Evaluation of Long-term Safety and Efficacy of XTMAB-16 in Pulmonary Sarcoidosis with or without Extrapulmonary Manifestations

The primary objective of this study is to evaluate the long-term **safety** and tolerability of XTMAB-16 in participants with pulmonary sarcoidosis, with or without extra-pulmonary manifestations. This is clinically relevant as it aims to ensure that the treatment is safe for prolonged use in managing this chronic condition, which can significantly impact respiratory function and overall quality of life.

Secondary objectives include:

• Evaluating the durability and maintenance of the effect of XTMAB-16 as characterized by corticosteroid dosing, aiming to maintain or lower steroid dosing.
• Assessing the durability and maintenance of the effect of XTMAB-16 through changes in quality of life or pulmonary tests.
• Evaluating the immunogenicity of XTMAB-16 in the context of long-term dosing.
• Assessing the long-term effect of XTMAB-16 on serum biomarkers important to the cytokine pathway and granuloma formation in sarcoidosis.

The clinical trial involves a total of **70 participants** diagnosed with **pulmonary sarcoidosis**, with or without extrapulmonary manifestations. The study population includes both male and female subjects, encompassing an age range that corresponds to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on their completion of the XTMAB-16-201 study, with specific requirements for a stable steroid dose prior to the commencement of the trial. The trial includes a vulnerable population, indicating that additional ethical considerations are in place. Participants' general health status is characterized by their ability to complete prior study assessments, and no specific lifestyle considerations such as diet or physical activity are highlighted. The trial aims to evaluate the long-term safety and tolerability of XTMAB-16 in this specific patient group.

The clinical trial is designed to evaluate the long-term safety and tolerability of **XTMAB-16** in patients diagnosed with pulmonary sarcoidosis, with or without extrapulmonary manifestations. This study is a phase 4, open-label, multicenter trial. Participants will receive **XTMAB-16** as a **solution for infusion** administered intravenously. The trial is expected to commence recruitment on January 28, 2025, and conclude by November 26, 2028, with a maximum treatment period of 156 weeks. The study will monitor the rate of adverse events, including serious adverse events and adverse events of special interest, throughout the trial duration.

Participants eligible for inclusion must have completed the XTMAB-16-201 study, either Part A or Part B, and should be on a stable steroid dose for at least two weeks prior to the informed consent/Day 1 of the current study. The primary endpoint is the rate of adverse events, while secondary endpoints include the evaluation of total corticosteroid dose, treatment failure rates, changes in quality-of-life measures, pulmonary function tests, and the presence of anti-drug antibodies. Biomarkers such as angiotensin-converting enzyme, interleukin-6, and C-reactive protein will also be assessed.

The trial involves several study visits, beginning with a screening visit to confirm eligibility. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected. Participants are expected to remain in the study for the entire duration unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The study aims to provide comprehensive data on the long-term effects of **XTMAB-16** in managing pulmonary sarcoidosis.

The clinical trial involves the administration of **XTMAB-16**, an investigational biologic medication, to evaluate its long-term safety and tolerability in patients with pulmonary sarcoidosis, with or without extra-pulmonary involvement. **XTMAB-16** is formulated as a **solution for infusion** and is administered intravenously. The dosing regimen for **XTMAB-16** is specified as a maximum daily dose of 4.00 mg/kg, with a total maximum dose of 160.00 mg/kg over the course of the treatment period. The maximum treatment duration is set at 156 weeks. The active substance in **XTMAB-16** is a protein of other origin, developed by XENTRIA, INC.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of **XTMAB-16**. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol. The trial is designed to assess the long-term effects of **XTMAB-16** in the specified patient population, with careful monitoring of safety and tolerability parameters.

Efficacy in the clinical trial evaluating XTMAB-16 for **pulmonary sarcoidosis** will be assessed through several secondary endpoints. These include the total corticosteroid dose, with a focus on the accumulated dose over the first 12 weeks, the average daily dose, and the percentage of time in the study with a dose of ≤ 5 mg. The proportion of participants experiencing treatment failure and the time to treatment failure will also be evaluated. Quality-of-life measures will be assessed using the King's Sarcoidosis Questionnaire (KSQ) for both the Lung Module and General Health Status Module, the Leicester Cough Questionnaire (LCQ), and the Steroid Toxicity Questionnaire (STQ). Changes in pulmonary function will be measured by forced vital capacity (FVC) from baseline to various assessment timepoints throughout the study.

Additionally, the trial will monitor the number and percentage of participants who test positive for XTMAB-16 anti-drug antibodies (ADA) and neutralizing antibodies (nAb). Biomarker levels will be evaluated for absolute and percent changes from baseline, including angiotensin converting enzyme (ACE), interleukin-6 (IL-6), soluble interleukin-2 receptor (sIL-2R), soluble tumor necrosis factor alpha (sTNFα), C-reactive protein (CRP), interleukin-1b (IL-1b), and calcitriol (Vitamin D1, 25). These assessments will be conducted at various timepoints throughout the study duration to determine the efficacy of XTMAB-16 in treating pulmonary sarcoidosis.