Benralizumab for Hypereosinophilic Syndrome

(NATRON Trial)

Not currently recruiting at 81 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must be taking: Corticosteroids

Disqualifiers: Life-threatening HES, FIP1L1-PDGFRA, Eosinophilic granulomatosis, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests benralizumab, a medication for hypereosinophilic syndrome (HES), a condition where excessive eosinophils (a type of white blood cell) can damage organs. Researchers aim to determine if benralizumab is safe and effective compared to a placebo, which resembles the medication but contains no active ingredients. Participants will receive either the drug or the placebo for 24 weeks, after which everyone can receive benralizumab. Individuals with persistent HES symptoms and flares despite stable treatment might be suitable for this study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to the potential availability of a new treatment.

Do I need to stop my current medications for this trial?

No, you do not need to stop your current medications. The trial allows you to continue your stable HES background therapy while participating.

Do I need to stop my current medications to join the trial?

No, you do not need to stop your current medications. The trial allows participants to continue their stable HES treatment while receiving either benralizumab or a placebo.

Is there any evidence suggesting that benralizumab is likely to be safe for humans?

Studies have shown that benralizumab is generally safe for patients with hypereosinophilic syndrome (HES). Research indicates that long-term use of benralizumab did not cause major side effects in HES patients, suggesting its safety. Additionally, benralizumab has been used for conditions like severe eosinophilic asthma, where it helped reduce the need for steroids. Overall, the available evidence supports the safety of benralizumab for people with HES. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for hypereosinophilic syndrome?

Unlike the standard treatments for hypereosinophilic syndrome, which often include corticosteroids and immunosuppressive drugs, benralizumab offers a novel approach by targeting the IL-5 receptor on eosinophils. This mechanism leads to the direct depletion of eosinophils, the problematic cells in this condition. Researchers are excited about benralizumab because it has the potential to be more effective in reducing eosinophil counts and may offer a more targeted therapy with fewer side effects. Plus, it's administered via a convenient subcutaneous injection, which could simplify treatment regimens for patients.

What evidence suggests that benralizumab might be an effective treatment for hypereosinophilic syndrome?

Research has shown that benralizumab, which participants in this trial may receive, effectively treats hypereosinophilic syndrome (HES). In earlier studies, patients who took benralizumab experienced a significant drop in eosinophil count, an important indicator of HES. Additionally, benralizumab helped 59% of patients achieve remission at certain times, meaning their symptoms were reduced or disappeared. This treatment also enables patients to use fewer steroids, which can have unwanted side effects. Overall, benralizumab is generally well-tolerated and effective for managing HES symptoms. ^{1 3 4 5 6}

Are You a Good Fit for This Trial?

This trial is for patients with Hypereosinophilic Syndrome (HES) who are 12 years or older, have a stable HES treatment regimen, and show signs of HES worsening. They must not have certain gene mutations or life-threatening events related to HES in the past 12 weeks. Women able to bear children must agree to use effective birth control.

Inclusion Criteria

I am experiencing worsening symptoms or lab results indicating my HES is getting worse.

I have been diagnosed with HES, showing high eosinophil counts twice, a month apart, affecting my organs.

AEC ≥1000 cells/μL at Visit 1 (assessed by local laboratory).

Exclusion Criteria

I had skin or cervical cancer but have been in remission for over a year.

I do not have any ongoing infections needing systemic treatment.

I have been diagnosed with eosinophilic granulomatosis with polyangiitis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

3 days

Double-blind Treatment

Participants receive either benralizumab or placebo for 24 weeks

24 weeks

Visits every 4 weeks for SC injection

Open-label Extension

Participants receive open-label benralizumab for at least 1 year for adults and at least 2 years for adolescents

At least 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Benralizumab
• Placebo

Trial Overview The study tests Benralizumab's effectiveness and safety against a placebo over 24 weeks in addition to standard HES therapy. Participants will be randomly assigned to either receive Benralizumab or a placebo without knowing which one they're getting until after the primary analysis phase.

How Is the Trial Designed?

Group I: Benralizumab arm Experimental Treatment 1 Intervention

1x Benralizumab SC injection

Group II: Placebo arm Placebo Group 1 Intervention

1x Benralizumab matching placebo SC injection

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?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

In a study involving 1684 autoantibody-positive patients over 52 weeks, belimumab significantly improved disease activity in key organ domains of systemic lupus erythematosus (SLE), particularly in musculoskeletal and mucocutaneous areas.

Patients receiving belimumab experienced less worsening in haematological, immunological, and renal domains compared to those on placebo, indicating its potential to enhance overall disease management in SLE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Manzi, S., Sánchez-Guerrero, J., Merrill, JT., et al.[2022]

A patient with severe hypereosinophilic syndrome (HES) showed significant improvement in respiratory symptoms and normalization of eosinophil counts after 6 months of treatment with benralizumab, an anti-IL-5 receptor monoclonal antibody.

Benralizumab treatment allowed for a significant reduction in glucocorticoid dosage without substantial side effects, suggesting it may be an effective alternative for patients who do not respond well to traditional therapies like glucocorticoids and mepolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe hypereosinophilic syndrome successfully treated with a monoclonal antibody against interleukin 5 receptor α - benralizumab. Kosałka-Węgiel, J., Milewski, M., Siwiec, A., et al.[2021]

In a real-world study of 205 patients with severe eosinophilic asthma treated with benralizumab for an average of 9.8 months, there was a dramatic reduction in exacerbations, with 81% of patients becoming exacerbation-free and a 93.3% decrease in the annualized exacerbation rate.

Benralizumab treatment also led to significant reductions in oral corticosteroid use, with 43.2% of patients able to stop OCS therapy and an overall dose reduction of 56%, indicating its effectiveness in managing severe asthma symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ChAracterization of ItaliaN severe uncontrolled Asthmatic patieNts Key features when receiving Benralizumab in a real-life setting: the observational rEtrospective ANANKE study. Menzella, F., Bargagli, E., Aliani, M., et al.[2022]

In a study of 839 patients with moderate-to-severe systemic lupus erythematosus (SLE), weekly subcutaneous belimumab (200 mg) significantly improved the SLE Responder Index (SRI4) response compared to placebo, with 61.4% of belimumab patients responding versus 48.4% of placebo patients.

Belimumab also reduced the risk and time to severe disease flares, with a median time of 171 days for belimumab compared to 118 days for placebo, while maintaining a safety profile similar to that of placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Subcutaneous Belimumab in Systemic Lupus Erythematosus: A Fifty-Two-Week Randomized, Double-Blind, Placebo-Controlled Study. Stohl, W., Schwarting, A., Okada, M., et al.[2022]

Benralizumab (Fasenra™) is a monoclonal antibody that targets the interleukin-5 receptor alpha chain, specifically designed to treat severe eosinophilic asthma and chronic obstructive pulmonary disease (COPD).

The drug has been approved by the US FDA as an add-on maintenance therapy for patients with severe asthma characterized by eosinophilia, highlighting its efficacy in depleting eosinophils, which are linked to asthma and COPD symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benralizumab: First Global Approval. Markham, A.[2022]

Mepolizumab significantly reduced the frequency of disease flares in patients with hypereosinophilic syndrome (HES), showing a reduction in flare rates by 58% to 84% across different baseline blood eosinophil count (BEC) subgroups, indicating its efficacy regardless of eosinophil levels.

The treatment was effective even in patients with undetectable baseline serum IL-5 levels, suggesting that low IL-5 should not prevent the use of mepolizumab in HES patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mepolizumab Reduces Hypereosinophilic Syndrome Flares Irrespective of Blood Eosinophil Count and Interleukin-5. Rothenberg, ME., Roufosse, F., Faguer, S., et al.[2022]

In a Phase 1 study involving 36 healthy Chinese adults, a single subcutaneous injection of benralizumab was found to be well tolerated, with only mild adverse events reported, indicating a favorable safety profile.

Benralizumab effectively depleted eosinophils within 2 days of administration, and this effect was maintained for up to 85 days, demonstrating its potential efficacy in targeting eosinophilic conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Pharmacokinetics of Benralizumab: A Phase 1, Randomized, Single-Blind Study of Healthy Chinese Participants. Cheung, TT., Mai, TH., Chia, YL., et al.[2023]

In a phase 2 trial involving 20 patients with PDGFRA-negative hypereosinophilic syndrome, benralizumab significantly reduced eosinophil counts, achieving a 50% reduction in 90% of patients compared to 30% in the placebo group.

The treatment led to sustained clinical and hematologic responses in 74% of patients over 48 weeks, with manageable side effects, indicating that benralizumab is a promising option for managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome. Kuang, FL., Legrand, F., Makiya, M., et al.[2020]

In a study of 164 patients with severe eosinophilic asthma, those with a baseline eosinophil count (BEC) of 300-450 cells/mm3 showed significant reductions in exacerbation rates and oral corticosteroid use after 48 weeks of treatment with benralizumab, similar to the overall population.

The treatment was well-tolerated, with no safety-related discontinuations reported, indicating that benralizumab is both effective and safe for patients with lower eosinophil counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Features and Efficacy of Benralizumab in Patients with Blood Eosinophil Count Between 300 and 450 Cells/mm3: A Post Hoc Analysis from the ANANKE Study. Senna, G., Aliani, M., Altieri, E., et al.[2022]

In a study of 441 patients with severe asthma, 19% were found to be eligible for benralizumab treatment, indicating a significant subset of patients who may benefit from this therapy.

Patients eligible for benralizumab had poorer lung function and asthma control, experiencing more frequent exacerbations and hospitalizations, highlighting the need for effective treatment options in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics of patients with severe, uncontrolled, eosinophilic asthma enrolled in a French cohort. Aubier, M., Thabut, G., Fabry-Vendrand, C.[2022]

In a study of 95 patients with systemic lupus erythematosus (SLE), 99% successfully self-administered subcutaneous belimumab using an autoinjector, demonstrating high feasibility for home treatment.

The pharmacokinetics of belimumab remained stable after switching from intravenous to subcutaneous administration, with low adverse events and manageable injection-site pain, indicating it is a safe and effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of a novel autoinjector for subcutaneous self-administration of belimumab in systemic lupus erythematosus . Sheikh, SZ., Hammer, AE., Fox, NL., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40120806/

Long-Term Efficacy and Safety of Benralizumab Treatment for ... Long-term BENRA therapy is effective and well-tolerated in HES patients without significant adverse effects.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2213219825002661

Long-Term Efficacy and Safety of Benralizumab Treatment ... Long-term BENRA therapy is effective and well-tolerated in HES patients without significant adverse effects.

3. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2024/mandara-phase-iii-data-published-in-new-england-journal-of-medicine-show-remission-is-an-achievable-goal-in-eosinophilic-granulomatosis-with-polyangiitis-egpa-with-fasenra.html

MANDARA Phase III data published in New England ... The primary endpoint of adjusted rate of remission was 59% for benralizumab-treated patients at weeks 36 and 48, compared with 56% for ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10429737/

PB2229: A PHASE 3 STUDY EVALUATING THE ... Benralizumab has demonstrated corticosteroid-sparing effects in patients with severe eosinophilic asthma and AEC reductions in patients with HES.

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1812185

Benralizumab for PDGFRA-Negative Hypereosinophilic ... Efficacy. During the first 12 weeks of the trial, a reduction of at least 50% in the absolute eosinophil count at week 12 (the primary end ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04191304

NCT04191304 | A Phase III Study to Evaluate the Efficacy ... This is a multicentre, randomised, DB, parallel-group, placebo-controlled, 24-week Phase III study to compare the efficacy and safety of benralizumab 30 mg ...