Afimetoran for Lupus

Recruiting at331 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Bristol-Myers Squibb

Disqualifiers: Severe lupus nephritis, Neuropsychiatric lupus, Mixed connective tissue disease, Antiphospholipid syndrome

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial is testing a new medication called Afimetoran to help people with active Systemic Lupus Erythematosus (SLE). The goal is to see if it can safely reduce symptoms by calming down the immune system. The study will also provide data on its effectiveness and safety over time.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Afimetoran for treating lupus?

Research on similar TLR7/8 inhibitors, like M5049, shows they can effectively treat lupus in mouse models by blocking immune responses that cause inflammation. This suggests that Afimetoran, which also targets TLR7/8, may have similar benefits for lupus patients. ^{1 2 3 4 5}

Is Afimetoran generally safe for humans?

The research articles provided do not contain specific safety data for Afimetoran or its related compounds in humans. They focus on the efficacy and mechanism of action in animal models and cellular assays. ^{1 3 6 7 8}

How is the drug Afimetoran unique in treating lupus?

Afimetoran is unique because it targets and blocks Toll-like receptors 7 and 8, which are involved in the immune response that contributes to lupus. This mechanism is different from other treatments, as it aims to prevent the overactive immune response by inhibiting these specific receptors, potentially offering a new way to manage the disease. ^{1 3 4 6 9}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for people with active Systemic Lupus Erythematosus (SLE) who meet specific criteria, including a positive test for certain lupus-related antibodies and a minimum disease activity score. It's not open to those with severe lupus nephritis, Antiphospholipid Syndrome, unstable neuropsychiatric symptoms, or if their main diagnosis isn't SLE.

Inclusion Criteria

I tested positive for lupus-related antibodies.

My lupus is active, with a score of 6 or more, and affects my joints or skin.

I was diagnosed with lupus over 12 weeks ago and meet the SLICC criteria.

Exclusion Criteria

I have been diagnosed with Antiphospholipid Syndrome.

I have been diagnosed with severe active lupus nephritis.

I do not have active or unstable mental health issues due to lupus.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Afimetoran or placebo to evaluate effectiveness, safety, and tolerability

48 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Extension

Participants initially randomized to placebo may receive Afimetoran for additional long-term safety and efficacy data

Long-term

Treatment Details

Interventions

• Afimetoran (Unknown)
• BMS-986256 (Oral) (Unknown)
• Placebo (Other)

Trial Overview The study tests the effectiveness and safety of Afimetoran versus a placebo in individuals with active SLE. Participants will be randomly assigned to receive either Afimetoran or a placebo to compare outcomes and gather long-term data on Afimetoran's performance.

Participant Groups

Group I: Afimetoran: Dose 3 Experimental Treatment 1 Intervention

Group II: Afimetoran: Dose 2 Experimental Treatment 1 Intervention

Group III: Afimetoran: Dose 1 Experimental Treatment 1 Intervention

Group IV: Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Bristol-Myers Squibb

Lead 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

Findings from Research

M5049 is a newly discovered dual inhibitor of TLR7 and TLR8 that shows potent and selective activity in blocking immune responses linked to autoimmune diseases, particularly lupus, as demonstrated in several murine models.

This compound not only effectively inhibits TLR7/8 activity but also preferentially accumulates in tissues, suggesting it could be a promising therapeutic option for a range of autoimmune conditions beyond those traditionally associated with TLR7/8 activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of M5049: A Novel Selective Toll-Like Receptor 7/8 Inhibitor for Treatment of Autoimmunity. Vlach, J., Bender, AT., Przetak, M., et al.[2021]

In a study using lupus-prone NZBW/F1 mice, an antagonist targeting TLR7, 8, and 9 significantly reduced serum levels of autoantibodies and improved kidney health, indicating its potential efficacy in treating lupus.

The antagonist treatment also led to a favorable shift in inflammatory markers, decreasing pro-inflammatory cytokines like IL-12 and IL-1β while increasing the anti-inflammatory cytokine IL-10, suggesting a mechanism for its therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel antagonist of Toll-like receptors 7, 8 and 9 suppresses lupus disease-associated parameters in NZBW/F1 mice. Zhu, FG., Jiang, W., Bhagat, L., et al.[2013]

Two compounds, AT791 and E6446, effectively inhibit Toll-like receptors (TLR) 7 and 9, which are involved in stimulating immune responses in lupus patients, showing potential as therapeutic agents.

In mouse models of lupus, E6446 slowed the development of certain autoimmune markers, although it did not significantly affect kidney damage or survival, indicating a need for further research on its overall efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. Lamphier, M., Zheng, W., Latz, E., et al.[2022]

The study indicates that type I interferons (IFN-α) are key drivers of lupus disease progression, as deleting the Ifnb gene did not alter disease outcomes in NZB mice.

Long-term treatment with an anti-IFN-α/β receptor antibody significantly reduced disease symptoms and improved survival in BXSB mice, especially when started early in the disease, suggesting potential for this treatment approach in human lupus and other autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-IFN-α/β receptor antibody treatment ameliorates disease in lupus-predisposed mice. Baccala, R., Gonzalez-Quintial, R., Schreiber, RD., et al.[2021]

A new compound, E6742, effectively blocks the activation of Toll-like receptors 7 and 8 (TLR7/8), which are involved in the progression of lupus, by binding specifically to their structure, suggesting a novel therapeutic approach for the disease.

In mouse models of lupus, E6742 demonstrated significant therapeutic potential by suppressing autoantibody levels and preventing organ damage when administered after disease onset, indicating its efficacy in managing lupus symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel Toll-like receptor 7/8-specific antagonist E6742 ameliorates clinically relevant disease parameters in murine models of lupus. Ishizaka, ST., Hawkins, L., Chen, Q., et al.[2023]

Oligodeoxyribonucleotides modified to act as TLR7 and TLR9 antagonists effectively inhibited immune responses in both mouse and human cell cultures, demonstrating their potential to suppress unwanted immune activation.

In mouse models, these antagonists provided dose-dependent inhibition of immune responses for several days, suggesting they could be useful in treating inflammatory and autoimmune diseases linked to excessive TLR activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oligodeoxyribonucleotide-based antagonists for Toll-like receptors 7 and 9. Wang, D., Bhagat, L., Yu, D., et al.[2009]

In a study of prediseased BXSB male and female B cells, male B cells showed a stronger response to TLR-7 ligands, especially when the B cell receptor (BCR) was also activated, leading to increased IL-6 secretion.

The research indicates that while TLR-7 antagonists could be potential treatments for lupus, their effectiveness may be compromised by the simultaneous activation of the BCR, which could promote the survival of autoreactive B cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engagement of the B cell receptor for antigen differentially affects B cell responses to Toll-like receptor-7 agonists and antagonists in BXSB mice. Layer, T., Steele, A., Goeken, JA., et al.[2021]

BMS-986126 is a highly selective inhibitor of IRAK4 that effectively suppresses MyD88-dependent immune responses, showing promise in reducing cytokine production from various TLR agonists in mouse models.

In lupus models, BMS-986126 not only inhibited pathogenic responses but also demonstrated potential for steroid-sparing effects when used in combination with prednisolone, indicating its therapeutic benefit for lupus treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity. Dudhgaonkar, S., Ranade, S., Nagar, J., et al.[2018]

References

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

Discovery of M5049: A Novel Selective Toll-Like Receptor 7/8 Inhibitor for Treatment of Autoimmunity. [2021]

2. England pubmed.ncbi.nlm.nih.gov

A novel antagonist of Toll-like receptors 7, 8 and 9 suppresses lupus disease-associated parameters in NZBW/F1 mice. [2013]

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

Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. [2022]

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

Anti-IFN-α/β receptor antibody treatment ameliorates disease in lupus-predisposed mice. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

A novel small molecule compound possesses immunomodulatory properties on bone marrow-derived dendritic cells via TLR7 signaling pathway and alleviates the development of SLE. [2018]

6. Netherlands pubmed.ncbi.nlm.nih.gov

A novel Toll-like receptor 7/8-specific antagonist E6742 ameliorates clinically relevant disease parameters in murine models of lupus. [2023]

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

Oligodeoxyribonucleotide-based antagonists for Toll-like receptors 7 and 9. [2009]

8. England pubmed.ncbi.nlm.nih.gov

Engagement of the B cell receptor for antigen differentially affects B cell responses to Toll-like receptor-7 agonists and antagonists in BXSB mice. [2021]

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

Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity. [2018]