Efficacy, Safety, and Tolerability of VRDN-003 in Chronic Thyroid Eye Disease: A Phase 3 Randomized, Double-Masked, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy**, **safety**, and **tolerability** of VRDN-003, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor with half-life extension, in participants with chronic **thyroid eye disease** (TED). The study aims to determine if VRDN-003 effectively impacts the signs and symptoms of TED when administered as subcutaneous injections every 4 or 8 weeks, compared to a placebo. This is clinically relevant as TED can significantly affect patients' quality of life, and effective treatment options are needed to manage its symptoms and progression.

The clinical trial for **thyroid eye disease** involves a total of 119 participants, comprising both adult males and females aged between 18 and 75 years. The study population was selected based on a clinical diagnosis of moderate to severe chronic thyroid eye disease, with participants having experienced eye-related signs or symptoms for more than 15 months prior to the first study visit. Participants were required to have any value on the Clinical Activity Score (CAS) scale and an eye bulging value in the study eye before the first dose. The trial includes individuals who are not part of a vulnerable population. Participants were required to agree to use highly effective contraception, and female participants needed to have a negative pregnancy test at the first study visit. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection criteria ensure a focus on individuals with chronic thyroid eye disease, providing a relevant and targeted study population for assessing the efficacy, safety, and tolerability of VRDN-003 compared to a placebo.

The clinical trial is a **randomized**, double-masked, placebo-controlled study designed to evaluate the efficacy, safety, and tolerability of VRDN-003, an **Insulin-like growth factor-1 receptor (IGF-1R) inhibitor**, in participants with chronic **thyroid eye disease (TED)**. The trial will involve subcutaneous injections of VRDN-003 administered every 4 or 8 weeks, compared to a placebo. The primary objective is to determine the effect of VRDN-003 on the signs and symptoms of TED, while secondary objectives include assessing changes in eye bulging, disease severity, and the resolution of double vision. The trial is expected to conclude by December 2026, with recruitment starting in February 2025.

Participants will be involved in the study for a maximum of 40 weeks, with the primary endpoint assessed at Week 24. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, clinical diagnosis of TED, and agreement to use contraception. Follow-up visits will occur at regular intervals to monitor the participants' response to treatment and any adverse events. The end-of-study visit will evaluate the overall outcomes and safety of the treatment. Participants may be withdrawn from the study early if they experience significant adverse effects or fail to comply with the study protocol.

Inclusion criteria require participants to be adults aged 18 to 75 with moderate to severe chronic TED, having experienced symptoms for more than 15 months prior to the first study visit. Female participants must have a negative pregnancy test at the initial visit. The primary endpoint will measure the percentage of participants achieving an Overall Responder Rate at Week 24, defined as a ≥2 mm reduction in eye bulging without worsening of the Clinical Activity Score. Secondary endpoints will further assess changes in eye bulging, disease severity, and safety throughout the study.

The clinical trial involves the administration of **VRDN-003**, an **Insulin-like growth factor-1 receptor (IGF-1R) inhibitor** with half-life extension, developed by Viridian Therapeutics, Inc. This experimental medication is provided in the form of an injection. The active substance, VRDN-003, is a protein of other origin. The medication is administered via subcutaneous injection, targeting the layer of fat between the skin and muscle. The dosing regimen includes a maximum daily dose of 600 mg and a total maximum dose of 4200 mg over a treatment period of up to 40 weeks. The injections are scheduled to be administered every 4 weeks or every 8 weeks, depending on the study arm. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **placebo** group, which receives a substance with no active drug ingredients, referred to as Ted sc placebo. The placebo is administered in the same manner as the experimental drug, via subcutaneous injection, to maintain the double-masked nature of the trial. This allows for a controlled comparison of the efficacy, safety, and tolerability of VRDN-003 in participants with chronic **thyroid eye disease (TED)**. The placebo administration schedule mirrors that of the experimental treatment, with injections given every 4 weeks or every 8 weeks, ensuring consistency across study arms.

The efficacy of VRDN-003 in the treatment of chronic **Thyroid Eye Disease (TED)** will be assessed through a series of predefined endpoints. The primary endpoint is the Overall Responder Rate at Week 24, which evaluates the percentage of participants achieving a ≥ 2 mm reduction in eye bulging without any worsening in the Clinical Activity Score (CAS) compared to baseline measurements. This endpoint is designed to measure the improvement in disease symptoms and severity.

Secondary endpoints will further assess the changes in eye bulging from baseline, the percentage of participants achieving the required reduction in eye bulging, disease severity, symptoms, and the reduction and resolution of double vision at Week 24. These endpoints aim to provide a comprehensive evaluation of the therapeutic effects of VRDN-003 on various aspects of TED.

Data collection will occur at specified intervals, with the primary and secondary endpoints being evaluated at Week 24. The study will utilize validated scales and measurements to ensure the accuracy and reliability of the efficacy assessments. The results will be analyzed to determine the overall efficacy of VRDN-003 compared to placebo in the study population.