A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO EVALUATE THE EFFICACY AND SAFETY OF OBEXELIMAB IN PATIENTS WITH IGG4-RELATED DISEASE (INDIGO)

The primary objective of this study is to evaluate the effect of weekly subcutaneous (**SC**) administration of **obexelimab** on IgG4-Related Disease (**IgG4-RD**) flare following an initial course of glucocorticoid (GC) therapy in patients with active IgG4-RD. This is clinically relevant as it aims to assess the potential of obexelimab to manage disease flares, which are a significant concern in the management of IgG4-RD, potentially reducing the dependency on long-term glucocorticoid therapy and its associated side effects.

Secondary objectives include:

• Evaluating the effect of weekly SC administration of obexelimab on measures of disease activity in patients with IgG4-RD.
• Assessing the safety and tolerability of weekly SC administration of obexelimab in patients with active IgG4-RD.

These secondary objectives are important for understanding the broader impact of obexelimab on disease management and patient safety, providing comprehensive insights into its therapeutic profile.

The clinical trial involves a total of **115 participants** diagnosed with **IgG4-Related Disease**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on their clinical diagnosis of IgG4-RD, meeting the 2019 ACR/EULAR Classification Criteria with a score of 20 or higher, and exhibiting active disease signs or symptoms necessitating glucocorticoid therapy. The trial includes individuals who are not pregnant or breastfeeding and who agree to adhere to contraceptive guidelines. Participants are required to have undergone glucocorticoid treatment for a minimum of three weeks and a maximum of six weeks prior to randomization. The trial population is characterized by a diverse age range and includes both genders, with a focus on ensuring the safety and tolerability of the investigational product. The study does not provide specific information regarding lifestyle considerations such as diet or physical activity.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of **Obexelimab** in patients with **IgG4-Related Disease**. The trial is structured in two phases: the Randomized Controlled Phase (RCP) and the Open-Label Extension (OLE). The primary objective of the RCP is to assess the effect of weekly subcutaneous administration of Obexelimab on IgG4-RD flare following an initial course of glucocorticoid (GC) therapy. The OLE aims to evaluate the safety and tolerability of Obexelimab, as well as its effect on IgG4-RD flare. The trial is expected to conclude by December 2027, with recruitment having commenced in June 2023.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, clinical diagnosis, and active disease symptoms. The inclusion criteria require participants to be at least 18 years old, have a clinical diagnosis of IgG4-RD, and meet the 2019 ACR/EULAR Classification Criteria with a score of 20 or higher. The screening visit will also include a negative serum pregnancy test for women of childbearing potential. Following randomization, participants will attend regular follow-up visits to monitor the time to first IgG4-RD flare and the incidence of adverse events. The end-of-study visit will assess the cumulative dose of GC rescue therapy and the proportion of patients achieving complete remission.

The expected duration of participant involvement is up to 104 weeks, with conditions for early termination including severe adverse events, pregnancy, malignancy, hypersensitivity to the investigational medicinal product (IMP), or any other safety concerns as determined by the investigator. Participants who complete the RCP and meet specific criteria may continue into the OLE, provided they have not discontinued the IMP due to safety reasons or received other biologic immunomodulatory agents within six months prior to enrollment in the OLE period. The study is designed to ensure rigorous monitoring and assessment of both efficacy and safety endpoints throughout the trial duration.

The clinical trial involves the administration of **Obexelimab**, an experimental medication, to evaluate its efficacy and safety in patients with **IgG4-related disease**. Obexelimab is provided in the form of an injection, specifically designed for subcutaneous administration. The active substance in Obexelimab is a protein of other origin, and it is supplied by Zenas Biopharma (USA) LLC. The maximum daily dose of Obexelimab is 250 mg, with a total maximum dose of 52,000 mg over the course of the treatment period, which spans up to 104 weeks. The medication is delivered using a single-use, ready-to-use glass prefilled syringe with a ½-inch staked needle and a rigid needle cap, known as the BD Hypak for BIOTECH syringe barrel. The administration schedule involves weekly subcutaneous injections, and participant compliance is monitored throughout the study.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is a sterile solution intended for subcutaneous injection, mirroring the administration route of Obexelimab. The placebo is used to ensure the integrity of the study by providing a control group for comparison against the effects of the experimental medication. The placebo is administered with the same frequency and method as Obexelimab, maintaining consistency in the treatment protocol for all participants.

The efficacy of the investigational product, **Obexelimab**, in the treatment of IgG4-Related Disease (IgG4-RD) will be assessed through a series of predefined primary and secondary endpoints. The primary endpoint for the Randomized Controlled Phase (RCP) is the time to first IgG4-RD flare, which is defined as the reappearance of previous signs or symptoms or the appearance of new signs or symptoms that necessitate the initiation of rescue therapy, as determined by the investigator and the Adjudication Committee (AC), from randomization to Week 52. In the Open-Label Extension (OLE) phase, the primary endpoint includes the incidence of adverse events (AEs), serious adverse events (SAEs), and any adverse events of special interest (AESIs), as defined by the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0), as well as the time to first IgG4-RD flare requiring rescue therapy.

Secondary endpoints for the RCP include the time to IgG4-RD flare requiring rescue therapy, the number of flares requiring rescue therapy, the proportion of patients achieving complete remission (defined as an IgG4-RD Responder Index score of 0, no AC-determined flare, and no treatment for flare) at Week 52, and the cumulative dose of IgG4-RD glucocorticoid (GC) rescue therapy from randomization to Week 52. Additionally, the incidence of AEs, SAEs, and AESIs will be monitored. In the OLE phase, secondary endpoints include the cumulative dose of IgG4-RD GC rescue therapy, changes in GC-associated toxicity as measured by the Glucocorticoid Toxicity Index (GTI), the number of flares requiring rescue therapy, and the time to first IgG4-RD flare requiring rescue therapy.