Evaluation of VRDN-001, an IGF-1R Inhibitor, for Safety, Tolerability, and Efficacy in Chronic Thyroid Eye Disease: A Randomized, Double-Masked, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **safety**, **tolerability**, and **efficacy** of VRDN-001, a humanized monoclonal antibody targeting the insulin-like growth factor-1 receptor (IGF-1R), in participants with chronic thyroid eye disease (TED). This is achieved by comparing the effects of five infusions of VRDN-001 at a dosage of 10 mg/kg to a placebo. The clinical relevance of this objective lies in the potential of VRDN-001 to offer a novel therapeutic option for managing chronic TED, a condition characterized by inflammation and tissue remodeling around the eyes, which can lead to significant morbidity. The study aims to provide insights into the therapeutic potential and safety profile of VRDN-001, which could inform future treatment strategies for TED.

The clinical trial involves a total of **120 participants** diagnosed with **thyroid eye disease** (TED). The study population includes both male and female subjects aged between 18 and 75 years, who have been clinically diagnosed with TED of any severity, as measured by the Clinical Activity Score (CAS) scale. Participants are required to have moderate to severe chronic TED with proptosis of at least 3 mm and a measurement greater than 17 mm at baseline in the study eye. The trial population was selected based on specific inclusion criteria, including the onset of eye-related symptoms more than 15 months prior to screening. Participants must agree to use highly effective contraception, and female participants are required to have a negative serum pregnancy test at screening. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring comprehensive safety and efficacy assessments of the investigational product, VRDN-001, compared to placebo.

The clinical trial is designed to evaluate the **safety**, tolerability, and efficacy of VRDN-001, a humanized monoclonal antibody targeting the insulin-like growth factor-1 receptor, in participants with chronic **thyroid eye disease** (TED). This study is structured as a randomized, double-masked, placebo-controlled trial. Participants will be randomly assigned to receive either VRDN-001 or a placebo, with the masking ensuring that neither the participants nor the investigators know which treatment is being administered. The trial is expected to last until December 2025, with recruitment starting in April 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease severity, and symptom duration. The primary inclusion criteria require participants to be aged 18 to 75 years, have moderate to severe chronic TED, and have experienced symptoms for more than 15 months prior to screening. The study will involve five infusions of VRDN-001 at a dose of 10 mg/kg, administered intravenously, with the primary endpoint being the overall response rate, including proptosis and clinical activity responder rates, assessed three weeks after the fifth infusion.

Follow-up visits will occur at regular intervals to monitor safety and efficacy, with secondary endpoints including changes in proptosis and diplopia resolution rates at Week 15. The end-of-study visit will conclude the participant's involvement, which is expected to last approximately 12 weeks. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or significant deviations from the protocol. Throughout the trial, adverse events and serious adverse events will be closely monitored and recorded to ensure participant safety.

The clinical trial involves the administration of **VRDN-001**, an experimental medication that functions as an **insulin-like growth factor-1 receptor (IGF-1R) inhibitor**. This investigational drug is provided in the form of a **concentrate for solution for infusion**. The active substance, VRDN-001, is a protein-based compound developed by Viridian Therapeutics, Inc. Participants will receive VRDN-001 via **intravenous infusion**. The dosing regimen consists of five infusions, each at a dose of 10 mg/kg, with a maximum total dose of 50 mg/kg over the course of the study. The treatment period is set for a maximum of 12 weeks. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study utilizes **sodium chloride** as a non-experimental treatment. Sodium chloride is administered as a **solution for infusion** and serves as a placebo comparator in this double-masked, placebo-controlled study. The solution is prepared by adjusting the volume of normal saline to 250 ml, starting from a 500 ml or 1000 ml bag, and a masked label is applied to the infusion bag to maintain blinding. The maximum daily dose of sodium chloride is 250 ml, with a total maximum dose of 1250 ml over the 12-week treatment period. The administration route is **intravenous infusion**, and participant compliance with the placebo regimen will be monitored to ensure the integrity of the study's blinding and data collection processes.

The efficacy of VRDN-001 in the treatment of chronic **Thyroid Eye Disease (TED)** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the Overall Response Rate, which includes the Proptosis Responder Rate and the Clinical Activity Responder Rate in the most proptotic eye, evaluated at 3 weeks post the fifth intravenous infusion. Secondary endpoints include the change from baseline in proptosis for the most proptotic eye at Week 15, measured by an exophthalmometer, and the Diplopia Responder and Resolution Rate, defined as a reduction in Diplopia Score to 0 from baseline for participants with a baseline Diplopia Score greater than 0, also assessed at Week 15.

Data collection will occur at specified timepoints, including baseline measurements and follow-up assessments at Week 15. The efficacy parameters will be analyzed using validated scales and measurement tools to ensure accuracy and reliability. The study is designed to provide comprehensive data on the efficacy of VRDN-001 in reducing symptoms associated with chronic TED, with a focus on proptosis and diplopia outcomes.