A Randomized, Double-blind, Placebo-controlled, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Exploratory Efficacy of AOC 1020 Administered Intravenously to Adult Participants with Facioscapulohumeral Muscular Dystrophy (FSHD)

The primary objective of this study is to evaluate the **safety** and **tolerability** of ascending doses of AOC 1020 in participants with **Facioscapulohumeral Muscular Dystrophy (FSHD)**. This is clinically relevant as it aims to determine the potential adverse effects and the maximum tolerated dose of AOC 1020, which is crucial for ensuring patient safety and guiding dosage recommendations in future clinical applications.

Secondary objectives include:

• To evaluate the **pharmacokinetic** profile of intravenous doses of AOC 1020 in participants with FSHD. Understanding the pharmacokinetics is essential for determining the absorption, distribution, metabolism, and excretion of the drug, which informs dosing regimens and potential drug interactions.

The clinical trial involves a total of **60 participants** diagnosed with **Facioscapulohumeral muscular dystrophy (FSHD)**. The study population includes both male and female subjects, with an age range of 18 to 65 years. Participants were selected based on a confirmed diagnosis of FSHD1 or FSHD2 through documented genetic testing. They must be ambulatory and capable of walking 10 meters, with or without assistive devices, and have at least one muscle region suitable for biopsy. The trial includes individuals with muscle weakness in both the upper and lower body, as determined by the investigator. The study population is considered vulnerable, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** Phase 1/2 study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of AOC 1020 administered intravenously to adult participants with **facioscapulohumeral muscular dystrophy (FSHD)**. The trial aims to assess the safety and tolerability of ascending doses of AOC 1020, a humanized IgG1 monoclonal antibody against TFR1 conjugated to double-stranded siRNA oligonucleotide against DUX4 mRNA via a non-cleavable linker. The study is expected to run from July 31, 2023, to September 1, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of FSHD1 or FSHD2 through genetic testing, ambulatory ability, and muscle weakness in both upper and lower body. The trial will include follow-up visits to monitor the incidence of treatment-emergent adverse events, estimate plasma pharmacokinetic parameters, and measure the concentration of the siRNA component in skeletal muscle on Day 120. The end-of-study visit will conclude the participant's involvement, which is expected to last until the trial's completion date.

Participants may be subject to early termination from the study if they experience significant adverse events or fail to comply with the study protocol. The placebo used in this study is saline (0.9% sodium chloride water for injection) for intravenous infusion, provided by the study site. The primary endpoint is the incidence of treatment-emergent adverse events, while secondary endpoints include the estimation of plasma pharmacokinetic parameters and the concentration of the siRNA component in skeletal muscle. The study is not classified as low intervention and is categorized as a first-in-human trial with a primary focus on safety and tolerability, with exploratory endpoints for efficacy.

The clinical trial involves the administration of **AOC 1020**, an investigational medicinal product, to evaluate its safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy in adult participants with **Facioscapulohumeral Muscular Dystrophy (FSHD)**. AOC 1020 is formulated as a powder for infusion and is administered intravenously. The active substance in AOC 1020 is a humanised IgG1 monoclonal antibody against TFR1, conjugated to a double-stranded siRNA oligonucleotide targeting DUX4 mRNA via a non-cleavable linker. The product is developed by Avidity Biosciences and is not a paediatric formulation. The dosing schedule involves ascending doses to assess the safety and tolerability in the study participants.

The study also includes a **placebo** control, which is saline (0.9% sodium chloride water for injection) for intravenous infusion. The placebo is provided by the study site and serves as a comparator to evaluate the effects of AOC 1020. The placebo administration follows the same route and frequency as the experimental treatment to maintain the study's double-blind design. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the investigational product's effects.

The efficacy of AOC 1020 in the clinical trial will be assessed through exploratory endpoints, as the primary focus of the study is on safety and tolerability. The trial is a randomized, double-blind, placebo-controlled, Phase 1/2 study involving adult participants with **Facioscapulohumeral Muscular Dystrophy (FSHD)**. Although the primary endpoints are centered on the incidence of treatment-emergent adverse events, exploratory efficacy assessments will be conducted to gather preliminary data on the potential therapeutic effects of AOC 1020.

Secondary endpoints include the estimation of plasma pharmacokinetic (PK) parameters such as maximum plasma concentration, half-life, and area under the curve of AOC 1020. Additionally, the concentration of the siRNA component in skeletal muscle will be measured on Day 120. These parameters will be collected and analyzed to provide insights into the pharmacodynamics and potential efficacy of the investigational product. The study will utilize validated laboratory tests and other appropriate methods to ensure the accuracy and reliability of the data collected during the trial.