Anti-Inflammatory Lipid Mediator for Asthma

(ALMA; LIMA Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Fernando Holguin, MD, MPH

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: University of Colorado, Denver

Must be taking: Inhaled corticosteroids, Long acting beta agonists

Disqualifiers: Recent infection, Recent steroids, Smoking, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests CXA-10, a synthetic compound that reduces inflammation, in obese adults with asthma. The goal is to see if it can help control asthma symptoms by calming down the body's immune response.

Will I have to stop taking my current medications?

The trial requires that you continue taking your regular asthma medications, such as inhaled corticosteroids, long-acting beta agonists, and long-acting muscarinic antagonists, as long as you have been on a stable dose for at least 4 weeks before starting the study.

What evidence supports the effectiveness of the drug CXA-10 for treating asthma?

Research shows that a similar compound, 10-nitro-oleic acid, reduced the severity of allergic airway disease in mice, suggesting it may help with asthma. This compound works by reducing inflammation and promoting the removal of certain immune cells, which could be beneficial for severe asthma that doesn't respond well to standard treatments. ^{1 2 3 4 5}

Is CXA-10 safe for humans?

In studies with healthy and obese people, CXA-10 was generally safe and well-tolerated, with the most common side effects being diarrhea, abdominal pain, and nausea. No serious health issues were found during physical exams or lab tests. ^{1 5 6 7 8}

How is the drug CXA-10 different from other asthma treatments?

CXA-10 is unique because it is an anti-inflammatory lipid mediator that works by promoting the resolution of inflammation, unlike traditional asthma treatments that mainly focus on blocking inflammation. This drug is part of a new class of compounds that have shown potential in reducing airway inflammation and hyper-responsiveness in asthma. ^{1 2 4 9 10}

Research Team

Fernando Holguin, MD, MPH

Principal Investigator

University of Colorado Denver- Anschutz Medical Campus

Eligibility Criteria

Adults aged 18-65 with obesity (BMI ≥30) and asthma, using regular inhaled corticosteroids or other long-term asthma medications. Women must be non-pregnant, post-menopausal, surgically sterile, or agree to use contraception. Excluded are those recently hospitalized for asthma, had a respiratory infection or steroid treatment within the last month, severe asthmatics with frequent exacerbations, or current/recent smokers.

Inclusion Criteria

Adequate completion of informed consent process with written documentation

I am between 18 and 65 years old.

You have a body mass index (BMI) of 30 or higher.

Exclusion Criteria

I was hospitalized for asthma in the last 6 weeks.

I have not taken any corticosteroids in the last 4 weeks.

I have not had a respiratory infection in the last 4 weeks.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CXA-10 or placebo orally, continuously, and daily for 6 weeks

6 weeks

1 visit (in-person) for drug dispensing

Washout

Participants undergo a washout period before crossover

4 weeks

Crossover Treatment

Participants receive the alternate treatment (CXA-10 or placebo) for an additional 6 weeks

6 weeks

1 visit (in-person) for drug dispensing

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

Treatment Details

Interventions

• CXA-10 (Lipid Mediator)

Trial Overview The trial is testing CXA-10's effectiveness against placebo in reducing inflammation in obese adults with asthma. It's a Phase 2 study where participants will receive either the synthetic nitro-fatty acid CXA-10 or a placebo without knowing which one they're getting to compare outcomes.

Participant Groups

Group I: CXA-10 Experimental Treatment 1 Intervention

Administered orally, continuously, and daily for at least 6 weeks. Dispensed at Visit 1. Washout period of at least 4 weeks and then enter crossover phase of an additional 6 weeks. Drug will be dispensed at Visit 4.

Group II: Matching Placebo Placebo Group 1 Intervention

Administered orally, daily, and continuously for at least 6 weeks. Dispensed at Visit 1. Washout period of at least 4 weeks and then enter crossover phase of an additional 6 weeks. Placebo will be dispensed at Visit 4.

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Aviva Abosch

University of Colorado, Denver

Chief Medical Officer since 2019

MD

Uday B. Kompella

University of Colorado, Denver

Chief Executive Officer since 2015

PhD in Pharmaceutical Sciences

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Dr. Gary H. Gibbons

National Heart, Lung, and Blood Institute (NHLBI)

Chief Executive Officer since 2012

MD from Harvard Medical School

Dr. James P. Kiley

National Heart, Lung, and Blood Institute (NHLBI)

Chief Medical Officer since 2011

MD from University of California, San Francisco

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Dr. Jeanne Marrazzo

National Institutes of Health (NIH)

Chief Medical Officer

MD from University of California, Los Angeles

Dr. Jay Bhattacharya

National Institutes of Health (NIH)

Chief Executive Officer

MD, PhD from Stanford University

Findings from Research

Individuals with severe asthma have significantly lower levels of Lipoxin A(4) (LXA(4)), a mediator that helps resolve inflammation, compared to those with nonsevere asthma, suggesting a potential deficiency in anti-inflammatory mechanisms.

The study found decreased expression of lipoxin biosynthetic enzymes and receptors in severe asthma, indicating that the inability to produce and respond to lipoxins may contribute to the persistent airway inflammation seen in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. Planagumà, A., Kazani, S., Marigowda, G., et al.[2021]

A new class of lipid mediators, including lipoxins, resolvins, protectins, and maresins, derived from polyunsaturated fatty acids, shows strong anti-inflammatory effects in both laboratory and animal studies.

These compounds have significant therapeutic potential for treating various inflammatory lung diseases, such as asthma, cystic fibrosis, and acute lung injury, addressing a critical need for effective anti-inflammatory treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pro-resolving lipid mediators in inflammatory lung diseases]. Eickmeier, O., Hilberath, JN., Zielen, S., et al.[2011]

Lipoxins (LXs) are important anti-inflammatory mediators derived from arachidonic acid metabolism, playing a crucial role in resolving inflammation in asthma, with their levels influenced by bronchial inflammation and glucocorticoid treatments.

Mild asthmatics have higher levels of lipoxin synthesis compared to severe asthmatics, suggesting that enhancing LX production in severe cases could be a potential therapeutic strategy for improving bronchial inflammation resolution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipoxins in asthma: potential therapeutic mediators on bronchial inflammation? Bonnans, C., Chanez, P., Chavis, C.[2013]

The review highlights the role of polyunsaturated fatty acids (PUFAs) and their metabolites, such as eicosanoids and specialized pro-resolving lipid mediators (SPMs), in the chronic inflammation and bronchial obstruction associated with asthma.

Recent advances in lipidomics suggest that SPMs could be potential therapeutic agents for managing asthma by promoting the resolution of inflammation, offering a new avenue for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pro-Resolving Lipid Mediators in the Pathophysiology of Asthma. Kytikova, O., Novgorodtseva, T., Denisenko, Y., et al.[2020]

Nitrated fatty acids (NFAs), specifically 10-nitro-oleic acid (OA-NO2), have shown promise as an effective treatment for allergic airway disease in preclinical models, reducing disease severity and demonstrating unique mechanisms of action compared to traditional inhaled steroids.

Unlike fluticasone, which is a common inhaled steroid, OA-NO2 not only reduced inflammation but also induced apoptosis of neutrophils, suggesting it may be particularly beneficial for patients with severe asthma that is resistant to steroid treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The nitrated fatty acid 10-nitro-oleate attenuates allergic airway disease. Reddy, AT., Lakshmi, SP., Dornadula, S., et al.[2022]

CXA-10, a novel nitro fatty acid, has shown promise in reducing biomarkers of inflammation and metabolic stress in healthy and obese subjects, indicating its potential therapeutic effects in conditions related to oxidative stress.

The compound was found to be safe and well-tolerated, with dose-related adverse events primarily including diarrhea, abdominal pain, and nausea, and no significant clinical abnormalities reported, paving the way for ongoing Phase II studies in patients with specific diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and Pharmacodynamic Effects of Oral CXA-10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects. Garner, RM., Mould, DR., Chieffo, C., et al.[2020]

CRBM-0244, a new derivative of docosahexaenoic acid (DHA), effectively prevents bronchial hyperresponsiveness and reduces inflammation in both human bronchi and a guinea pig model of allergic asthma, indicating its potential as a therapeutic agent for asthma.

The mechanism of action involves the inhibition of NF-κB activation and COX-2 overexpression, along with a reduction in Ca(2+) sensitivity of bronchial smooth muscle, suggesting that CRBM-0244 modulates inflammatory responses through specific biochemical pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docosahexaenoic acid derivative prevents inflammation and hyperreactivity in lung: implication of PKC-Potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17 kD in asthma. Morin, C., Fortin, S., Cantin, AM., et al.[2020]

Lipoxins, a type of eicosanoid, have unique anti-inflammatory properties that can significantly reduce airway hyperresponsiveness and inflammation in asthma, as shown in experimental models.

The administration of a stable analog of lipoxin A(4) not only decreased inflammation but also indicated that targeting lipoxin pathways could offer new therapeutic strategies for managing asthma and airway inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring new approaches to the treatment of asthma: potential roles for lipoxins and aspirin-triggered lipid mediators. Levy, BD., Serhan, CN.[2019]

Lipoxin A4 (LXA4) stable analogs, specifically ATLa and ZK-994, effectively reduced inflammation in allergen-driven models by preventing excessive accumulation and activation of immune cells like eosinophils and T lymphocytes, showing over 50% reduction in leukocyte trafficking at doses below 0.5 mg/kg.

Unlike the CysLT1 receptor antagonist montelukast, LXA4 analogs not only reduced inflammatory cytokines such as IL-4 and IL-13 but also demonstrated a unique mechanism of action, highlighting their potential as new therapeutic agents for managing allergic airway inflammation and hyper-responsiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism. Levy, BD., Lukacs, NW., Berlin, AA., et al.[2021]

References

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

Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. [2021]

2. Germany pubmed.ncbi.nlm.nih.gov

[Pro-resolving lipid mediators in inflammatory lung diseases]. [2011]

3. Denmark pubmed.ncbi.nlm.nih.gov

Lipoxins in asthma: potential therapeutic mediators on bronchial inflammation? [2013]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Pro-Resolving Lipid Mediators in the Pathophysiology of Asthma. [2020]

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

The nitrated fatty acid 10-nitro-oleate attenuates allergic airway disease. [2022]

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

Pharmacokinetic and Pharmacodynamic Effects of Oral CXA-10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity. [2013]

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

Docosahexaenoic acid derivative prevents inflammation and hyperreactivity in lung: implication of PKC-Potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17 kD in asthma. [2020]

9. Spain pubmed.ncbi.nlm.nih.gov

Exploring new approaches to the treatment of asthma: potential roles for lipoxins and aspirin-triggered lipid mediators. [2019]

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

Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism. [2021]