Evaluation of AMG 732 Efficacy and Safety in Moderate-to-Severe Thyroid Eye Disease: A Phase 1/2 Randomized, Double-Masked, Placebo-Controlled Study

The primary objective of this study is to investigate the **efficacy** of AMG 732 in subjects with moderate-to-severe active **Thyroid Eye Disease** (TED) following multiple subcutaneous doses. This is clinically relevant as it aims to determine the therapeutic potential of AMG 732 in managing TED, a condition that can significantly impact patients' quality of life and visual function.

Secondary objectives include:

• To investigate the **safety** and **tolerability** of AMG 732 after multiple subcutaneous doses.
• To assess the **pharmacokinetics** (PK) of AMG 732 following repeated subcutaneous administration.
• To characterize the **immunogenicity** of AMG 732 after multiple subcutaneous doses.
• To further investigate the efficacy of AMG 732 in subjects with TED after multiple subcutaneous doses.
• To evaluate the effect of AMG 732 on the **quality of life** (QoL) of subjects with TED using the GO-QoL Visual Functioning (VF) and Appearance (A) subscale scores.

The clinical trial investigating the efficacy of AMG 732 in subjects with **Thyroid Eye Disease** (TED) includes a total of 20 participants. The study population comprises both male and female subjects, with an age range of 18 to 55 years for Part A and 18 to 65 years for Part B. Participants were selected based on specific inclusion criteria, including the provision of informed consent and, for Part B, a clinical diagnosis of moderate-to-severe active TED associated with Graves disease. The trial does not involve a vulnerable population. Participants are required to be euthyroid or have mild hypo or hyperthyroidism, with efforts made to maintain a euthyroid state throughout the trial. The study excludes individuals requiring immediate surgical ophthalmological intervention or planning corrective surgery or irradiation during the trial. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, double-masked, placebo-controlled, multicenter study designed to assess the safety, pharmacokinetics, and efficacy of **AMG 732** in healthy subjects and those with moderate-to-severe active **Thyroid Eye Disease** (TED). The trial is structured in two phases, Phase 1 and Phase 2, and is expected to conclude by August 2027. The study involves multiple subcutaneous doses of AMG 732, with a placebo group receiving site-sourced normal saline in sterile single-use vials or ampoules. The trial will commence recruitment in October 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age and the presence of moderate-to-severe active TED. The inclusion criteria for Part B of the study require subjects to have a clinical diagnosis of Graves' disease associated with active TED, with a Clinical Activity Score (CAS) of 3 or more for the most severely affected eye. Subjects must also be euthyroid or have mild hypo or hyperthyroidism, which should be corrected promptly. The study excludes individuals requiring immediate surgical intervention or planning corrective surgery during the trial.

Following the screening visit, participants will attend regular follow-up visits to monitor treatment-emergent adverse events, pharmacokinetic parameters, and the incidence of antidrug antibodies. The primary endpoint is the change from baseline in proptosis measurement by an exophthalmometer in the study eye. Secondary endpoints include the incidence of adverse events, pharmacokinetic parameters, and changes in the GO-QoL Visual Functioning and Appearance subscale scores.

The expected length of participant involvement will vary depending on the phase of the trial and individual response to treatment. Conditions that may lead to early termination from the study include the development of serious adverse events or the need for immediate surgical intervention. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the overall efficacy and safety of AMG 732.

The clinical trial involves the administration of **AMG 732**, an investigational medication formulated as a **solution for injection**. This experimental drug is developed by Amgen Inc. and is characterized as a protein of other origin. AMG 732 is administered via the **subcutaneous route**. The dosing schedule involves multiple doses, although specific dosage amounts and frequency are not detailed in the provided data. The trial aims to evaluate the safety, pharmacokinetics, and efficacy of AMG 732 in subjects with moderate-to-severe active **Thyroid Eye Disease** (TED).

In addition to AMG 732, the study includes a **placebo** control, which consists of site-sourced normal saline. The placebo is provided in sterile single-use vials or ampoules. The placebo is intended to mimic the administration of AMG 732 without containing the active investigational substance. The use of a placebo allows for a double-masked, placebo-controlled study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias in the assessment of the investigational drug's efficacy and safety.

The efficacy of AMG 732 in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the change from baseline in **proptosis** measurement by an exophthalmometer in the study eye. This measurement will be taken at a specified time point during the trial. Secondary endpoints include the incidence of treatment-emergent adverse events, pharmacokinetic parameters such as maximum observed concentration (Cmax), time to maximum observed concentration (Tmax), area under the concentration-time curve (AUC), and the presence of antidrug antibodies (ADAs). Additionally, the proptosis response status in the study eye and the fellow eye will be evaluated, along with mean changes from baseline in the GO-QoL Visual Functioning (VF) and Appearance (A) subscale scores.