Evaluation of the Efficacy and Safety of Intravenous AOC 1001 in Myotonic Dystrophy Type 1: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this Phase 3 randomized, double-blind, placebo-controlled study is to evaluate the **efficacy** of AOC 1001 on hand function in patients with Myotonic Dystrophy Type 1. This objective is clinically relevant as hand function is a critical aspect of daily living and quality of life for individuals affected by this condition. The study aims to determine whether AOC 1001 can provide a meaningful improvement in this specific functional domain.

Secondary objectives include evaluating the efficacy of AOC 1001 on measures of mobility, muscle strength, muscle function, and patient-reported outcomes. These objectives are important for understanding the broader impact of AOC 1001 on the physical capabilities and overall well-being of patients, providing a comprehensive assessment of its therapeutic potential.

The clinical trial involves a total of **111 participants** diagnosed with **Myotonic Dystrophy Type 1**. The study population includes both male and female subjects, aged between 16 and 65 years, with a specific age range of 18 to 65 years for participants from Denmark and Germany. Participants were selected based on a clinical and genetic diagnosis, specifically a CTG repeat length of 100 or more. All participants must have the ability to walk independently, although the use of orthoses and ankle braces is permitted for a distance of at least 10 meters during screening. The trial population includes individuals who are considered vulnerable, ensuring a comprehensive evaluation of the efficacy of AOC 1001 on hand function across a diverse group. Lifestyle factors such as diet and physical activity were not specified in the available data.

The clinical trial is a **Phase 3 randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy and safety of intravenous AOC 1001 for the treatment of **Myotonic Dystrophy Type 1**. The trial aims to assess the impact of AOC 1001 on hand function, with the primary endpoint being the change from baseline to Week 30 in video Hand Opening Time (vHOT). Secondary endpoints include changes in hand grip strength, QMT total composite score, and DM1-ActivC, among others, measured at various intervals up to Week 54.

Participants will be involved in the study for a maximum treatment period of 54 weeks. The trial is expected to commence recruitment on October 1, 2024, and conclude by October 1, 2026. The study will include an initial screening visit to confirm eligibility based on criteria such as age (16-65 years, with specific age criteria for Denmark and Germany), clinical and genetic diagnosis of DM1, and the ability to walk independently for at least 10 meters. Following the screening, participants will be randomized to receive either AOC 1001 or a placebo, administered as a **solution for infusion**.

Study visits will be scheduled at regular intervals to monitor the participants' progress and collect data on the primary and secondary endpoints. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience adverse effects, fail to comply with study procedures, or withdraw consent. The trial is not classified as low intervention, emphasizing the rigorous evaluation of the investigational product's safety and efficacy.

The clinical trial involves the administration of **AOC 1001**, an investigational medicinal product, which is a **solution for infusion**. AOC 1001 is a **humanised IgG1 monoclonal antibody** against TFR1, conjugated to a double-stranded siRNA oligonucleotide against DMPK via a non-cleavable linker. The pharmaceutical form is a solution for infusion, and it is administered intravenously. The dosing regimen for AOC 1001 is set at a maximum daily dose of 4 mg/kg, with a total maximum dose of 28 mg/kg over a treatment period of 54 weeks. The product is developed by Avidity Biosciences and is designated as an orphan drug under the designation number EU/3/21/2485.

In addition to the experimental treatment, the study includes the use of a **placebo** control, which is 0.9% saline for intravenous administration. The placebo is administered in the same manner as the experimental drug, serving as a comparator to evaluate the efficacy and safety of AOC 1001. The placebo is not a paediatric formulation and is used to maintain the double-blind nature of the study. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The efficacy of the investigational product, AOC 1001, in the treatment of **Myotonic Dystrophy Type 1** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline to Week 30 in video Hand Opening Time (vHOT). Secondary endpoints include changes from baseline to Week 30 in hand grip strength, Quantitative Muscle Testing (QMT) total composite score, and DM1-ActivC. Additional secondary endpoints involve changes in QMT upper and lower extremity composite scores, QMT individual muscle group scores, 10-Meter Walk/Run Test (10MWRT), Patient Global Impression of Severity (PGI-S), and EQ-5D-5L. Furthermore, changes from baseline to Week 54 will be evaluated for vHOT, QMT composite and individual muscle group scores, DM1-ActivC, 10MWRT, EQ-5D-5L, and PGI-S, with PGI-C assessed at Week 30 and Week 54.

These efficacy parameters will be measured at specified timepoints, including Week 30 and Week 54, using validated scales and tests. The data collection will involve both objective measures, such as QMT and vHOT, and patient-reported outcomes, such as DM1-ActivC and EQ-5D-5L. The analysis will focus on the comparison of changes from baseline to the designated timepoints to determine the efficacy of AOC 1001 in improving hand function and other related symptoms in patients with Myotonic Dystrophy Type 1.