Obexelimab for IgG4-Related Disease

(INDIGO Trial)

Recruiting at 112 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

194 Participants Needed

Trial Summary

What is the purpose of this 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. These patients have active symptoms that need steroid treatment. Obexelimab works by calming the immune system to stop it from causing inflammation and other symptoms.

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.

What data supports the idea that Obexelimab for IgG4-Related Disease is an effective treatment?

The available research does not provide specific data on the effectiveness of Obexelimab for IgG4-Related Disease. However, it mentions a similar drug, XmAb5574, which is a CD19 antibody like Obexelimab, showing preliminary effectiveness in treating another condition, chronic lymphocytic leukemia (CLL). In a trial, 66.7% of patients showed improvement based on physical exams and lab studies. This suggests that CD19 antibodies can be effective, but more specific research on Obexelimab for IgG4-Related Disease is needed to confirm its effectiveness. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Obexelimab for IgG4-Related Disease?

Research on a similar drug, XmAb5574, which is also a CD19-targeting antibody, showed preliminary effectiveness in treating chronic lymphocytic leukemia (a type of cancer), suggesting potential for Obexelimab in IgG4-Related Disease. ^{1 2 3 4 5}

What safety data is available for Obexelimab in treating IgG4-Related Disease?

The safety data for Obexelimab, also known as XmAb 5871, is primarily derived from a phase 1 trial of a similar Fc-engineered CD19 antibody, XmAb5574, in patients with relapsed CLL. In this trial, XmAb5574 was generally well tolerated, with the most common toxicities being mild infusion reactions. More severe toxicities, such as neutropenia, thrombocytopenia, and tumor lysis syndrome, were observed in some patients. The trial demonstrated preliminary efficacy and justified further investigation in phase 2 trials. This suggests that Obexelimab may have a similar safety profile, but specific data for IgG4-Related Disease is not detailed in the provided research. ^{4 5 6 7 8}

Is Obexelimab generally safe for humans?

A phase 1 trial of a similar CD19 antibody, XmAb5574, showed it was generally well tolerated in patients with chronic lymphocytic leukemia, with most side effects being mild infusion reactions. Some patients experienced more serious side effects like low white blood cell counts and liver enzyme changes, but no maximum tolerated dose was reached, indicating a favorable safety profile. ^{4 5 6 7 8}

Is the drug Obexelimab a promising treatment for IgG4-Related Disease?

Yes, Obexelimab is a promising treatment because it is a specially designed antibody that targets CD19, a protein found on certain immune cells. This drug has shown strong potential in fighting diseases by enhancing the body's immune response, as seen in trials for similar conditions. It has been engineered to work more effectively and last longer in the body, making it a promising option for treating IgG4-Related Disease. ^{4 5 9 10 11}

What makes the drug Obexelimab unique for treating IgG4-Related Disease?

Obexelimab is unique because it is a humanized monoclonal antibody engineered to target CD19, a protein found on B cells, and it enhances immune system functions by improving binding to Fc receptors. This design aims to increase the drug's effectiveness in clearing B cells, which is different from traditional treatments that may not specifically target CD19 or utilize Fc engineering. ^{4 5 9 10 11}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Rituximab for IgG4-related disease: a prospective, open-label trial. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Fc glycoengineering of a PD-L1 antibody harnesses Fcγ receptors for increased antitumor efficacy. [2023]

3. United States 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. [2022]

4. United States 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. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Harnessing Fc receptor biology in the design of therapeutic antibodies. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Methods to engineer and identify IgG1 variants with improved FcRn binding or effector function. [2012]

8. Germany pubmed.ncbi.nlm.nih.gov

Development and characterisation of monoclonal antibodies specific for the murine inhibitory FcγRIIB (CD32B). [2012]

9. United States pubmed.ncbi.nlm.nih.gov

Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. [2021]

10. United States 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. [2021]

11. Germany pubmed.ncbi.nlm.nih.gov

FcγRIIB as a key determinant of agonistic antibody efficacy. [2016]