Dupilumab + Benralizumab for Asthma

(EPIPHANY Trial)

Recruiting at 2 trial locations

Overseen By Deborah A Meyers, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of California, San Diego

Must be taking: Inhaled corticosteroids, Asthma controllers

Must not be taking: Biologics, Methotrexate

Disqualifiers: COPD, Cystic fibrosis, Hypertension, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks for each biologic

120 Participants Needed

Trial Summary

What is the purpose of this trial?

In this study, a new method will be used to evaluate response to 2 approved biologic therapies, and assess how well each patient responds to each asthma treatment. This study will measure the response to these treatments using genomic and biologic measurements obtained from participants biosamples. By evaluating response to 2 different biologic therapies, this study has the potential to provide an in-depth understanding of the mechanisms underlying severe asthma that will inform and change treatment decisions, and may ultimately lead to a change in the way that asthma patients are evaluated for potential personalized therapies and maximize the probability that the subject will respond to treatment.

Will I have to stop taking my current medications?

The trial requires that your asthma medications remain stable, meaning no changes for the past 2 months, and you must not be on any asthma biologics or certain immune-modulating therapies. If you meet these criteria, you can continue your current asthma medications.

What data supports the effectiveness of the drug Dupilumab for asthma?

Dupilumab is approved for treating various type 2 inflammatory diseases, which suggests it may help with asthma, a condition often linked to type 2 inflammation. ^{1 2 3 4 5}

Is the combination of Dupilumab and Benralizumab safe for treating asthma?

Dupilumab is generally considered safe for treating asthma, with minimal adverse events reported. However, it has been associated with increased blood eosinophils (a type of white blood cell) and some ocular (eye-related) adverse events, mainly in patients treated for other conditions. Large studies are needed to confirm its long-term safety. ^{6 7 8 9 10}

What makes the drug combination of Dupilumab and Benralizumab unique for treating asthma?

The combination of Dupilumab and Benralizumab is unique because Dupilumab targets the IL-4 and IL-13 pathways, which are involved in type 2 inflammation, and may be effective in both eosinophilic and non-eosinophilic severe asthma, while Benralizumab specifically targets eosinophils, a type of white blood cell involved in asthma. This dual approach could offer broader efficacy for patients with severe asthma not well-controlled by existing treatments. ^{6 7 11 12 13}

Research Team

Kelan Tantisira, MD

Principal Investigator

University of California, San Diego

Eligibility Criteria

This trial is for asthma patients who've been on stable medication for 2 months, with poor or uncontrolled symptoms. They must be willing to follow the study rules and not use any other biologics, have no recent respiratory infections, and agree to lifestyle requirements. Pregnant women, heavy smokers, those with a high BMI (>38), or anyone on certain immune therapies can't join.

Inclusion Criteria

Stated willingness to comply with all study procedures and availability for the duration of the study

My asthma medication has been the same for the last 2 months.

My asthma is poorly controlled or gets worse with certain tests.

Exclusion Criteria

I am currently using or have used an asthma biologic in the last 3 months.

I have not had a respiratory infection in the last month.

Allergic to any of the drugs, biologics or chemicals used in this study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive biologic therapies (Dupilumab and Benralizumab) in a random order, with genomic and biologic measurements obtained from biosamples.

16 weeks for each biologic

Bi-weekly visits for Dupilumab, monthly visits for Benralizumab

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments including quality of life and asthma control questionnaires.

60 weeks

Regular visits throughout the follow-up period

Treatment Details

Interventions

• Benralizumab
• Dupilumab

Trial Overview The study tests how well patients respond to two approved asthma treatments: Benralizumab and Dupilumab. It uses genomic data from participants' biosamples to understand treatment effects better and aims at personalizing therapy based on genetic response patterns.

Participant Groups

Group I: Dupilumab Active Control 1 Intervention

600 mg once subcutaneously (given as two 300 mg injections), followed by 300 mg subcutaneously every other week.

Group II: Benralizumab Active Control 1 Intervention

30 mg subcutaneously every 4 weeks.

Benralizumab is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Fasenra for:

• Severe eosinophilic asthma

Approved in United States as Fasenra for:

• Severe asthma with an eosinophilic phenotype

Approved in Canada as Fasenra for:

• Severe eosinophilic asthma

Approved in Japan as Fasenra for:

• Severe eosinophilic asthma

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Mayo Clinic

Collaborator

Trials

3,427

Recruited

3,221,000+

Yale University

Collaborator

Trials

1,963

Recruited

3,046,000+

Brigham and Women's Hospital

Collaborator

Trials

1,694

Recruited

14,790,000+

University of Arizona

Collaborator

Trials

545

Recruited

161,000+

Harvard University

Collaborator

Trials

237

Recruited

588,000+

Findings from Research

Dupilumab treatment significantly reduces levels of eotaxin-3 and PARC in patients, with notable decreases observed at various time points, particularly from weeks 2 to 52 for eotaxin-3 and weeks 4 to 16 for PARC.

The meta-analysis included four studies, indicating that while eotaxin-3 levels did not show significant decreases at weeks 1 and 12, they were significantly reduced at later weeks, suggesting a delayed response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in eotaxin-3 and pulmonary and activation-regulated chemokine levels in patients after dupilumab treatment: a systematic review and meta-analysis. Wang, L., Cheng, H., Zhou, B., et al.[2023]

Adalimumab has a favorable long-term safety profile for treating moderate to severe chronic plaque psoriasis, with data from 13 clinical trials showing no evidence of cumulative toxicity over up to 5 years of treatment.

The incidence rates of serious adverse events and serious infectious adverse events were stable or decreased with longer exposure to adalimumab, indicating that the treatment remains safe even with extended use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The long-term safety of adalimumab treatment in moderate to severe psoriasis: a comprehensive analysis of all adalimumab exposure in all clinical trials. Leonardi, C., Papp, K., Strober, B., et al.[2016]

In a study of 472 patients with severe rheumatoid arthritis, a daily dose of 150 mg of anakinra significantly improved response rates and productivity after 6 months compared to placebo, while lower doses (30 or 75 mg) did not show similar benefits.

Anakinra, whether used alone or in combination with methotrexate, effectively slowed disease progression and was generally well tolerated, with mild injection-site reactions being the most common side effect, and serious infections occurring rarely.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anakinra. Cvetkovic, RS., Keating, G.[2018]

Sarilumab, a biotherapeutic targeting interleukin-6, has shown strong efficacy in treating rheumatoid arthritis (RA) in clinical trials, supporting its application for FDA approval.

While sarilumab has a higher receptor affinity than tocilizumab, another IL-6 blocker, both drugs exhibit similar efficacy and safety profiles, leaving the distinct advantages of sarilumab to be further evaluated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Room for more IL-6 blockade? Sarilumab for the treatment of rheumatoid arthritis. June, RR., Olsen, NJ.[2022]

Tocilizumab 8 mg monotherapy was found to be the most effective treatment for achieving ACR20 response rates in rheumatoid arthritis patients who did not respond adequately to methotrexate, outperforming both sarilumab and adalimumab.

Sarilumab 200 mg was identified as potentially the safest option among the treatments studied, although there were no significant differences in serious adverse events across the different biologics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the efficacy and safety of tocilizumab, sarilumab, and sirukumab in comparison with adalimumab as monotherapy in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials. Sung, YK., Lee, YH.[2021]

Dupixent (dupilumab) is set to receive FDA approval for asthma treatment on October 20, expanding its use beyond atopic dermatitis.

Once approved, Dupixent will be part of a group of monoclonal antibodies, including Nucala, Cinqair, and Fasenra, that target type 2 inflammation in severe asthma, highlighting its role in managing this specific asthma phenotype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dupixent, a New Entrant In the Asthma Lists. Reinke, T.[2019]

Dupilumab is a monoclonal antibody that targets the IL-4 receptor, blocking signals from IL-4 and IL-13, and is currently in phase III trials for treating moderate-to-severe asthma, showing promise for both eosinophilic and non-eosinophilic asthma phenotypes.

While dupilumab appears to be generally well tolerated, further large-scale studies are necessary to fully evaluate its long-term safety and efficacy, especially in pediatric populations where data is currently lacking.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dupilumab for the treatment of asthma. Santini, G., Mores, N., Malerba, M., et al.[2019]

In a study of 46 adult patients with moderate-to-severe atopic dermatitis treated with dupilumab, 34.8% experienced ocular adverse events (OAEs), primarily mild to moderate dry eye disease and superficial punctate keratitis.

Patients with pre-existing conditions such as dry eye disease, eyelid eczema, or high IgE levels were more likely to develop OAEs, suggesting that these factors should be considered before starting dupilumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and risk factors for dupilumab associated ocular adverse events: a real-life prospective study. Touhouche, AT., Cassagne, M., Bérard, E., et al.[2021]

Dupilumab significantly improves lung function and asthma control in patients with moderate to severe asthma, as evidenced by better forced expiratory volume and asthma control questionnaire scores over 12 and 24 weeks in 13 trials.

The treatment is generally safe, showing no significant increase in adverse events compared to placebo, although it was associated with higher blood eosinophil levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dupilumab efficacy and safety in patients with moderate to severe asthma: A systematic review and meta-analysis. Zaazouee, MS., Alwarraqi, AG., Mohammed, YA., et al.[2022]

Dupilumab (Dupixent) has been associated with a risk of ocular adverse reactions, highlighting the importance of monitoring patients for eye-related side effects during treatment.

Prompt management of any ocular issues is essential for patients receiving dupilumab, ensuring their safety and well-being while benefiting from the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety update: dupilumab and ocular adverse reactions. [2022]

In a study of 64 patients with severe asthma, dupilumab significantly improved asthma control and lung function after 12 months, as evidenced by a notable increase in asthma control test scores and forced expiratory volume.

Dupilumab also reduced the need for oral steroids and the frequency of asthma exacerbations, although some patients experienced hypereosinophilia, which did not affect the overall clinical response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of dupilumab for the treatment of severe asthma in a real-life French multi-centre adult cohort. Dupin, C., Belhadi, D., Guilleminault, L., et al.[2021]

Dupilumab significantly improved the quality of life for adolescents with uncontrolled severe asthma within just 4 weeks of treatment, with 80% of participants able to reduce their inhaled corticosteroid dosage.

Throughout the 24-week study, none of the five adolescents experienced asthma exacerbations, indicating that dupilumab effectively controlled their asthma symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Time effect of dupilumab to treat severe uncontrolled asthma in adolescents: A pilot study. Indolfi, C., Dinardo, G., Klain, A., et al.[2023]

In a study of 18 severe asthma patients treated with dupilumab for 12 months, significant improvements were observed in asthma control, with the Asthma Control Test (ACT) score increasing from 15.7 to 22.4, and a complete cessation of oral corticosteroid use in all patients.

Dupilumab treatment also led to a notable reduction in asthma exacerbations from an average of 2 to 0, and an increase in lung function (FEV1%) from 73.5% to 87.1%, confirming its effectiveness in a real-world setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Experience with Dupilumab in Severe Asthma: One-Year Data from an Italian Named Patient Program. Campisi, R., Crimi, C., Nolasco, S., et al.[2022]

References

1. Poland pubmed.ncbi.nlm.nih.gov

Changes in eotaxin-3 and pulmonary and activation-regulated chemokine levels in patients after dupilumab treatment: a systematic review and meta-analysis. [2023]

2. New Zealand pubmed.ncbi.nlm.nih.gov

The long-term safety of adalimumab treatment in moderate to severe psoriasis: a comprehensive analysis of all adalimumab exposure in all clinical trials. [2016]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Anakinra. [2018]

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

Room for more IL-6 blockade? Sarilumab for the treatment of rheumatoid arthritis. [2022]

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

Comparison of the efficacy and safety of tocilizumab, sarilumab, and sirukumab in comparison with adalimumab as monotherapy in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials. [2021]

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

Dupixent, a New Entrant In the Asthma Lists. [2019]

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

Dupilumab for the treatment of asthma. [2019]

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

Incidence and risk factors for dupilumab associated ocular adverse events: a real-life prospective study. [2021]

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

Dupilumab efficacy and safety in patients with moderate to severe asthma: A systematic review and meta-analysis. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Safety update: dupilumab and ocular adverse reactions. [2022]

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

Effectiveness and safety of dupilumab for the treatment of severe asthma in a real-life French multi-centre adult cohort. [2021]

12. Singapore pubmed.ncbi.nlm.nih.gov

Time effect of dupilumab to treat severe uncontrolled asthma in adolescents: A pilot study. [2023]

13. New Zealand pubmed.ncbi.nlm.nih.gov

Real-World Experience with Dupilumab in Severe Asthma: One-Year Data from an Italian Named Patient Program. [2022]