenopausal hormone replacement therapy ≤16 weeks prior to Day 1. Note: Use of intrauterine device (IUD) with levonorgestrel (single hormone) or copper (non-hormonal) is allowed.
ALT or AST >2.5×ULN at Screening.
Any contraindications to muscle biopsy.
Any contraindications to MRI.
History of any illness or any clinical condition that, in the opinion of the PI, might confound the results of the study or pose an additional risk in administering study drug to the subject. This may include, but is not limited to, a history of relevant drug or food allergies; history of cardiovascular or central nervous system disease; neuromuscular diseases except FSHD (eg, myopathy, neuropathy, neuromuscular junction disorders); or clinically significant history of mental disease. a. In the case of an upper respiratory infection within 7 days of first dose, PI may elect to extend Screening period such that the first dose is given within ≤7 days following clinical resolution of the infection.
For subjects who are on drug(s) or supplements that may affect muscle function, as determined by the treating physician, or that are listed in Section 8.2.3, subjects must be on a stable dose of that drug(s) or supplement for at least 28 days prior to the first dose of study drug and with no plans to change dose or treatment regimens during the duration of the study. Changes to the dose or treatment discontinuation during the study can only be done for medical reasons as part of standard management by the treating physician with clear documentation and notification to the sponsor.