A Phase III Study to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES)

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.

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 versus placebo administered by SC injection Q4W in patients with HES. This study will be conducted at approximately 68 sites in 18 countries.

The target patient population is male and female patients 12 years of age and older with symptomatic active HES. Eligible patients must be negative for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation.

Potentially eligible patients will enter a 3-day screening period and will be required to have documented stable HES therapy for at least 4 weeks prior to Visit 1 and AEC ≥ 1000 cells/μL at local laboratory testing to proceed to the second day of the screening period. Patients will be assessed for corticosteroid responsiveness (defined as an AEC \< 1000 cells/μL after 2 days of OCS \[prednisone/prednisolone\] 1 mg/kg/day given on top of the patient's background therapy for HES) prior to randomisation; other OCSs in equivalent doses are permitted. Patients who are not corticosteroid responsive or fail any other eligibility criteria will be screen failed.

It is expected that approximately 120 patients will be randomised at a 1:1 ratio at the randomisation/baseline visit (Visit 3) to receive either benralizumab or matching placeboQ4W for a 24-week DB treatment period. Recruitment may continue beyond 120 patients if required to achieve the target number of HES worsening/flares. Recruitment of adolescent patients is targeted to be broadly in line with expected prevalence rates of adolescents in the overall population. Approximately 4 to 6 adolescent patients (aged 12 to 17) are targeted to be randomised. Randomisation will be stratified. Approximately 40 patients will participate in a noninterventional interview to collect data on HRQoL and the patients' experience during the DB portion of the study.

All patients will remain on stable dose(s) and regimen of background HES therapy during the screening period and throughout 36 weeks of treatment (until Visit 12/Week 36 when the therapy can be adjusted). During this time, background HES therapy may only be modified if a patient has an HES clinical worsening/flare or an AE thought to be due to background therapy.

AstraZeneca, sites, and patients will be blinded to the absolute eosinophil, basophil, and monocyte counts, differential blood counts (percentages) for all WBCs (eosinophils, basophils, monocytes, neutrophils, and lymphocytes), and biopsy cell counts (if applicable) after randomisation/baseline (Visit 3/Week 0), during the entire DB treatment period, and for the first 4 weeks of the OLE treatment period (until Visit 10/Week 28) after which no blinding to WBC counts or biopsy cell counts is required. After the primary DBL, AstraZeneca will become unblinded to all patients' blood and biopsy cell counts obtained during DB treatment period.

The final dose of the DB treatment period will be given at Week 20, and the DB treatment period will complete at Week 24.

All patients who complete the DB treatment period on IP may be eligible to continue into an OLE treatment period on benralizumab (30 mg SC Q4W). The OLE is intended to allow treatment with open-label benralizumab for at least 1 year for adults and at least 2 years for adolescents after completion of the DB treatment period of the study (earlier enrolled patients may therefore be in the OLE for longer than 1 year). AstraZeneca may choose to extend the study depending on the overall development program. Moreover, AstraZeneca reserves the right of terminating the OLE early (eg, if development of the asset is terminated or marketing authorisation is obtained).

The primary 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. Treatment allocation will remain blinded until the primary DBL. A patient must complete the 24-week DB treatment period on IP to be eligible to enter the OLE treatment period. The final DBL will occur after the last patient completes the OLE. Data from the OLE treatment period of the study will be presented in an addendum to the primary analysis CSR and/or a separate OLE treatment period CSR.

Eligibility Criteria:
Inclusion Criteria

1. Provision of the signed and dated written informed consent of the patient or the patient's legally authorised representative, and informed assent from the patient (per local regulations) prior to any mandatory study-specific procedures, sampling, and analyses
2. Males and females 12 years of age and older at the time of signing the ICF
3. Documented diagnosis of HES (history of persistent eosinophilia \> 1500 cells/μL without secondary cause on 2 examinations \[interval ≥ 1 month; Valent et al 2012\] and evidence of end organ manifestations attributable to the eosinophilia)
4. Documented negative testing for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation
5. Stable HES treatment dose(s) and regimen for ≥ 4 weeks at the time of Visit 1
6. Signs or symptoms of HES worsening/flare and/or laboratory abnormalities indicative of HES worsening/flare (other than isolated eosinophilia) at Visit 1 OR a documented history of 2 or more HES worsening/flares within 12 months prior to Visit 1 requiring an escalation in therapy

   a. At least one flare within the past 12 months must not be related to a decrease in HES therapy during the 4 weeks prior to the flare
7. AEC ≥ 1000 cells/μL at Visit 1 (assessed by local laboratory)
8. Corticosteroid responsiveness defined as an AEC \< 1000 cells/μL after a 2-day course of OCS (prednisone/prednisolone) 1 mg/kg/day at Visit 2 (assessed by local laboratory). Other OCSs in equivalent doses are permitted
9. WOCBP must agree to use a highly effective method of birth control (confirmed by the investigator) from enrolment, throughout the study duration, and within 12 weeks after last dose of IP and have a negative urine dipstick pregnancy test result on Visit 1. Highly effective methods of birth control (those that can achieve a failure rate of less than 1% per year when used consistently and correctly) include:

   1. Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
   2. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable
   3. Intrauterine device
   4. Intrauterine hormone-releasing system
   5. Bilateral tubal occlusion
   6. Sexual abstinence, ie, refraining from heterosexual intercourse (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient)
   7. Vasectomised sexual partner (provided that partner is the sole sexual partner of the WOCBP study patient and that the vasectomised partner has received medical assessment of the surgical success)

Exclusion Criteria

1. Life-threatening HES and/or HES complication(s) as judged by the investigator:

   1. Medical intervention for HES-related life-threatening event(s) within 12 weeks prior to randomization
   2. History of thrombotic complications, stroke, or significant cardiac damage related to HES, if the respective events were life threatening and currently represent a risk of life-threatening disease complications. Events that occurred in the past but considered resolved or stable, can be accepted if, as per investigator's judgment, participation in the study will not put the patient at risk
   3. Disease severity that in the opinion of the investigator makes the patient inappropriate for inclusion in the study
2. Presence of FIP1L1-PDGFRA fusion tyrosine kinase gene translocation or other known imatinib-sensitive mutation
3. Definitive diagnosis of eosinophilic granulomatosis with polyangiitis
4. Known, preexisting, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory, or any other system abnormalities that are not associated with HES and are uncontrolled with standard treatment which, in the opinion of the investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient's ability to complete the entire duration of the study
5. Hypereosinophilia of unknown significance
6. Cardiovascular: Documented history of any clinically significant cardiac damage, clinically significant echocardiography (if available) or ECG findings within 12 months prior to Visit 1 or clinically significant ECG findings at screening that in the opinion of the investigator may put the patients at risk
7. Known currently active liver disease

   1. Chronic stable hepatitis B and C (including positive testing for hepatitis B surface antigen or hepatitis C antibody) or other stable chronic liver disease are acceptable if patient otherwise meets eligibility criteria. Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis
   2. ALT or AST level ≥ 3 × ULN during the screening period (AST or ALT \> 5 × ULN if documented HES with liver manifestations). Transient increase of AST/ALT level that resolves by the time of randomisation is acceptable if, in the investigator's opinion, the patient does not have an active liver disease and meets other eligibility criteria
8. Current or history of malignancy within 5 years before the screening visit with the following exceptions:

   1. Patients treated for in situ carcinoma of the cervix who have completed curative therapy and are in remission for at least 12 months prior to signing the informed consent and
   2. Patients with basal cell or superficial squamous skin cancer
   3. Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent was obtained
9. Diagnosis of systemic mastocytosis
10. Chronic or ongoing active infections requiring systemic treatment, as well as clinically significant viral, bacterial, or fungal infection within 4 weeks prior to Visit 1
11. A helminth parasitic infection diagnosed within 24 weeks prior to Visit 1 that has not been treated or has failed to respond to standard of care therapy. A confirmation of a complete resolution of any helminth parasitic infection prior to Visit 1 should be available
12. A history of known immunodeficiency disorder other than that explained by the use of OCS or other therapy taken for HES. Positive HIV test

14. Evidence of prior benralizumab treatment failure