A Multicenter, Extension Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Two Doses of Linsitinib in Subjects with Active, Moderate to Severe Thyroid Eye Disease (TED)

The primary objective of this study is to evaluate the effect of **linsitinib** on the proptosis responder rate at Extension Study Week 24 in subjects with active, moderate to severe **Thyroid Eye Disease**. The responder rate is defined as the percentage of subjects achieving a reduction of ≥ 2 mm in proptosis from baseline in the primary study eye, without any deterioration (≥ 2 mm increase) in the contralateral non-study eye. This is clinically relevant as proptosis is a significant symptom of Thyroid Eye Disease, and its reduction can lead to improved patient outcomes and quality of life.

Secondary objectives include: - Evaluating the effect of linsitinib on the mean change from baseline through Extension Study Week 24 in proptosis measurement in the primary study eye. - Assessing the overall responder rate, defined as the percentage of subjects with a ≥ 2-point reduction in the 7-point Clinical Activity Scale (CAS) and a ≥ 2 mm reduction in proptosis from baseline, without corresponding deterioration in the contralateral non-study eye at Week 24. - Determining the percentage of subjects with a CAS value of 0 or 1 through Extension Study Week 24 in the primary study eye. - Evaluating the mean change from baseline through Extension Study Week 24 in the Graves’ Ophthalmopathy Quality of Life (GOQoL) questionnaire overall score.

The clinical trial involves a total of **69 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 represent adults and older adults. Participants were selected based on their completion of the 24-week double-mask period of the VGN-TED-301 study, specifically those who were proptosis non-responders or responders who relapsed. All subjects are required to be euthyroid or have mild hypo- or hyperthyroidism, with efforts made to maintain a euthyroid state throughout the trial. The trial population includes a vulnerable group, and participants must not require immediate ophthalmic surgery or other interventions during the study. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of two doses of **linsitinib** in subjects with active, moderate to severe **Thyroid Eye Disease** (TED). This is a multicenter, randomized, double-blind, controlled extension study. The trial will involve a placebo group to match the 75 mg linsitinib film-coated tablet, ensuring the placebo tablets are formulated to match the physical characteristics of the active tablets. The trial is expected to run until August 2026, with recruitment having commenced in July 2023.

Participants will be involved in the study for a maximum treatment period of 24 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor the participants' response to the treatment and any adverse effects. The primary endpoint is the proptosis responder rate at Week 24, defined as the percentage of subjects with a ≥ 2 mm reduction from baseline in the primary study eye without deterioration in the contralateral non-study eye. Secondary endpoints include the mean change from baseline through Week 24 in proptosis measurement and the overall responder rate.

Inclusion criteria require subjects to have completed the 24-week double-mask period of the VGN-TED-301 study and be proptosis non-responders or responders who relapse during the follow-up period. Participants must be euthyroid or have mild hypo- or hyperthyroidism at baseline, with efforts made to maintain a euthyroid state throughout the trial. Exclusion criteria include the need for immediate ophthalmic surgery or other interventions during the study period. Participants may be terminated early from the study if they require such interventions or if they do not adhere to the study protocol.

The clinical trial involves the administration of **Linsitinib**, a film-coated tablet, as the experimental medication. Linsitinib is chemically derived and is provided by Vasaragen, Inc. The active substance in the tablet is Linsitinib, also known by other names such as OSI-906AA, ASP7487, and VGN-001. The pharmaceutical form of Linsitinib is a film-coated tablet, and it is administered orally. The maximum daily dose is 300 mg, with a total maximum dose of 50,400 mg over a treatment period of 24 weeks. The dosing schedule is designed to ensure consistent administration, and participant compliance is monitored throughout the study.

The study also includes a **placebo** treatment to match the 75 mg Linsitinib film-coated tablet. The placebo tablets are formulated to mimic the physical characteristics of the active Linsitinib tablets. The placebo is a tablet formulation compressed from a direct powder blend containing microcrystalline cellulose, lactose monohydrate, and magnesium stearate. The placebo is administered orally, following the same schedule as the active treatment, to maintain the study's blinding and integrity. Compliance with the placebo administration is similarly monitored to ensure adherence to the study protocol.

Efficacy in this clinical trial will be assessed primarily through the **proptosis responder rate** at Extension Study Week 24. This primary endpoint is defined as the percentage of subjects achieving a reduction of ≥ 2 mm in proptosis from Baseline in the primary study eye, without a deterioration (≥ 2 mm increase) in the contralateral non-study eye. Secondary endpoints include the mean change from Baseline through Week 24 in proptosis measurement in the primary study eye and the overall responder rate. The overall responder rate is characterized by a ≥ 2-point reduction in the Clinical Activity Scale (CAS) and a ≥ 2 mm reduction in proptosis from Baseline, provided there is no corresponding deterioration (≥ 2-point/mm increase) in CAS or proptosis in the contralateral non-study eye through Week 24.

Measurements will be collected at specified timepoints, with the primary assessment occurring at Week 24. The trial will utilize validated scales and measurement techniques to ensure accuracy and reliability of the data collected. The analysis will focus on comparing the changes from Baseline to Week 24, evaluating both the primary and secondary endpoints to determine the efficacy of the treatment. The study is designed to provide comprehensive data on the efficacy of linsitinib in subjects with active, moderate to severe Thyroid Eye Disease (TED).