Open-Label Evaluation of VRDN-001 in Non-Responders with Thyroid Eye Disease from VRDN-001-101 and VRDN-001-301 Studies

The primary objective of this study is to provide **open-label** access to VRDN-001 for participants who were non-responders at 3 weeks post the fifth intravenous infusion in the VRDN-001-101 and VRDN-001-301 pivotal studies. This objective is clinically relevant as it aims to evaluate the potential benefits of continued treatment with VRDN-001, an **Insulin-like growth factor-1 receptor (IGF-1R) inhibitor**, in individuals with **Thyroid eye disease** who did not initially respond to the treatment. Additionally, the study seeks to assess the safety and efficacy of VRDN-001 in these participants, which is crucial for understanding the therapeutic potential and risk profile of the drug in this specific patient population.

The clinical trial involves a total of **71 participants** diagnosed with **thyroid eye disease**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically encompass adults and older adults. Participants were selected based on their previous involvement in the VRDN-001-101 or VRDN-001-301 pivotal studies, specifically those who were non-responders at 3 weeks post the fifth intravenous infusion. The trial includes individuals who are part of a vulnerable population, indicating additional ethical considerations in their selection and participation. Participants are required to have completed at least five IV infusions and assessments to determine their proptosis responder status. Lifestyle factors such as diet and physical activity are not specified, but participants must be willing and able to comply with all study requirements. Both male and female participants must adhere to specific contraception guidelines to ensure safety throughout the study duration.

The clinical trial is designed to evaluate the safety and efficacy of **VRDN-001**, an **insulin-like growth factor-1 receptor (IGF-1R) inhibitor**, in participants with **thyroid eye disease** who were non-responders in previous pivotal studies. This open-label study will provide access to VRDN-001 for participants who did not achieve the desired reduction in proptosis or experienced an increase in proptosis in the fellow eye after the fifth intravenous infusion in the prior studies. The trial is categorized as a Phase III study and is not considered low intervention.

The trial will follow a structured methodology, employing a controlled, open-label design. Participants will receive VRDN-001 via **intravenous infusion**. The study will span an estimated duration from March 2024 to January 2026, with a maximum treatment period of 12 weeks for each participant. The primary endpoints include the overall responder rate, which encompasses the proptosis responder rate and clinical activity responder rate in the most proptotic eye at three weeks post the fifth infusion. Safety endpoints will monitor adverse events (AEs) and serious adverse events (SAEs) throughout the study.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as previous participation in the VRDN-001-101 or VRDN-001-301 studies and non-responder status. Follow-up visits will occur at regular intervals to assess treatment response and monitor safety. The end-of-study visit will conclude the participant's involvement, ensuring all safety assessments are completed. The expected length of participant involvement is approximately 12 weeks, with conditions for early termination including the need for immediate ophthalmological or orbital surgery or the occurrence of significant adverse events.

Inclusion criteria require participants to provide informed consent, have completed the necessary infusions in previous studies, and not require immediate surgery. Female participants must have a negative pregnancy test and agree to use effective contraception. Participants must comply with all protocol requirements for the study's duration. The trial aims to provide valuable data on the efficacy and safety of VRDN-001 in treating thyroid eye disease, contributing to the understanding and management of this condition.

The clinical trial involves the administration of **VRDN-001**, an **Insulin-like growth factor-1 receptor (IGF-1R) inhibitor**. This experimental medication is provided in the form of a **concentrate for solution for infusion**. The active substance, VRDN-001, is a protein of non-chemical origin, developed by Viridian Therapeutics, Inc. The administration route is via **intravenous infusion**, with a maximum daily dose of 10 mg/kg and a total maximum dose of 50 mg/kg over a treatment period of up to 12 weeks. The dosing schedule is designed to ensure participant safety and efficacy, with compliance monitored throughout the study.

In addition to the experimental treatment, the study utilizes **Sodium Chloride 0.9% Intravenous Infusion** as a non-experimental treatment. This solution, produced by Fresenius Kabi Limited, serves as an auxiliary treatment and is classified under the ATC code B05BB01, indicating its role as an electrolyte solution. The pharmaceutical form is a **solution for infusion**, administered intravenously. The maximum daily dose is 250 ml, with a total maximum dose of 1250 ml over the same 12-week period. For clinical trial purposes, if starting with a 500 ml or 1000 ml bag, the volume is adjusted to 250 ml, and a masked label is applied to the infusion bag to maintain blinding. This ensures the integrity of the trial while providing necessary hydration and electrolyte balance to participants.

Efficacy in this clinical trial will be assessed using specific primary and secondary endpoints. The primary endpoints include the **Overall Responder Rate**, which is comprised of the **Proptosis Responder Rate** in the most proptotic eye, defined as a reduction of proptosis of ≥ 2 mm from baseline without a corresponding increase of ≥ 2 mm in the other eye, and the **Clinical Activity Responder Rate** in the most proptotic eye, defined as no worsening in the Clinical Activity Score (CAS) from baseline without a corresponding increase of ≥ 2 points in the other eye. These assessments will be conducted at 3 weeks post the fifth intravenous infusion, corresponding to Week 15 of the study.

Secondary endpoints include the change from baseline in proptosis in the most proptotic eye at Week 15, as well as the Proptosis Responder Rate in the most proptotic eye, measured by an exophthalmometer at the same time point. The change from baseline in proptosis in the most proptotic eye, also measured by an exophthalmometer, will be evaluated at Week 15. These efficacy parameters will be collected and analyzed to determine the effectiveness of VRDN-001 in participants who were non-responders in previous pivotal studies.