IC14 for Heart Failure

Recruiting at 1 trial location

Overseen By Ben Van Tassell, PharmD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Implicit Bioscience

Must be taking: Loop diuretics

Must not be taking: Immunosuppressives, Anti-inflammatories

Disqualifiers: Acute coronary syndromes, Uncontrolled hypertension, Active infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 1 day

10 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to learn if drug atibuclimab (IC14) works to treat adults hospitalized with acute decompensated heart failure (ADHF). It will also learn about the safety of IC14. The main questions it aims to answer are: Is the drug IC14 safe in patients with ADHF? What are the IC14 drug levels in the bloodstream after treatment with IC14? What is the impact of IC14 treatment on markers of disease in the bloodstream? What is the impact of IC14 treatment on measures of heart failure? There is no placebo arm in this study. Participants will: Take drug IC14 once via an intravenous infusion After the infusion, be visited in the hospital or visit the clinic 5 times for checkups and tests Answer questions about their medical status via a phone call 3 months after the infusion

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you have used immunosuppressive or anti-inflammatory drugs recently, you may not be eligible to participate.

What data supports the effectiveness of the drug Atibuclimab (IC14, Anti-CD14 antibody) for heart failure?

Research suggests that the immune system plays a significant role in heart failure, and targeting immune components like CD14 could be beneficial. Elevated levels of soluble CD14 are linked to poor outcomes in heart failure, indicating that targeting CD14 with treatments like Atibuclimab might help improve heart failure conditions. ^{1 2 3 4 5}

Is Atibuclimab (IC14) safe for human use?

The research articles focus on immune checkpoint inhibitors (ICIs) and their potential heart-related side effects, such as myocarditis (inflammation of the heart muscle) and other cardiovascular issues. While these articles do not specifically mention Atibuclimab (IC14), they highlight the importance of monitoring for heart-related side effects when using similar treatments. ^{6 7 8 9 10}

What makes the drug Atibuclimab unique for treating heart failure?

Atibuclimab is unique because it is an anti-CD14 antibody, which targets a specific protein involved in immune response, potentially offering a novel mechanism of action compared to traditional heart failure treatments that typically focus on managing symptoms or improving heart function. ^{11 12 13 14 15}

Research Team

Antonio Abbate, MD

Principal Investigator

University of Virginia

Eligibility Criteria

This trial is for adults hospitalized with acute decompensated heart failure (ADHF). Participants must be currently admitted for ADHF to qualify. Specific inclusion and exclusion criteria details are not provided, but typically these would outline the health status and other conditions that either qualify or disqualify a person from participating.

Inclusion Criteria

Patients must be symptomatic for moderate to severe dyspnea, have received or scheduled to receive intravenous loop diuretics, be at least 21 years old, willing to provide informed consent, have screening plasma C-reactive protein levels >3 mg/L, and use effective contraception if of childbearing potential

I was hospitalized for worsening heart failure, experiencing shortness of breath, and have a weak heart pump.

Exclusion Criteria

I do not have severe heart failure, major health issues, recent surgeries, or use medications that could interfere with the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single intravenous infusion of IC14 and are monitored for safety and efficacy

1 day

1 visit (in-person)

Monitoring

Participants are monitored in the hospital or clinic for safety and efficacy, including biomarker and pharmacokinetic assessments

10 days

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a phone call assessment

3 months

1 visit (virtual)

Treatment Details

Interventions

• Atibuclimab

Trial Overview The trial is testing atibuclimab (IC14), administered once via IV infusion, to treat ADHF. It aims to assess the safety of IC14, its levels in the bloodstream post-treatment, its effect on disease markers in blood, and how it impacts heart failure measures. There's no placebo comparison; all participants receive IC14.

Participant Groups

Group I: IC14 (atibuclimab) Experimental Treatment 1 Intervention

20 mg/kg intravenously once at baseline

Atibuclimab is already approved in United States for the following indications:

Approved in United States as Atibuclimab for:

• Acute Decompensated Heart Failure (clinical trial phase, not yet approved)

Who Is Running the Clinical Trial?

Implicit Bioscience

Lead Sponsor

Trials

12

Recruited

140+

Virginia Commonwealth University

Collaborator

Trials

732

Recruited

22,900,000+

University of Virginia

Collaborator

Trials

802

Recruited

1,342,000+

Findings from Research

In a study of 5217 older adults over 13.6 years, higher levels of soluble CD14 (sCD14) were significantly associated with an increased risk of developing heart failure (HF), with a hazard ratio of 1.56 per doubling of sCD14, indicating a stronger association than other inflammatory markers like hsCRP and IL-6.

The association between sCD14 and heart failure was specifically noted in cases of heart failure with preserved ejection fraction (HFpEF), suggesting that sCD14 could be a potential biomarker for predicting this subtype of heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Soluble CD14 and Risk of Heart Failure and Its Subtypes in Older Adults. Al-Kindi, SG., Buzkova, P., Shitole, SG., et al.[2022]

The immune system plays a crucial role in heart failure, yet it is often overlooked as a target for treatment, which could limit the effectiveness of current therapies.

Current heart failure treatments have various immunomodulatory effects beyond their primary actions, suggesting that understanding these effects could help develop new immunomodulatory therapies tailored for specific patient subpopulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulation and immunopharmacology in heart failure. Markousis-Mavrogenis, G., Baumhove, L., Al-Mubarak, AA., et al.[2023]

In heart failure (HF) models, immune checkpoint ligands like sPD-L1, sPD-L2, and galectin-9 were found to be elevated and associated with disease severity, indicating their potential role in HF pathogenesis.

Higher serum levels of sPD-L1 and galectin-9 were linked to an increased risk of HF hospitalization and all-cause mortality, suggesting they could serve as important prognostic biomarkers in HF patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating immune checkpoints predict heart failure outcomes. Screever, EM., Yousif, LIE., Moslehi, JJ., et al.[2023]

Celacade treatment in rats significantly reduced the production of transforming growth factor beta-1 in the heart after a myocardial infarction, indicating its potential to modulate inflammatory responses during acute heart injury.

While Celacade did not prevent chronic cardiac dilation following myocardial infarction, it successfully restored the heart's ability to contract more forcefully and reduced diastolic dysfunction, suggesting it may improve heart function post-injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of therapy using the Celacade system on structural and functional cardiac remodelling in rats following myocardial infarction. Zhang, ML., Mei, J., Archer, LA., et al.[2021]

The review highlights advancements in chronic heart failure treatment from 2014, focusing on improved medication regimens, including beta blockers and mineralocorticoid receptor antagonists, which are essential for managing this common disease.

New pharmacological developments, such as angiotensin receptor neprilysin inhibition, are discussed as promising options for enhancing heart failure therapy, alongside insights into managing comorbidities like atrial fibrillation and hyperkalemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Update on therapy of chronic heart failure. Innovations and studies from last year]. Ewen, S., Linicus, Y., Böhm, M.[2018]

Immune checkpoint inhibitors (ICIs) have shown strong anti-tumor effects in cancer treatment by preventing tumor cells from inhibiting T-cell activation, but they can also lead to serious immune-related adverse events (irAEs), particularly affecting the cardiovascular system.

The review highlights that while ICIs can induce life-threatening conditions like myocarditis and cardiomyopathy due to increased autoimmunity and T-cell activity, understanding the mechanisms of IC function in cardiovascular disease may help identify therapeutic targets to prevent or treat these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of immune checkpoints in cardiovascular disease. Yousif, LI., Tanja, AA., de Boer, RA., et al.[2022]

Immune checkpoint inhibitors (ICIs) significantly improve survival rates in patients with advanced cancers, but they can also lead to serious cardiovascular adverse events (CVAEs), with myocarditis being the most common.

Management of severe myocarditis caused by ICIs requires immediate treatment with high-dose corticosteroids and stopping the ICI therapy, highlighting the need for physicians to be vigilant about these potential toxicities as ICI use becomes more widespread.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular Toxicities of Immune Checkpoint Inhibitors: JACC Review Topic of the Week. Ball, S., Ghosh, RK., Wongsaengsak, S., et al.[2020]

Immune checkpoint inhibitors (ICIs), while effective in treating tumors, can lead to serious immune-related adverse events (irAEs), including rare but potentially lethal cardiotoxicity.

PD-1 and PD-L1 inhibitors can affect the cardiovascular system due to their expression in heart cells, highlighting the need for careful monitoring and management of heart-related side effects in patients receiving these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiotoxicity associated with immune checkpoint inhibitors: Current status and future challenges. Gan, L., Liu, D., Ma, Y., et al.[2022]

Immune checkpoint inhibitors (ICIs), particularly those targeting PD-1 and PD-L1, have transformed cancer treatment but are associated with serious immune-related adverse events (IRAEs), including myocarditis, which can complicate patient care.

Current management of IRAEs typically involves high-dose corticosteroids and discontinuation of ICIs, which can be detrimental since these therapies are often the last resort for advanced cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors: Cardiotoxicity in Pre-clinical Models and Clinical Studies. Xu, S., Sharma, UC., Tuttle, C., et al.[2021]

Immune checkpoint inhibitors (ICIs) effectively activate the immune system against various cancers, but they can also lead to serious immune-related adverse events (irAEs), particularly affecting the heart, such as myocarditis.

The study identifies potential immune mechanisms behind cardiac irAEs, including the recruitment of T cells, autoantibody-mediated damage, and inflammatory cytokines, suggesting that factors like cancer severity and the release of self-antigens from cardiac tissues may contribute to this cardiotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety. Rubio-Infante, N., Ramírez-Flores, YA., Castillo, EC., et al.[2022]

The study explored various engineered anti-Fn14 antibody variants, revealing that those with four or more binding sites effectively activate the alternative NFκB pathway and enhance TNF-induced cell death, similar to the natural ligand TWEAK.

Certain antibody constructs, particularly IgG1-scFv fusion proteins, were found to preferentially activate the classical NFκB pathway, indicating potential for developing targeted therapies that harness Fn14 signaling without unwanted side effects from Fcγ receptor interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity. Zaitseva, O., Hoffmann, A., Löst, M., et al.[2023]

XmAb5871 effectively suppresses B cell activation by coengaging the Fcγ receptor IIb (FcγRIIb) and the B cell antigen receptor (BCR), demonstrating its potential as a therapeutic strategy for rheumatoid arthritis (RA).

The study found that XmAb5871's efficacy in inhibiting B cell activation was consistent across patients with RA and healthy donors, indicating that it may work effectively regardless of the presence of rheumatoid factor or anti-citrullinated protein antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fcγ receptor IIb inhibitory receptor. Chu, SY., Yeter, K., Kotha, R., et al.[2017]

The recombinant human IgG 3A2 specifically inhibits MMP-14, a matrix metalloproteinase involved in tumor growth and metastasis, without affecting similar MMPs, showcasing its potential as a targeted cancer therapy.

In a breast cancer model, IgG 3A2 significantly reduced primary tumor growth and metastatic spread to the lungs and liver by 94%, while also inhibiting the proliferation of tumor stem cells, indicating its effectiveness in preventing cancer progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of a novel camelid-inspired human antibody demonstrates the importance of MMP-14 to cancer stem cell function in the metastatic process. Chen, KE., Chen, C., Lopez, T., et al.[2019]

Monoclonal antibody 14C5 specifically binds to the vascular integrin alphavbeta5, which is expressed in various epithelial cancer cell lines, indicating its potential as a targeted therapy.

In tissue samples, 14C5 antigen was found in 50% of colon cancer tumors and in a subset of non-small cell lung cancers, suggesting that mAb 14C5 could be useful for identifying patients who may benefit from anti-alphavbeta5 therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monoclonal antibody 14C5 targets integrin alphavbeta5. Burvenich, I., Schoonooghe, S., Vervoort, L., et al.[2020]

The first-in-human trial of the CD28-specific monoclonal antibody TGN1412 led to severe cytokine release syndrome, highlighting potential safety concerns with this treatment.

The study found that the binding of TGN1412 to different Fcγ receptors does not predict T-cell activation; specifically, weaker binding to certain receptors resulted in stronger T-cell proliferation, suggesting that the design of therapeutic monoclonal antibodies should consider these complex interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Fcγ receptors compete for TGN1412 binding that determines the antibody's effector function. Dudek, S., Weißmüller, S., Anzaghe, M., et al.[2020]

References

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

Soluble CD14 and Risk of Heart Failure and Its Subtypes in Older Adults. [2022]

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

Immunomodulation and immunopharmacology in heart failure. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Circulating immune checkpoints predict heart failure outcomes. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Effects of therapy using the Celacade system on structural and functional cardiac remodelling in rats following myocardial infarction. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

[Update on therapy of chronic heart failure. Innovations and studies from last year]. [2018]

6. Switzerland pubmed.ncbi.nlm.nih.gov

The role of immune checkpoints in cardiovascular disease. [2022]

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

Cardiovascular Toxicities of Immune Checkpoint Inhibitors: JACC Review Topic of the Week. [2020]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Cardiotoxicity associated with immune checkpoint inhibitors: Current status and future challenges. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibitors: Cardiotoxicity in Pre-clinical Models and Clinical Studies. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity. [2023]

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

Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fcγ receptor IIb inhibitory receptor. [2017]

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

Use of a novel camelid-inspired human antibody demonstrates the importance of MMP-14 to cancer stem cell function in the metastatic process. [2019]

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

Monoclonal antibody 14C5 targets integrin alphavbeta5. [2020]

15. Germany pubmed.ncbi.nlm.nih.gov

Human Fcγ receptors compete for TGN1412 binding that determines the antibody's effector function. [2020]