Benralizumab for Hypereosinophilic Syndrome

(NATRON Trial)

Recruiting at 66 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

117 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This is a multicentre, randomised, double-blind (DB), parallel-group, placebo-controlled, 24-week Phase III study to compare the efficacy and safety of benralizumab versus placebo administered by SC injection Q4W in patients with hypereosinophilic syndrome (HES). This study comprises 2 distinct periods (together defined as the 'main study'): A 24-week, DB treatment period, during which patients will be randomised to receive either benralizumab or placebo, in addition to their prior stable HES background therapy, and an open-label extension (OLE) period, during which all patients will receive benralizumab. The primary database lock (DBL) will occur when approximately 38 patients have had their first HES worsening/flare event during the DB treatment period and all randomised patients have had the opportunity to be followed up for the 24-week DB treatment period. A patient must complete the 24-week DB treatment period on investigational product (IP) to be eligible to enter the OLE treatment period. The final DBL will occur after the last patient completes the OLE.

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.

What safety data is available for Benralizumab in treating hypereosinophilic syndrome?

The safety data for Benralizumab, also known as Fasenra, has been primarily evaluated in the context of severe eosinophilic asthma. Studies, including phase 1 trials in healthy participants and phase 3 trials in patients with severe eosinophilic asthma, have demonstrated its safety and tolerability. However, specific safety data for its use in hypereosinophilic syndrome is not detailed in the provided research. ^{1 2 3 4 5}

Is Benralizumab safe for humans?

Research shows that Benralizumab has been studied for safety in both healthy individuals and those with severe eosinophilic asthma, and it has been found to be generally safe and well-tolerated. ^{1 2 3 4 5}

Is the drug Benralizumab a promising treatment for Hypereosinophilic Syndrome?

Yes, Benralizumab is a promising drug for treating Hypereosinophilic Syndrome. It has shown significant improvement in symptoms and reduced the need for other medications in patients with severe cases. ^{1 2 3 4 6}

What makes the drug Benralizumab unique for treating hypereosinophilic syndrome?

Benralizumab is unique because it specifically targets and reduces eosinophils, a type of white blood cell involved in hypereosinophilic syndrome, by blocking the interleukin-5 receptor. This mechanism is different from other treatments that may not specifically target eosinophils. ^{7 8 9 10 11}

What data supports the idea that Benralizumab for Hypereosinophilic Syndrome is an effective treatment?

The available research does not provide specific data on Benralizumab's effectiveness for Hypereosinophilic Syndrome. Instead, it focuses on its use for severe eosinophilic asthma, where it has been shown to reduce asthma flare-ups and improve patient outcomes. For Hypereosinophilic Syndrome, another drug, Mepolizumab, is mentioned as effective in reducing disease flares. Therefore, while Benralizumab is effective for asthma, there is no direct evidence in the provided research supporting its effectiveness for Hypereosinophilic Syndrome. ^{1 3 5 12 13}

What data supports the effectiveness of the drug Benralizumab for treating hypereosinophilic syndrome?

Benralizumab has been shown to effectively reduce severe asthma attacks in patients with high levels of eosinophils (a type of white blood cell) in their blood, suggesting it may also help manage hypereosinophilic syndrome, which involves similar eosinophil-related issues. ^{1 3 5 12 13}

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 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 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 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]

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 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]

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]

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]

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 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]

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]

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

Characteristics of patients with severe, uncontrolled, eosinophilic asthma enrolled in a French cohort. [2022]

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

Safety, Tolerability, and Pharmacokinetics of Benralizumab: A Phase 1, Randomized, Single-Blind Study of Healthy Chinese Participants. [2023]

3. England 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. [2022]

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

Mepolizumab Reduces Hypereosinophilic Syndrome Flares Irrespective of Blood Eosinophil Count and Interleukin-5. [2022]

5. New Zealand 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. [2022]

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

Benralizumab: First Global Approval. [2022]

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

Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome. [2020]

8. Poland pubmed.ncbi.nlm.nih.gov

Severe hypereosinophilic syndrome successfully treated with a monoclonal antibody against interleukin 5 receptor α - benralizumab. [2021]

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

Expedited Desensitization to Canakinumab. [2022]

10. France pubmed.ncbi.nlm.nih.gov

Anakinra effectiveness in refractory polyserositis: An Italian multicenter study. [2022]

11. United States 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. [2022]

12. England 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. [2022]

13. Germany pubmed.ncbi.nlm.nih.gov

Evaluation of a novel autoinjector for subcutaneous self-administration of belimumab in systemic lupus erythematosus . [2019]