A Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous AOC 1020 for the Treatment of Facioscapulohumeral Muscular Dystrophy (FSHD)

The primary objective is to evaluate the efficacy of AOC 1020 on functional mobility in patients with facioscapulohumeral muscular dystrophy (FSHD). This assessment is clinically relevant as functional mobility represents a key indicator of disease progression and therapeutic response in this progressive neuromuscular disorder characterized by asymmetric skeletal muscle weakness.

The secondary objectives include:

• To evaluate the efficacy of AOC 1020 on functional mobility and muscle strength in the upper and lower extremities

• To evaluate the efficacy of AOC 1020 on muscle strength, functional mobility, and patient-reported outcome measures

• To evaluate the effects of AOC 1020 on FSHD circulating biomarkers

This clinical trial enrolled a total of **120 participants** diagnosed with **Facioscapulohumeral Muscular Dystrophy (FSHD)**, confirmed through documented genetic testing for either FSHD1 or FSHD2. The study population included both **male and female** participants aged **18 to 70 years** at the time of informed consent. All participants were required to be capable of walking independently for at least 10 meters, with the use of orthoses or ankle braces permitted. The trial population was selected based on confirmed genetic diagnosis and functional mobility criteria. This study included a vulnerable population, with provisions for enrollment of minors requiring consent from a legally designated representative in addition to age-appropriate information provided to the participant.

This is a randomized, double-blind, placebo-controlled, Phase 3 clinical trial designed to evaluate the efficacy and safety of intravenous AOC 1020 for the treatment of Facioscapulohumeral Muscular Dystrophy (FSHD). The study employs a rigorous methodology to assess the therapeutic potential of the investigational medicinal product, which is a humanised IgG1 monoclonal antibody against TFR1 conjugated to double stranded siRNA oligonucleotide against DUX4 mRNA via a non-cleavable linker. AOC 1020 is administered as a powder for infusion via the intravenous route and has been designated as an orphan drug (EU/3/23/2756). The control group receives 0.9% saline for IV administration as placebo. The maximum daily dose of the investigational product is 2 mg/kg, with a maximum total dose of 26 mg over the treatment period.

The primary objective of this trial is to evaluate the efficacy of AOC 1020 on functional mobility. The primary endpoint is the change from baseline to Week 78 in 10-Meter Walk/Run Test (10MWRT) velocity measured in meters per second. Secondary endpoints include changes from baseline to Week 78 in Timed-Up-and-Go (TUG), NeuroQoL Upper Extremity Function, and Quantitative Muscle Testing (QMT) total composite score. Additional secondary endpoints assess changes from baseline at multiple timepoints in various functional measures, including QMT upper and lower extremity composite scores, individual muscle group scores, Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function and Fatigue instruments, Worst Pain Numerical Rating Scale (NRS), Patient Global Impression of Severity (PGI-S) and Patient Global Impression of Change (PGI-C), a DUX4-regulated circulating biomarker of FSHD disease biology, and plasma creatine kinase (CK).

The overall trial duration extends from the estimated recruitment start date of October 2025 to the estimated end date of April 2028. The maximum treatment period for individual participants is 78 weeks. Participant involvement begins with a screening visit to assess eligibility based on specific inclusion and exclusion criteria. Principal inclusion criteria require participants to have provided written informed consent and be willing to comply with all study requirements. For participants who are minors, consent from a legally designated representative is required, and information is provided in a manner adapted to the participant's age and mental maturity. Participants must be male or female with FSHD confirmed by documented genetic diagnosis (FSHD1 or FSHD2), aged 18 to 70 years at the time of informed consent, and able to walk independently for at least 10 meters (orthoses or ankle braces are allowed).

Following successful screening, participants proceed through a series of scheduled study visits during the treatment period for administration of the investigational product or placebo, safety monitoring, and efficacy assessments. Follow-up visits are conducted at predetermined intervals to evaluate changes in functional measures, patient-reported outcomes, and biomarkers. The end-of-study visit occurs at Week 78, at which time the primary and key secondary endpoints are assessed. Conditions that may lead to early termination from the study include withdrawal of consent, safety concerns, protocol deviations, loss to follow-up, or at the discretion of the investigator or sponsor based on the participant's best interest.

The experimental treatment in this clinical trial is **AOC 1020**, a **humanised IgG1 monoclonal antibody** against **TFR1** conjugated to double-stranded **siRNA oligonucleotide** against **DUX4 mRNA** via a non-cleavable linker. The investigational medicinal product is supplied as a **powder for infusion** and is administered via the **intravenous** route. The maximum daily dose is **2 mg/kg**, with a maximum total dose of **26 mg** per administration. The treatment period extends for **78 weeks**. AOC 1020 has been designated as an **orphan drug** under the designation number EU/3/23/2756 and is manufactured by Avidity Biosciences.

The comparator treatment consists of **placebo**, which is **0.9% saline solution** for **intravenous administration**. The placebo is used to maintain the double-blind design of the study and is administered following the same schedule as the experimental treatment to ensure methodological consistency.

This randomized, double-blind, placebo-controlled Phase 3 study evaluates the efficacy and safety of AOC 1020 in participants with **facioscapulohumeral muscular dystrophy**. The study design incorporates appropriate blinding procedures and compliance monitoring to ensure the integrity of the clinical data throughout the treatment period.

Efficacy will be assessed using multiple parameters to evaluate the impact of **AOC 1020** on functional mobility and disease-related outcomes in participants with **facioscapulohumeral muscular dystrophy**. The primary endpoint is the change from baseline to Week 78 in 10-Meter Walk/Run Test velocity measured in meters per second. Secondary endpoints include change from baseline to Week 78 in Timed-Up-and-Go, NeuroQoL Upper Extremity Function, and Quantitative Muscle Testing total composite score. Additional secondary assessments encompass changes from baseline in 10-Meter Walk/Run Test velocity at timepoints excluding Week 78, Quantitative Muscle Testing total composite score and individual muscle group scores at various timepoints, Timed-Up-and-Go at timepoints excluding Week 78, Patient-reported Outcomes Measurement Information System instruments for Physical Function and Fatigue, Worst Pain Numerical Rating Scale, Patient Global Impression of Severity and Patient Global Impression of Change, Quality of Life in Neurological Disorders Upper Extremity Function at timepoints excluding Week 78, a DUX4-regulated circulating biomarker of disease biology, and plasma creatine kinase levels. The treatment period extends up to 78 weeks, during which these efficacy parameters will be measured and analyzed at specified timepoints to comprehensively evaluate the therapeutic effect of the investigational product.