Evaluation of VRDN-001, an IGF-1R Inhibitor, in a Multiple Ascending Dose Study for Safety, Tolerability, and Efficacy in Thyroid Eye Disease Patients

The primary objective of this study is to establish the **safety**, tolerability, and efficacy of VRDN-001, a humanized monoclonal antibody directed against the **insulin-like growth factor-1 receptor (IGF-1R)**, in normal healthy volunteers and subjects with **thyroid eye disease (TED)**. This evaluation will include the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of VRDN-001 over a dose range of 3.0 to 20.0 mg/kg. Understanding the safety and efficacy of VRDN-001 is clinically relevant as it may offer a novel therapeutic option for managing TED, a condition characterized by inflammation and tissue remodeling around the eyes, potentially leading to vision impairment.

The clinical trial for **Thyroid eye disease (TED)** involves a total of 109 participants. The study population includes both male and female adults, aged 18 years and older, who have been clinically diagnosed with moderate to severe active TED. Participants were selected based on their ability to understand study procedures, provide informed consent, and comply with protocol requirements. The trial includes individuals with a Clinical Activity Score (CAS) of 3 or higher on the 7-item scale for the study eye, and those with proptosis of 3 mm above normal values for race and gender. Participants may have additional symptoms such as lid retraction, soft tissue involvement, diplopia, retrobulbar pain, or conjunctival swelling. The trial population is diverse, including individuals with diabetes mellitus, provided their glycated hemoglobin (HbA1c) is below 8.5% at study entry. Both male and female participants are required to adhere to specific contraceptive measures if applicable. The trial does not require participants to have achieved euthyroid status, and those with diabetes are monitored by appropriate healthcare professionals. The study does not include individuals requiring immediate surgical intervention for ophthalmological or orbital conditions in the study eye.

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 (IGF-1R)**, in participants with thyroid eye disease (TED). This study is a randomized, double-blind, controlled trial involving multiple ascending doses (MAD) of VRDN-001. The trial is expected to last until April 2025, with participant recruitment having commenced in August 2023. The trial will include both normal healthy volunteers and subjects with TED, with a focus on establishing the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of VRDN-001 over a dose range of 3.0 to 20.0 mg/kg.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, clinical diagnosis of TED, and willingness to comply with study requirements. Following the screening, participants will receive the investigational product or placebo via intravenous infusion over a maximum treatment period of 56 days. The study will include several follow-up visits to monitor safety endpoints, such as adverse events (AEs) and serious adverse events (SAEs), and to assess primary and secondary efficacy endpoints, including proptosis responder rate and clinical activity score (CAS) changes.

The end-of-study visit will occur after the final infusion, where comprehensive assessments will be conducted to evaluate the overall response and durability of the treatment effects. Participant involvement is expected to last up to 52 weeks, with conditions for early termination including significant protocol deviations, withdrawal of consent, or the occurrence of severe adverse events. The trial aims to provide valuable insights into the therapeutic potential of VRDN-001 for managing TED, with data collected contributing to the understanding of its safety and efficacy profile.

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 product is provided in the form of a **concentrate for solution for infusion**. The active substance, VRDN-001, is of biological/biotechnological origin, specifically a protein. The medication is administered intravenously. The dosing regimen for VRDN-001 ranges from 3.0 to 20.0 mg/kg, with the maximum treatment period extending up to 56 days. The trial aims to evaluate the safety, tolerability, and efficacy of VRDN-001, as well as its pharmacokinetic and pharmacodynamic profiles in normal healthy volunteers and subjects with thyroid eye disease.

In addition to the experimental treatment, the study utilizes **Sodium Chloride** as a non-experimental treatment. Sodium Chloride is used in the form of a **solution for injection/infusion** and serves as a placebo or comparator treatment. It is administered intravenously, similar to the experimental medication. The use of Sodium Chloride in the trial is intended to provide a control for evaluating the effects of VRDN-001. The maximum treatment period for Sodium Chloride is also 56 days, ensuring consistency in the study's design and administration protocols.

The efficacy of VRDN-001, a humanized monoclonal antibody targeting the **Insulin-like growth factor-1 receptor (IGF-1R)**, will be assessed in a clinical trial involving normal healthy volunteers and subjects with thyroid eye disease (TED). The primary efficacy endpoint in the USA, Canada, and China is the Proptosis Responder Rate in the study eye, defined as a reduction of proptosis by at least 2 mm from baseline without a corresponding increase in the fellow eye, measured by exophthalmometer at 3 weeks post the fifth infusion (Week 15). In Australia, the EU, and the UK, the primary endpoint also includes the Clinical Activity Responder Rate, which is a reduction in the Clinical Activity Score (CAS) by at least 2 points from baseline without a corresponding increase in the fellow eye at the same time point.

Secondary endpoints include changes from baseline in proptosis and CAS in the study eye at Week 15, the Diplopia Resolution Rate, and the proportion of participants with a CAS score of zero or one. Exploratory endpoints will evaluate the Proptosis Responder Rate and Clinical Activity Responder Rate at Weeks 24, 36, and 52, as well as changes in proptosis and extraocular muscle measurements by MRI or CT, and quality of life assessments using the Graves' Orbitopathy-Quality of Life (GO-QoL) questionnaire and the EQ-5D-5L QoL questionnaire. Efficacy assessments will be conducted at specified time points, including Weeks 15, 24, 36, and 52, to determine the durability and time to response of the treatment.