Alpha-proteinase Inhibitor for Eosinophilic Esophagitis

(ZEEPS Trial)

Recruiting at 1 trial location

Overseen By Regina Yearout

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital Medical Center, Cincinnati

Must not be taking: Anticoagulants, Systemic steroids

Disqualifiers: COPD, IgA deficiency, Cancer, others

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

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 4 weeks

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing Zemaira, a medication that protects tissues from damage, in patients with Eosinophilic Esophagitis. These patients have chronic inflammation in their esophagus due to an overactive immune response. Zemaira works by blocking harmful enzymes to reduce inflammation and prevent further damage.

Will I have to stop taking my current medications?

The trial does not require you to stop your current medications if they are stable and related to Eosinophilic Esophagitis. You must keep the same dosage for certain medications like proton pump inhibitors and leukotriene inhibitors during the study.

What data supports the effectiveness of the drug Alpha-proteinase inhibitor for treating eosinophilic esophagitis?

Research indicates that the drug Alpha-1 antitrypsin (a type of Alpha-proteinase inhibitor) can inhibit experimental eosinophilic esophagitis, suggesting it may help manage this condition by balancing protease activity in the esophagus. ^{1 2 3 4 5}

Is Alpha-proteinase Inhibitor safe for human use?

Alpha-proteinase Inhibitor, used under various names like Prolastin and Zemaira, has been used safely for over 20 years to treat conditions like alpha-1-antitrypsin deficiency and cystic fibrosis. Studies show it is well tolerated, with a low incidence of treatment-related adverse events and no documented viral transmission. ^{6 7 8 9 10}

How does the drug Alpha-proteinase inhibitor differ from other treatments for eosinophilic esophagitis?

Alpha-proteinase inhibitor is unique because it is primarily used to protect tissues from damage by enzymes like elastase, which is different from typical treatments for eosinophilic esophagitis that focus on reducing inflammation or suppressing the immune response. This drug's novel approach may help address tissue damage in eosinophilic esophagitis by balancing protease activity, which is not the focus of standard treatments. ^{8 11 12 13 14}

Research Team

Marc E Rothenberg, MD, PhD

Principal Investigator

Cincinnati Children's Hospital Medical Center

Eligibility Criteria

Adults aged 18-70 with Eosinophilic Esophagitis (EoE) who've had moderate to severe abdominal/chest pain or swallowing difficulties at least twice a week, and whose symptoms weren't controlled by standard treatments. Participants must be willing to maintain their current diet and medical management for EoE throughout the study.

Inclusion Criteria

Willing and able to comply with study visits and activities

Willing to maintain current dietary regimen throughout the course of the study. Diet must have been stable for 8 weeks prior to baseline endoscopy

My esophagus has inflammation with more than 15 eosinophils per high powered field, not caused by another known condition.

Exclusion Criteria

I do not have Crohn's, inflammatory bowel disease, or Celiac disease.

Known immunoglobulin A (IgA) deficiency (i.e., IgA level < 8 mg/dL at screening)

I am taking blood thinners other than aspirin or NSAIDs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

12 weeks

Treatment

Participants receive weekly intravenous infusions of Zemaira (120 mg/kg body weight) for 4 weeks

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Alpha-proteinase inhibitor

Trial Overview The trial is testing Zemaira (alpha-1 trypsin inhibitor) in patients with Eosinophilic Esophagitis. It's an open-label study, meaning both researchers and participants know what treatment is being given, focusing on how effective this drug is for treating EoE.

Participant Groups

Group I: Active Drug Experimental Treatment 1 Intervention

Zemaira alpha-proteinase inhibitor

Alpha-proteinase inhibitor is already approved in United States, European Union for the following indications:

Approved in United States as Aralast for:

• Chronic augmentation therapy in adults with clinically evident emphysema due to severe congenital deficiency of alpha1-proteinase inhibitor (alpha1-antitrypsin deficiency)

Approved in United States as Glassia for:

• Chronic augmentation and maintenance therapy in adults with clinically evident emphysema due to severe hereditary deficiency of alpha1-proteinase inhibitor (alpha1-antitrypsin deficiency)

Approved in United States as Prolastin-C for:

• Chronic augmentation and maintenance therapy in adults with clinical evidence of emphysema due to severe hereditary deficiency of alpha1-proteinase inhibitor (alpha1-antitrypsin deficiency)

Approved in United States as Zemaira for:

• Chronic augmentation therapy in adults with clinically evident emphysema due to severe congenital deficiency of alpha1-proteinase inhibitor (alpha1-antitrypsin deficiency)

Approved in European Union as Alpha-1-proteinase inhibitor for:

• Congenital Alpha1–Proteinase Inhibitor deficiency

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

CSL Behring

Industry Sponsor

Trials

204

Recruited

1,207,000+

Dr. Paul McKenzie

CSL Behring

Chief Executive Officer since 2023

PhD in Chemical Engineering from Carnegie Mellon University, B.S. in Chemical Engineering from the University of Pennsylvania

Dr. Bill Mezzanotte

CSL Behring

Chief Medical Officer since 2021

MD from Duke University

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Findings from Research

Loss of the protein SPINK7 in the esophagus contributes to eosinophilic esophagitis (EoE) by increasing the activity of kallikrein 5 (KLK5), which impairs the barrier function of esophageal cells and leads to inflammation.

Inhibiting KLK5 or its receptor PAR2 shows promise as a potential treatment for EoE, as demonstrated by reduced eosinophilia and cytokine production in both murine models and clinical samples from patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional role of kallikrein 5 and proteinase-activated receptor 2 in eosinophilic esophagitis. Azouz, NP., Klingler, AM., Pathre, P., et al.[2022]

In a study of 80 patients with eosinophilic esophagitis, both oral prednisone and swallowed fluticasone were effective in improving esophageal histology and alleviating symptoms, with prednisone showing a greater degree of histologic improvement.

Despite the greater histologic benefits of prednisone, there was no significant difference in symptom resolution or relapse rates between the two treatments, and both groups experienced a high rate of symptom relapse after therapy was stopped, indicating the need for ongoing maintenance treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children. Schaefer, ET., Fitzgerald, JF., Molleston, JP., et al.[2022]

In a randomized, placebo-controlled trial involving 41 adult patients with eosinophilic esophagitis (EoE), montelukast was found to be well tolerated, with no reported side effects.

After 26 weeks, 40% of patients taking montelukast maintained remission from EoE symptoms, but this was not significantly different from the 23.8% remission rate in the placebo group, indicating that montelukast may not be effective for maintaining remission after steroid therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Montelukast Does not Maintain Symptom Remission After Topical Steroid Therapy for Eosinophilic Esophagitis. Alexander, JA., Ravi, K., Enders, FT., et al.[2021]

Eosinophilic esophagitis is a chronic disorder that mimics GERD symptoms but does not respond to anti-GERD treatments; effective management includes dietary restrictions and topical corticosteroids.

Current research is exploring anti-interleukin-5 monoclonal antibodies as a potential treatment, aiming to target the underlying causes of esophageal remodeling and fibrosis associated with the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of pediatric eosinophilic esophagitis: an update. Khan, S.[2021]

In a study of 36 adult patients with eosinophilic esophagitis, treatment with mometasone furoate significantly reduced dysphagia symptoms compared to placebo, with a median score reduction of 6.5 versus 0 (p < 0.01).

While mometasone improved dysphagia, it did not show a significant benefit in overall health-related quality of life as measured by two different questionnaires, indicating that while it helps with swallowing difficulties, it may not enhance broader quality of life aspects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topically applied mometasone furoate improves dysphagia in adult eosinophilic esophagitis - results from a double-blind, randomized, placebo-controlled trial. Tytor, J., Larsson, H., Bove, M., et al.[2021]

A new plasma-derived alpha1-Proteinase Inhibitor (Zemaira) was shown to be bioequivalent to the existing treatment (Prolastin) in restoring serum Alpha1-antitrypsin levels in individuals with AAT deficiency, achieving levels above the protective threshold of 11 microM.

The study, involving 44 subjects over a 10-week double-blind phase, found that Zemaira was well tolerated with a lower incidence of treatment-related adverse events (7%) compared to Prolastin (21%), and there were no cases of viral transmission, indicating its safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-center study: the biochemical efficacy, safety and tolerability of a new alpha1-proteinase inhibitor, Zemaira. Stocks, JM., Brantly, M., Pollock, D., et al.[2019]

Prolastin-C, a new formulation of alpha1-proteinase inhibitor, showed pharmacokinetic equivalence to the original Prolastin in a study involving 24 subjects, indicating that both products deliver similar levels of the active protein in the bloodstream.

Both treatments had comparable safety profiles, with no significant differences in adverse events or treatment-emergent viral infections, suggesting that Prolastin-C is a safe alternative for patients with alpha1-antitrypsin deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic comparability of Prolastin®-C to Prolastin® in alpha₁-antitrypsin deficiency: a randomized study. Stocks, JM., Brantly, ML., Wang-Smith, L., et al.[2021]

Zemaira showed the highest purity and specific activity among the three alpha-1-proteinase inhibitor products tested, indicating it may be the most effective option for treating alpha-1-proteinase deficiency.

Prolastin had the lowest purity and higher levels of inactive A1-PI compared to Zemaira and Aralast, suggesting it may be less effective in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study comparing the purity, functionality and isoform composition of alpha-1-proteinase inhibitor (human) products. Cowden, DI., Fisher, GE., Weeks, RL.[2006]

Alpha 1-proteinase inhibitor (Prolastin) has been used since 1988 as an intravenous treatment for pulmonary emphysema caused by alpha 1-antitrypsin deficiency, although no formal controlled studies have confirmed its efficacy.

Prolastin has a strong safety record and has also been used experimentally for inhalation in cystic fibrosis and to treat panniculitis, but its future may be challenged by newer antiproteases that could offer better administration routes and pricing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha 1-antitrypsin augmentation therapy. Sandhaus, RA.[2005]

Prolastin aerosol therapy significantly increased sputum levels of alpha-1 proteinase inhibitor (alpha1-PI) in cystic fibrosis patients, indicating effective delivery of the treatment, with a three-fold increase observed (P = 0.002).

The therapy led to a decrease in sputum taurine levels, which correlates with respiratory exacerbations, suggesting that Prolastin may help reduce airway inflammation in cystic fibrosis without adversely affecting pulmonary function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolastin aerosol therapy and sputum taurine in cystic fibrosis. Cantin, AM., Berthiaume, Y., Cloutier, D., et al.[2013]

The improved purification method for alpha-proteinase inhibitor (PI) from fraction IV-1 paste achieved approximately 90% purity and a yield of 60-70%, making it effective for large-scale production.

This method incorporates advanced techniques like ion exchange chromatography and virus inactivation, ensuring both the safety and efficacy of the alpha 1 PI for potential treatment of congenital emphysema.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Purification of alpha 1 proteinase inhibitor from human plasma fraction IV-1 by ion exchange chromatography. Chen, SX., Hammond, DJ., Lang, JM., et al.[2013]

In vitro tests showed that yeast-derived recombinant alpha(1)-proteinase inhibitor did not directly affect the migration of neutrophils or eosinophils, indicating it does not act as a chemoattractant for these immune cells.

Despite its lack of direct chemotactic effects, the recombinant alpha(1)-proteinase inhibitor may still help maintain antibacterial defenses in patients receiving inhalation therapy, suggesting it has beneficial anti-inflammatory properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulation by alpha(1)-proteinase inhibitor: lack of chemotactic effects of recombinant human alpha(1)-proteinase inhibitor from yeast on human peripheral blood granulocytes. Mosheimer, B., Alzner, R., Wiedermann, CJ.[2021]

In a pilot study involving six patients with recalcitrant atopic dermatitis who did not respond to high potency topical steroids, treatment with alpha 1-proteinase inhibitor (alpha 1-PI) led to significant clinical improvement in symptoms like pain and itching within 6 to 21 days.

The therapy was safe, with no adverse side effects reported after 120 days, suggesting that alpha 1-PI may effectively address the imbalance of serine proteases in atopic dermatitis without causing harm.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of atopic dermatitis with alpha 1-proteinase inhibitor. Wachter, AM., Lezdey, J.[2004]

Alpha 1-antitrypsin is crucial for protecting the lungs from damage caused by neutrophil elastase, and its deficiency can lead to emphysema, especially in smokers, highlighting the importance of avoiding smoking for affected individuals.

The abnormal Z-mutant form of alpha 1-antitrypsin can accumulate in the liver, leading to serious liver diseases, including cirrhosis and cancer, with liver transplantation being a potential treatment for end-stage liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha 1-antitrypsin deficiency: an overview. van Steenbergen, W.[2022]

References

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

Functional role of kallikrein 5 and proteinase-activated receptor 2 in eosinophilic esophagitis. [2022]

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

Comparison of oral prednisone and topical fluticasone in the treatment of eosinophilic esophagitis: a randomized trial in children. [2022]

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

Montelukast Does not Maintain Symptom Remission After Topical Steroid Therapy for Eosinophilic Esophagitis. [2021]

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

Management of pediatric eosinophilic esophagitis: an update. [2021]

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

Topically applied mometasone furoate improves dysphagia in adult eosinophilic esophagitis - results from a double-blind, randomized, placebo-controlled trial. [2021]

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

Multi-center study: the biochemical efficacy, safety and tolerability of a new alpha1-proteinase inhibitor, Zemaira. [2019]

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

Pharmacokinetic comparability of Prolastin®-C to Prolastin® in alpha₁-antitrypsin deficiency: a randomized study. [2021]

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

A pilot study comparing the purity, functionality and isoform composition of alpha-1-proteinase inhibitor (human) products. [2006]

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

Alpha 1-antitrypsin augmentation therapy. [2005]

10. Canada pubmed.ncbi.nlm.nih.gov

Prolastin aerosol therapy and sputum taurine in cystic fibrosis. [2013]

11. England pubmed.ncbi.nlm.nih.gov

Purification of alpha 1 proteinase inhibitor from human plasma fraction IV-1 by ion exchange chromatography. [2013]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Immunomodulation by alpha(1)-proteinase inhibitor: lack of chemotactic effects of recombinant human alpha(1)-proteinase inhibitor from yeast on human peripheral blood granulocytes. [2021]

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

Treatment of atopic dermatitis with alpha 1-proteinase inhibitor. [2004]

14. England pubmed.ncbi.nlm.nih.gov

Alpha 1-antitrypsin deficiency: an overview. [2022]