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An Open-label Study to Evaluate the Pharmacokinetics and Pharmacodynamics and Long-term Safety of Benralizumab Administered Subcutaneously in Children With Severe Eosinophilic Asthma

TATE

30

- Aged 6 to 11 years; 28 patients were assigned to study treatment: 15 patients were stratified in the < 35 kg weight cohort and, therefore received 10 mg benralizumab treatment and 13 patients were stratified in the 36 kg or more weight chort and received 30 mg benralizumab treatment. - Aged 6 to 14 years from Japan; 11 patients (out of which 9 were included in the 6 to 11 years cohort) were assigned to study treatment: 8 patients were stratified in the < 35 kg weight cohort and,therefore, received 10 mg benralizumab treatment and 3 patients were given 30 mg benralizumab treatment.

Aged 6 to 11 years; All 28 (100.0%) patients aged 6 to 11 years who were assigned to study treatment completed the study treatment and the study. Aged 6 to 14 years from Japan; 11 patients dosed, a total of 10 (90.9%) patients aged 6 to 14 years from Japan completed the study treatment and 1 (9.1%) patient aged 13 years at enrolment and in the 35 kg or more weight cohort discontinued study treatment early due to the patient's decision and was withdrawn from the study by a parent / guardian decision.

For patients overall (aged 6 to 14 years), AEs were reported in 13 (86.7%) patients in the < 35 kg weight cohort and in 11 (73.3%) patients in the 35 kg or more weight cohort. There were no meaningful patterns of AEs observed. There were no AEs with the outcome of death or study treatment discontinuation in any weight cohort. Of the 28 patients aged 6 to 11 years, 22 (78.6%) patients experienced 76 AEs. Of these, 3 (10.7%) patients experienced a total of 3 SAEs. All (11) patients from Japan, aged 6 to 14 years, experienced a total of 64 AEs. Of these, 2 (18.2%) patients (both in the 35 kg or more cohort) experienced a total of 3 SAEs. A total of 4 patients, all aged 6 to 11 years, reported AEs that were considered related to study treatment by the Investigator. These AEs were of mild intensity, and all resolved. No action on study treatment was taken for any of these AEs.

1. Pharmacokinetics - Patients aged 6 to 11 years Following the first SC injection of benralizumab on Day 0, maximal serum concentrations of benralizumab were achieved by Day 7 in patients in both weight cohorts. Geometric mean maximal serum concentrations were 1788.30 ng/mL in the <35 kg weight cohort (patients in this cohort received 10 mg benralizumab) and 3193.43 ng/mL in the 35 kg or more weight cohort (patients in this cohort received 30 mg benralizumab). Higher serum benralizumab concentrations were observed in patients in the 35 kg or more weight cohort at all time points compared to those in patients in the <35 kg weight cohort. A decline in serum benralizumab trough concentrations after Day 112 was observed for patients in both weight cohorts. - Patients aged 6 to 14 years from Japan Patients from Japan aged 6 to 14 years also reached peak serum concentration of benralizumab (Tmax) by Day 7. Maximal serum concentrations were higher in the 35 kg or more weight cohort: geometric mean concentration=1791.91 ng/mL in the <35 kg weight cohort and 3292.61 ng/mL in the 35 kg or more weight cohort. Similar trends for serum benralizumab concentrations as non-Japanese patients were observed for patients in both Japanese weight cohorts. Due to the switch from every 4 weeks to every 8 weeks dosing, a decline in serumbenralizumab trough concentrations after Day 112 was also observed for patients in both Japanese weight cohorts. 2. Pharmacodinamics - Patients aged 6 to 11 years Blood eosinophil values in the safety analysis set showed near-complete depletion from baseline in both weight cohorts at all post-dose time points (Weeks 4 to 48): for the <35 kg weight cohort, median blood eosinophil values fell from 400.0 cells/micro litter to 10.0 to 20.0 cells/miceo litter and for the 35 kg or more weight cohort, median blood eosinophil values fell from340.0 cells/micro litter to 20.0 to 30.0 cells/micro litter. - Patients aged 6 to 14 years from Japan Blood eosinophil values in the safety analysis set showed near-complete depletion from baseline in both weight cohorts at all post-dose time points (Weeks 4 to 48): for the <35 kg weight cohort, median blood eosinophil values fell from 435.0 cells/micro litter to 5.0 to 20.0 cells/micro litter and for the 35 kg or more weight cohort, median blood eosinophil values fell from 430.0 cells/micro litter to 5.0 to 20.0 cells/micro litter.

- In the overall study population, the anti-drug antibody (ADA) prevalence was of 14.3%, with 4 patients. No consistent pattern was observed for any AEs reported in patients with ADA positive results and no SAEs were reported by any of these patients. - Some improvements in lung function (FEV1), symptoms and other asthma control metrics were observed, most consistently in the 35 kg or more weight cohort. Of note, patients in the <35 kg weight cohort appeared to have milder disease at baseline compared to patients in the 35 kg or more weight cohort. - Most patients showed an improvement in ACQ-IA score results from Week 12 to Week 52 compared to baseline values. - Results in both CGIC and PGIC-IA questionnaires agreed that more patients had improved. - Adverse Events; Refer to 'adverse events'. - There were no clinically meaningful trends in safety laboratory values, vital signs, or electrocardiogram (ECG) measurements.

-With regard to the primary PK endpoints, overall systemic exposure to benralizumab increased from 10mg to 30mg(the 35kg or more weight cohort)as expected. -The expected PD effect of near-complete eosinophil depletion was seen in both weight cohorts from the first time point and was maintained throughout the treatment period.-Treatment with benralizumab was generally safe and well tolerated, with no unexpected safety findings, and the safety data were consistent with the known safety profile of benralizumab

Aug. 29, 2023

Yes

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

Ugeishi Yuji

Astrazeneka K.K

3-1, Ofuka-cho, Kita-ku, Osaka-shi, Osaka

RD-clinical-information-Japan@astrazeneca.com

Ugeishi Yuji

Astrazeneka K.K

3-1, Ofuka-cho, Kita-ku, Osaka-shi, Osaka

+81-6-4802-3533

RD-clinical-information-Japan@astrazeneca.com

completed

Dec. 09, 2019

Interventional

"Allocation: Non-Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Basic Science"

treatment purpose

3

Patients are eligible to be included in the study only if all of the following inclusion criteria and none of the exclusion criteria apply 1.Parent(s) guardian are able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. If applicable, the participant must be able and willing to give assent to take part in the study according to the local requirement. 2.Patient must be 6 to 11 years of age inclusive (6 to 14 years of age inclusive in Japan), at the time of signing the ICF. 3.Diagnosis of severe asthma, defined by the regional guidelines for at least 12 months prior to Visit 1. 4.A previously confirmed history of two or more exacerbations requiring treatment with systemic corticosteroids and or hospitalization in the 12 months prior to Visit 1. 5.Peripheral blood eosinophil count of 150 cells or more at Visit 1. 6.A well-documented requirement for regular treatment with ICS eg. total daily dose equivalent to or more 250 mg uticasone propionate, in the 12 months prior to Visit 1, with or without maintenance oral corticosteroids.
7.Current treatment with at least 1 additional controller medication, such as inhaled LABA, leukotriene receptor antagonist, long acting anti-muscarinic agent, or theophylline, since at least 3 months prior to Visit 1.
8. Pre-bronchodilator FEV1 110 percent or less predicted normal, or, FEV1/Forced Vital Capacity (FVC) ratio 0.8 or less.
9.Body weight 15 kilogram or more.
10.Male or female
11.Females of childbearing potential (FOCBP) who are sexually active, as judged by the investigator, must commit to consistent and correct use of an acceptable method of contraception for the duration of the study and for 4 months after the last dose of IP.

Patients are eligible to be included in the study only if all of the inclusion criteria and none of the exclusion criteria apply:

Any history of life-threatening asthma (eg, requiring intubation).
Clinically important pulmonary disease other than asthma such as active lung infection, bronchiectasis, pulmonary fibrosis, cystic fibrosis, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia.
Previous diagnosis of pulmonary or systematic disease, other than asthma, that is associated with elevated peripheral eosinophil counts such as allergic bronchopulmonary aspergillosis/mycosis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), and hypereosinophilic syndrome.
Ever been diagnosed with malignant disease.
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, immunological, psychiatric, or major physical impairment that is not stable in the opinion of the investigator and could:

Affect the safety of the patient throughout the study.
Influence the findings of the study or their interpretations.
Impede the patient's ability to complete the entire duration of the study.
History of anaphylaxis to any biologic therapy.
Any clinically significant abnormal findings in physical examination, vital signs, haematology, clinical chemistry, or urinalysis during screening period, 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.
Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality obtained during the screening period, which in the opinion of the investigator may put the patient at risk or interfere with study assessments.
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Patients with a history of hepatitis B vaccination without history of hepatitis B are allowed to enrol.
A helminth parasitic infection diagnosed within 24 weeks prior to the date of informed consent and assent is obtained that has not been treated with, or has failed to respond to, standard of care therapy.
Alanine aminotransferase or aspartate aminotransferase level 1.5 or more times the upper limit of normal confirmed during the screening period.
A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.
Use of immunosuppressive medication, including, but not limited to, methotrexate, troleandomycin, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroid, or any experimental anti-inflammatory therapy, within 3 months prior to Visit 1. Chronic maintenance corticosteroid for the treatment of asthma is allowed.
Receipt of immunoglobulin or blood products within 30 days prior to Visit 1.
Receipt of any marketed (eg, Omalizumab, Mepolizumab, or off-label Benralizumab) or investigational biologic within 4 months or 5 half-lives, whichever is longer, prior to Visit 1.
Receipt of live attenuated vaccines 30 days prior to the date of first dose of IP.
Initiation of new allergen immunotherapy is not allowed within 30 days prior to Visit 1. However, allergen immunotherapy initiated prior to this period can be continued provided there is a gap of 7 days between the immunotherapy and IP administration.
Current use of any oral or ophthalmic non-selective beta adrenergic antagonist (eg, propranolol).
Planned surgical procedures during the conduct of the study.
Participation in another clinical study with an investigational nonbiologic product administered in the last 30 days or 5 half-lives prior to enrolment, whichever is longer.
Known history of allergy or reaction to any component of the IP formulation.
Concurrent enrolment in another clinical study.
Parent/guardian has a history of psychiatric disease, intellectual deficiency, substance abuse, or other condition (eg, inability to read, comprehend and write) which will limit the validity of consent to participate in this study.
Unwillingness or inability of the participant or parent/guardian to follow the procedures outlined in the protocol.
Children who are wards of the state or government.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
Judgement by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
Previous treatment in the present study.

Both

Severe Eosinophilic Asthma

investigational material(s)
Generic name etc : Benralizumab
INN of investigational material : Benralizumab
Therapeutic category code : 229 Other agents affecting respiratory organs
Dosage and Administration for Investigational material : "Dose will be stratified by body weight at screening: Patients will receive Dose 1 or Dose 2 of Benralizumab administered by SC injection at Day 0 and Weeks 4, 8, and 16, 24, 32, and 40.

Experimental: Dose 1
Below 35 kilos
Intervention: Drug: Benralizumab
Experimental: Dose 2
Greater than/equal to 35 kilos
Intervention: Drug: Benralizumab"


control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

pharmacokinetics
pharmacodynamics
-

safety
efficacy
exploratory
pharmacokinetics
-

Nov. 15, 2019