Phase 3 Randomized Double-Blind Study of Inebilizumab Efficacy and Safety in IgG4-Related Disease

The primary objective of this study is to evaluate the **efficacy** of inebilizumab in reducing the risk of a disease flare in patients with **Immunoglobulin G4-related disease (IgG4-RD)**. This is clinically relevant as IgG4-RD is a chronic inflammatory condition that can lead to significant organ damage if not effectively managed. By assessing the ability of inebilizumab to prevent disease flares, the study aims to provide insights into a potential therapeutic option that could improve patient outcomes and quality of life.

Secondary objectives include:

• To evaluate the **safety** and tolerability of inebilizumab in patients with IgG4-RD, which is crucial for understanding the risk-benefit profile of the treatment.
• To evaluate the effect of inebilizumab on other measures of **disease activity**, providing a comprehensive assessment of its impact on the disease beyond flare prevention.

The clinical trial involves a total of **110 participants** diagnosed with **Immunoglobulin G4-related disease (IgG4-RD)**. The study population includes both male and female adults who have reached the age of consent, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on a clinical diagnosis of IgG4-RD, fulfilling the 2019 ACR/EULAR classification criteria, and experiencing or having recently experienced a disease flare requiring glucocorticoid treatment. The trial population is characterized by individuals with IgG4-RD affecting at least two organs or sites. Both genders are represented, and the study includes a vulnerable population. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is a **Phase 3**, randomized, double-blind, multicenter, placebo-controlled study designed to evaluate the efficacy and safety of **inebilizumab** in patients with **Immunoglobulin G4-related disease (IgG4-RD)**. The primary objective is to assess the efficacy of inebilizumab in reducing the risk of disease flare. The trial is expected to last until November 2028, with participant recruitment having commenced in August 2020. The study involves a series of visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical diagnosis, and disease activity. Participants must have a clinical diagnosis of IgG4-RD and meet the 2019 ACR/EULAR classification criteria, among other requirements.

Following the screening, eligible participants will be randomized to receive either inebilizumab or a placebo, administered via **intravenous use**. The trial includes a 52-week randomized controlled period (RCP) during which the primary endpoint is the time to disease flare, defined as the time from the first dose to the initiation of any flare treatment. Secondary endpoints include the annualized flare rate, the proportion of subjects achieving flare-free remission, and the incidence of treatment-emergent adverse events. Participants will have regular follow-up visits to monitor disease activity, treatment response, and safety outcomes.

The expected length of participant involvement is up to 52 weeks, with conditions for early termination including the occurrence of severe adverse events or withdrawal of consent. The end-of-study visit will assess the overall treatment efficacy and safety, with a focus on achieving flare-free remission and minimizing glucocorticoid use. The study is not classified as low intervention, and the trial phase is categorized as Phase 3, emphasizing its focus on evaluating the therapeutic benefit and safety profile of inebilizumab in a controlled setting.

The clinical trial involves the administration of **Inebilizumab**, a humanized, affinity-optimized, afucosylated immunoglobulin G1 kappa (IgG1k) monoclonal antibody. This experimental medication is provided in the form of a **solution for injection**. The route of administration is **intravenous use**, with a maximum daily dose of 300 mg and a total maximum dose of 3000 mg over the course of the study. The treatment period extends up to 48 weeks. Inebilizumab is identified by the sponsor product code MEDI-551 and is not formulated for pediatric use. The primary objective of the trial is to evaluate the efficacy of inebilizumab in reducing the risk of disease flare in patients with IgG4-Related Disease.

The study also includes a **placebo** comparator, which is a 10 mL nominal solution containing 20 mM histidine/histidine hydrochloride, 70 mM sodium chloride, 106 mM (4% [w/v]) trehalose dihydrate, and 0.01% (w/v) polysorbate 80. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo does not contain any active pharmaceutical ingredients and serves as a control to assess the efficacy and safety of inebilizumab.

The efficacy of **inebilizumab** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the time to disease flare, defined as the time in days from Day 1 (dosing) to the date of the first treated and adjudication committee (AC)-determined IgG4-Related Disease (IgG4-RD) flare within the 52-week randomized controlled period (RCP). The date of disease flare is marked by the initiation of any flare treatment deemed necessary by the investigator.

Secondary endpoints include the annualized flare rate for treated and AC-determined flares during the RCP, and the proportion of subjects achieving flare-free, treatment-free complete remission at Week 52. This is defined as the absence of evident disease activity, no AC-determined flare, and no treatment for flare or disease control except the required 8-week glucocorticoid (GC) taper. Additionally, the proportion of subjects achieving flare-free, corticosteroid-free complete remission at Week 52 will be evaluated. Other secondary endpoints include the time to initiation of first treatment for new or worsening disease activity, annualized flare rate for AC-determined flares, glucocorticoid use, incidence of treatment-emergent adverse events (TEAEs), and the incidence of anti-drug antibodies (ADAs) directed against inebilizumab during the RCP.