Obexelimab for IgG4-Related Disease

(INDIGO Trial)

Not currently recruiting at 138 trial locations

Overseen By Zenas Patient Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Zenas BioPharma (USA), LLC

Must be taking: Glucocorticoids

Must not be taking: Non-biologics, Immunosuppressives

Disqualifiers: Tuberculosis, Hepatitis B, Hepatitis C, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how well obexelimab prevents flare-ups of IgG4-related disease, a condition where the immune system attacks the body's tissues, causing inflammation and organ damage. Participants will receive either obexelimab (a humanized Fc-engineered monoclonal antibody against CD19) or a placebo, both administered as injections. The trial aims to determine if this treatment can safely prevent symptoms from returning. Individuals diagnosed with IgG4-related disease and experiencing active symptoms that require changes in their glucocorticoid (steroid) treatment may be suitable for this trial. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot have taken certain medications like non-biologic disease-modifying drugs or immunosuppressive agents (other than glucocorticoids) within 4 weeks before screening, or B cell depleting agents within 6 months before randomization.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot have taken certain drugs like non-biologic disease-modifying drugs or immunosuppressive agents other than glucocorticoids (GCs) in the 4 weeks before screening. You also cannot have used B cell depleting agents within 6 months before joining the trial.

Is there any evidence suggesting that obexelimab is likely to be safe for humans?

Research has shown that obexelimab has been tested for safety in people with IgG4-related disease. In a previous study, obexelimab was generally well-tolerated, with most participants not experiencing serious side effects. Some had mild reactions, such as headaches, but these were uncommon.

Studies have also examined obexelimab in other diseases, such as systemic lupus erythematosus. These studies found similar results, with the treatment being well-tolerated and causing only mild side effects in some participants.

Since this treatment is in a late stage of testing, it has already passed earlier safety checks, indicating that obexelimab is considered safe enough for further research in humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for IgG4-related disease?

Obexelimab is unique because it targets CD19, a protein found on B cells, which play a role in IgG4-Related Disease. Unlike standard treatments that mainly suppress the immune system, Obexelimab specifically modulates B cell activity, potentially leading to fewer side effects. Researchers are excited because this targeted approach could offer a more precise and effective treatment, improving patient outcomes without the broad immune suppression seen in current therapies.

What evidence suggests that obexelimab might be an effective treatment for IgG4-related disease?

Research has shown that obexelimab, which participants in this trial may receive, may help manage IgG4-related disease (IgG4-RD). In a previous study, most patients experienced fewer disease flare-ups when treated with obexelimab. This treatment targets certain immune cells, calming the body's immune response. Early findings suggest it can effectively prevent the immune system from overreacting, a major problem in IgG4-RD. Additionally, similar treatments have shown positive effects in related conditions like rheumatoid arthritis. Overall, the evidence supports obexelimab as a promising option for controlling IgG4-RD symptoms. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

Adults diagnosed with IgG4-Related Disease showing active symptoms needing treatment can join this trial. They must meet specific criteria for the disease's classification. Excluded are those with only one affected organ system, high-dose steroid use in the last month, recent other treatments or live vaccines, and certain infections or use of B cell targeting drugs within six months.

Inclusion Criteria

I have been diagnosed with IgG4-Related Disease.

Patients must meet the 2019 ACR/EULAR Classification Criteria for IgG4-RD

Other inclusion criteria apply

Exclusion Criteria

I have not received a live vaccine or therapy with live agents in the last 2 weeks.

Other exclusion criteria apply

Has received an investigational treatment or direct medical intervention on another clinical study within 12 weeks or < 5 half-lives of the investigational treatment, whichever is shorter, prior to screening

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Randomized Control Period (RCP)

Participants receive either obexelimab or placebo with steroid tapering, monitored for IgG4-RD flares

52 weeks

Scheduled in-clinic visits and any unscheduled visits

Open-label Extension (OLE)

All participants receive obexelimab, continuation of monitoring for IgG4-RD flares

104 weeks

Regular in-clinic visits

Follow-up

Participants are monitored for safety after the main trial phases

12 weeks

1 in-clinic safety follow-up visit

What Are the Treatments Tested in This Trial?

Interventions

• Obexelimab
• Placebo

Trial Overview The trial is testing Obexelimab against a placebo to see if it prevents flare-ups of IgG4-Related Disease when added to standard therapy. Participants will be randomly assigned to receive either Obexelimab or a placebo alongside their usual treatment.

How Is the Trial Designed?

Group I: ZB012 Experimental Treatment 1 Intervention

Obexelimab administered as an SC injection.

Group II: Placebo Placebo Group 1 Intervention

Placebo administered as an SC injection.

Who Is Running the Clinical Trial?

Zenas BioPharma (USA), LLC

Lead Sponsor

Trials

8

Recruited

760+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

The study identifies that the effectiveness and safety of anti-4-1BB monoclonal antibody agonists (mAb-AG) are influenced by their isotype and intrinsic agonistic strength, which can lead to either robust anti-tumor activity or severe liver toxicity.

The newly developed LVGN6051 mAb-AG demonstrates high anti-tumor efficacy without causing liver toxicity in mouse models, suggesting a promising approach for improving cancer immunotherapy by balancing agonistic activity and FcγR interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity. Qi, X., Li, F., Wu, Y., et al.[2021]

XmAb5574, a humanized anti-CD19 antibody, significantly enhances immune cell functions, showing 100 to 1,000 times greater antibody-dependent cell-mediated cytotoxicity against various B-lymphoma and leukemia cell lines compared to a standard IgG1 analogue.

In mouse models, XmAb5574 effectively inhibited lymphoma growth and demonstrated superior antitumor activity, highlighting the importance of Fcgamma receptor engagement for its efficacy, suggesting it is a promising candidate for treating CD19(+) hematologic cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. Horton, HM., Bernett, MJ., Pong, E., et al.[2021]

Rituximab (RTX) was found to be highly effective in treating IgG4-related disease (IgG4-RD), with a clinical response observed in 93.5% of symptomatic patients, and over half of the patients able to withdraw from glucocorticoids after treatment.

However, relapses occurred in 41.9% of responders, and maintenance therapy with RTX was linked to longer relapse-free survival, although the treatment was associated with a significant risk of severe infections and temporary effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of rituximab in IgG4-related disease: Data from a French nationwide study of thirty-three patients. Ebbo, M., Grados, A., Samson, M., et al.[2022]

In a phase 1 trial involving 27 patients with relapsed or refractory chronic lymphocytic leukemia (CLL), the novel monoclonal antibody XmAb5574 was found to be generally well tolerated, with the most common side effects being mild infusion reactions.

XmAb5574 demonstrated preliminary efficacy, with 66.7% of patients showing a response based on physical examination and laboratory studies, indicating its potential as a treatment option for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL. Woyach, JA., Awan, F., Flinn, IW., et al.[2021]

Therapeutic antibodies are highly effective due to their specific binding capabilities and the long half-life provided by the Fc portion interacting with the FcRn receptor, which enhances their therapeutic potential.

Engineering the Fc portion of antibodies can improve their efficacy by increasing their binding to FcRn or enhancing their ability to trigger immune responses, potentially leading to better patient outcomes and more convenient dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methods to engineer and identify IgG1 variants with improved FcRn binding or effector function. Kelley, RF., Meng, YG.[2012]

The Fc-engineered anti-CD19 antibody, XmAb5574, caused significant B-cell depletion in cynomolgus monkeys, reducing B-cell levels to less than 10% of baseline, while also leading to a temporary reduction in natural killer (NK) cells.

In contrast, the non-engineered anti-CD19 IgG1 did not result in B-cell depletion or sustained NK-cell reduction, highlighting that enhanced Fcgamma receptor binding in XmAb5574 is crucial for its antitumor activity and suggests potential for improved treatment of B-cell malignancies in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of Fc engineering on an anti-CD19 antibody: increased Fcgamma receptor affinity enhances B-cell clearing in nonhuman primates. Zalevsky, J., Leung, IW., Karki, S., et al.[2021]

Fc gamma Receptor IIB (FcγRIIB) plays a crucial role in regulating immune responses, particularly in the context of immunotherapy, by inhibiting signals from other receptors like activatory FcγRs and the B cell receptor.

Recent studies suggest that FcγRIIB can enhance the effectiveness of certain immunomodulatory monoclonal antibodies (mAbs), indicating its potential as a therapeutic target to improve immunotherapy outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FcγRIIB as a key determinant of agonistic antibody efficacy. White, AL., Beers, SA., Cragg, MS.[2016]

The study developed three unique monoclonal antibodies (mAbs) that specifically target the inhibitory Fc gamma receptor II (FcγRIIB), which is crucial for regulating immune responses, particularly in the context of cancer therapy and autoimmunity.

These mAbs are categorized into agonistic, which activate FcγRIIB, and antagonistic, which block its activation, demonstrating distinct effects in biochemical and cellular assays, thus providing new tools for manipulating FcγRIIB in therapeutic settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and characterisation of monoclonal antibodies specific for the murine inhibitory FcγRIIB (CD32B). Williams, EL., Tutt, AL., French, RR., et al.[2012]

Monoclonal antibodies have enhanced our understanding of Fc receptor biology, leading to the development of new therapeutic strategies that can improve treatment efficacy and reduce side effects.

Recent advances in biologics are focused on optimizing Fc receptor interactions to create tailored immunotherapies, with several innovative drugs currently being tested in clinical trials for their effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Harnessing Fc receptor biology in the design of therapeutic antibodies. Sondermann, P., Szymkowski, DE.[2018]

In a pilot trial involving 30 patients with IgG4-related disease, rituximab (RTX) demonstrated a high efficacy, with 97% of participants showing disease response and 77% achieving the primary outcome after 6 months.

The treatment led to significant reductions in disease activity scores and serum IgG4 levels, with 47% of patients reaching complete remission at 6 months, indicating RTX's potential as an effective therapy even without glucocorticoid use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rituximab for IgG4-related disease: a prospective, open-label trial. Carruthers, MN., Topazian, MD., Khosroshahi, A., et al.[2022]

Both wild-type and Fc-mutated anti-PD-L1 monoclonal antibodies showed similar antitumor efficacy in humanized FcγR mice, indicating that the ability to engage Fcγ receptors does not significantly impact their therapeutic activity.

Enhancing the binding of the anti-PD-L1 antibody avelumab through Fc glycoengineering (removing fucose) improved its antitumor effects and immune response, suggesting that optimizing FcγR engagement could enhance the effectiveness of PD-L1 immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fc glycoengineering of a PD-L1 antibody harnesses Fcγ receptors for increased antitumor efficacy. Cohen Saban, N., Yalin, A., Landsberger, T., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38251576/

an open-label, single-arm, single centre, phase 2 pilot trial We aimed to evaluate the safety, clinical efficacy, and pharmacodynamic effects of obexelimab in patients with active IgG4-related disease.

2. sciencedirect.com sciencedirect.com/topics/immunology-and-microbiology/xmab5871

Xmab5871 - an overview | ScienceDirect Topics Preclinical data also suggest a role in the treatment of RA [53,54] In RA patients, XmAb5871 10 mg/kg reduced disease activity levels; AEs included nausea, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02725476

NCT02725476 | Study to Evaluate the Effect of XmAb® ... Study to Evaluate the Effect of XmAb®5871 on Disease Activity in Patients With IgG4-Related Disease (RD). ClinicalTrials.gov ID NCT02725476. Sponsor Xencor ...

4. withpower.com withpower.com/trial/phase-3-immunoglobulin-g4-related-disease-8-2022-6231d

Obexelimab for IgG4-Related Disease (INDIGO Trial) This trial is testing obexelimab, a medication given through injections, to see if it can prevent flare-ups in patients with IgG4-related disease.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05662241

A Phase 3 Study of Obexelimab in Patients With IgG4- ... This study aims to examine the efficacy and safety of obexelimab for the prevention of flare of IgG4-related disease (IgG4-RD)

6. go.drugbank.com go.drugbank.com/drugs/DB15032

Obexelimab: Uses, Interactions, Mechanism of Action Obexelimab is under investigation in clinical trial NCT02725515 (A Study of the Effect of XmAb®5871 in Patients With Systemic Lupus ...

7. investors.xencor.com investors.xencor.com/news-releases/news-release-details/xencor-announces-topline-results-phase-2-study-xmabr5871

Xencor Announces Topline Results from Phase 2 Study of ... Xencor announces topline results from Phase 2 study of XmAb®5871 in systemic lupus erythematosus and selection of late-breaking abstract for presentation.