Safety Study of Tezepelumab (AMG 157) in Healthy Adults and Adults With Atopic Dermatitis

Phase 1

Completed

• Conditions: Atopic Dermatitis; Healthy Volunteers
• Interventions: Drug: Placebo; Drug: Tezepelumab

• Registration Number: NCT00757042
• Lead Sponsor: Amgen

Brief Summary

This study is a single dose escalation study of tezepelumab (AMG 157) in healthy adults (Part A) and adults with moderate to severe atopic dermatitis (Part B). The purpose of the study is to evaluate the safety, tolerability, immunogenicity and pharmacokinetics of tezepelumab.

Detailed Description

Not available

Study Timeline

• Study Start: 2008-09-18
• Study First Submitted: 2008-09-18
• Study First Submitted QC: 2008-09-19
• Study First Posted: 2008-09-22
• Primary Completion: 2011-01-05
• Study Completion: 2011-01-05
• Results First Submitted: 2022-03-19
• Results First Submitted QC: 2022-03-19
• Results First Posted: 2022-07-18
• Status Verified: 2022-09
• Last Update Submitted: 2022-09-08
• Last Update Posted: 2022-09-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 78

Inclusion Criteria

• Subject must sign an Institutional Review Board (IRB) approved informed consent form before any study specific procedures
• Subjects must be aged between 18 and 45 years, inclusive (Part A only)
• Female subjects must be of non-reproductive potential
• Male subjects with partners of childbearing potential should inform their partner of their participation in this clinical study and use highly effective methods of birth control during the study
• Healthy subjects must have a body mass index (BMI) between 18 to 32 kg/m^2, inclusive
• Subject must have normal or clinically acceptable physical examination, clinical laboratory tests and electrocardiogram (ECG) results
• For Part B, subject must have active atopic dermatitis (AD) affecting ≥ 10% body surface area; Eczema Area and Severity Index (EASI) score ≥ 15, aged between 18 and 60 years, inclusive and BMI between 18 and 35 kg/m^2, inclusive

Exclusion Criteria

• Subject who has history or evidence of a clinically significant disorder, condition or disease that, in the opinion of the Investigator in consultation with the Amgen physician, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
• Subject who has evidence of any active or suspected bacterial, viral, fungal or parasitic infections within the past 30 days prior to randomization
• Subject who has known positive tuberculin skin test or recent (within 6 months from randomization) exposure to an individual with active tuberculosis
• Subject who has history of malignancy within 5 years before randomization
• Subject who has history of significant dermatological conditions (except for atopic dermatitis in Part B)
• Subject who has previously received any investigational drug (or is currently using an investigational device) within 30 days prior to randomization
• Subject who has tested positive for drugs and/or alcohol use at screening or before randomization
• Female subjects who are pregnant or lactating
• Subject who has used nicotine or tobacco containing products during 6 months before randomization and during the study (except for Part B below)
• Subject has known type I/II diabetes
• Subject used nonprescription drugs within 14 days prior to randomization and during the study
• Subject used any cytotoxic or immunosuppressive drugs with 30 days or 5 half-lives prior to randomization and during the study
• Subject previously received a monoclonal antibody
• Subject donated blood or had loss of blood of equal to or greater than 500 mL with 2 months of screening
• Subject positive for human immunodeficiency virus antibodies, hepatitis B surface antigen, or hepatitis C antibodies
• Subject has any condition that might compromise informed consent or compliance to the protocol
• For atopic dermatitis subjects in Part B (Cohorts 9 and 10) only, additional exclusion criteria are as follows:
• Subject who has concurrent skin disease (eg, acne) of such severity in the study area that it could interfere with study evaluation;
• Subject who has active or recent skin infections (within 7 days of randomization);
• Subject who has received phototherapy (eg, ultraviolet [UV] A, UVB) known or suspected to have an effect on AD within 6 weeks prior to randomization;
• Subject who has received corticosteroids by other than topical, inhaled or intranasal delivery within 4 weeks prior to randomization;
• Subject who has been treated with topical calcineurin inhibitors within 14 days prior to randomization;
• Subject who uses any medications that interfere with blood coagulation (eg nonsteroidal anti-inflammatory drugs [NSAIDs]) or wound healing within 7 days or 5 half-lives (whichever is longer) prior to enrolling into the study and for the duration of the study.
• Subject who smokes more than 10 cigarettes per day within the 6 months prior to randomization and during the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants will receive matching placebo administered subcutaneously or intravenously.
Tezepelumab	Tezepelumab	Participants will receive a single dose of tezepelumab administered subcutaneously or intravenously. The starting dose will be 2.1 mg tezepelumab.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events	For Part A Tezepelumab/Placebo 2.1 mg, 7 mg, 21 mg, 70 mg, and 210 mg SC: 85 days. For Part A Tezepelumab/Placebo 420 mg SC, 210 mg IV, and 700 mg IV and Part B: 113 days	Adverse events (AEs) include any untoward medical occurrence in a trial participant administered a study drug and does not necessarily have a causal relationship with this treatment. AEs include worsening of a pre-existing medical condition and laboratory value changes requiring therapy or adjustment in prior therapy.; AEs were assessed for severity according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 3, where Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = severe AE, Grade 4 = life-threatening AE and Grade 5 = death due to AE.; Relationship to study treatment was determined by the investigator.; A serious adverse event (SAE) is defined as an AE that met 1 or more of below criteria: * was fatal; * was life threatening; * required in-patient hospitalization or prolongation of existing hospitalization; * resulted in persistent or significant disability/incapacity; * was a congenital anomaly/birth defect; * other significant medical hazard.
Number of Participants Who Developed Anti-tezepelumab Antibodies	Blood samples for the measurement of antibodies were collected on Days 29, 57, 85, and (for cohorts who received 420 mg Tezepelumab/placebo SC or any IV dose) 113.	All study samples (tezepelumab and placebo) were tested using an electrochemiluminescence (ECL) based immunoassay to detect and confirm the presence of antibodies capable of binding to tezepelumab. Samples identified as positive in the immunoassay were tested in a receptor-binding ECL-based assay to detect neutralizing or inhibitory effects toward tezepelumab.; The number of participants with positive anti-tezepelumab binding antibodies / neutralizing antibodies at any time post-baseline with a negative or no result at baseline is reported.

Secondary Outcome Measures

Name	Time	Method
Part A: Time of Maximum Observed Concentration (Tmax) of Tezepelumab	Day 1 predose, 0.25, 0.5, and 1 hour after start of infusion (for IV cohorts only), 4, 8, 24, 48, 72 hours postdose and days 5, 6, 7, 11, 15, 22, 29, 43, 57, 71, 85, and (for cohorts who received 420 mg tezepelumab SC or any IV dose) 113.	The time at which the maximum concentration of tezepelumab was observed was estimated based on the serum concentrations of tezepelumab using noncompartmental methods.; The concentration of tezepelumab in human serum was measured using a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification of the assay was 10 ng/mL.
Part A: Maximum Observed Concentration (Cmax) of Tezepelumab	Day 1 predose, 0.25, 0.5, and 1 hour after start of infusion (for IV cohorts only), 4, 8, 24, 48, 72 hours postdose and days 5, 6, 7, 11, 15, 22, 29, 43, 57, 71, 85, and (for cohorts who received 420 mg tezepelumab SC or any IV dose) 113.	The maximum observed serum concentration of tezepelumab was estimated based on the serum concentrations of tezepelumab using noncompartmental methods.; The concentration of tezepelumab in human serum was measured using a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification of the assay was 10 ng/mL.
Part A: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Tezepelumab	Day 1 predose, 0.25, 0.5, and 1 hour after start of infusion (for IV cohorts only), 4, 8, 24, 48, 72 hours postdose and days 5, 6, 7, 11, 15, 22, 29, 43, 57, 71, 85, and (for cohorts who received 420 mg tezepelumab SC or any IV dose) 113.	The PK parameter AUC0-t was estimated based on the serum concentrations of tezepelumab using noncompartmental methods and the linear/log trapezoidal method. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Part A: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Tezepelumab	Day 1 predose, 0.25, 0.5, and 1 hour after start of infusion (for IV cohorts only), 4, 8, 24, 48, 72 hours postdose and days 5, 6, 7, 11, 15, 22, 29, 43, 57, 71, 85, and (for cohorts who received 420 mg tezepelumab SC or any IV dose) 113.	The PK parameter AUCinf was estimated based on the serum concentrations of tezepelumab using noncompartmental methods and the linear/log trapezoidal method. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Part A: Elimination Half-life (t1/2) of Tezepelumab	Day 1 predose, 0.25, 0.5, and 1 hour after start of infusion (for IV cohorts only), 4, 8, 24, 48, 72 hours postdose and days 5, 6, 7, 11, 15, 22, 29, 43, 57, 71, 85, and (for cohorts who received 420 mg tezepelumab SC or any IV dose) 113.	Elimination half-life was estimated based on the serum concentrations of tezepelumab using noncompartmental methods based on the terminal phase of the concentration-time profile.; The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Part B: Time of Maximum Observed Concentration (Tmax) of Tezepelumab	Day 1 predose, 0.25, 0.5, 1, 4, 8, 72 hours postdose and days, 7, 15, 22, 29, 43, 57, 71, 85, and 113.	Tmax was estimated based on the serum concentrations of tezepelumab using noncompartmental methods.; The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Part B: Maximum Observed Concentration (Cmax) of Tezepelumab	Day 1 predose, 0.25, 0.5, 1, 4, 8, 72 hours postdose and days, 7, 15, 22, 29, 43, 57, 71, 85, and 113.	Cmax was estimated based on the serum concentrations of tezepelumab using noncompartmental methods.; The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Part B: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Tezepelumab	Day 1 predose, 0.25, 0.5, 1, 4, 8, 72 hours postdose and days, 7, 15, 22, 29, 43, 57, 71, 85, and 113.	The PK parameter AUC0-t was estimated based on the serum concentrations of tezepelumab using noncompartmental methods and the linear/log trapezoidal method. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Part B: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Tezepelumab	Day 1 predose, 0.25, 0.5, 1, 4, 8, 72 hours postdose and days, 7, 15, 22, 29, 43, 57, 71, 85, and 113.	The PK parameter AUCinf was estimated based on the serum concentrations of tezepelumab using noncompartmental methods and the linear/log trapezoidal method. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Part B: Elimination Half-life (t1/2) of Tezepelumab	Day 1 predose, 0.25, 0.5, 1, 4, 8, 72 hours postdose and days, 7, 15, 22, 29, 43, 57, 71, 85, and 113.	Elimination half-life was estimated based on the serum concentrations of tezepelumab using noncompartmental methods based on the terminal phase of the concentration-time profile.; The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Part B: Percentage of Participants Achieving at Least a 50% Reduction From Baseline in Eczema Area and Severity Index (EASI 50) Score	Baseline and days 15, 29, 43, 57, 85, and 113	EASI is a tool used to measure the severity of AD. The index involves an assessment of the average intensity of 4 clinical signs (erythema, infiltration/papulation, excoriations, and lichenification) at 4 body areas (head/neck, upper extremities, trunk, lower extremities) assessed on a scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe.; The percent of affected area for each of the 4 body areas is also assessed using the following 6-point scale: 0 = 0%, 1 = \< 10%, 2 =10% to 29%, 3 = 30% to 49%, 4 = 50% to 69%, 5 = 70% to 89%, 6 = 90% to 100%. The total score for each body region is obtained by multiplying the sum of the severity scores of the 4 clinical signs by the area score, with adjustment for the proportion of the body region to the whole body.; The sum of the scores for each body region gives the total EASI score, which ranges from 0 to 72, with higher scores indicating greater disease severity.
Part B: Percentage of Participants Achieving at Least a 75% Reduction From Baseline in Eczema Area and Severity Index (EASI 75) Score	Baseline and days 15, 29, 43, 57, 85, and 113	EASI is a tool used to measure the severity of AD. The index involves an assessment of the average intensity of 4 clinical signs (erythema, infiltration/papulation, excoriations, and lichenification) at 4 body areas (head/neck, upper extremities, trunk, lower extremities) assessed on a scale: 0 = none, 1 = mild, 2 = moderate, 3 = severe.; The percent of affected area for each of the 4 body areas is also assessed using the following 6-point scale: 0 = 0%, 1 = \< 10%, 2 =10% to 29%, 3 = 30% to 49%, 4 = 50% to 69%, 5 = 70% to 89%, 6 = 90% to 100%. The total score for each body region is obtained by multiplying the sum of the severity scores of the 4 clinical signs by the area score, with adjustment for the proportion of the body region to the whole body.; The sum of the scores for each body region gives the total EASI score, which ranges from 0 to 72, with higher scores indicating greater disease severity.
Part B: Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score	Baseline and days 15, 29, 43, 57, 85, and 113	EASI is a tool used to measure the severity of AD. The index involves an assessment of the intensity of 4 clinical signs (erythema, infiltration/papulation, excoriations, and lichenification) at 4 body areas (head/neck, upper extremities, trunk, lower extremities) assessed on a scale from 0 (none) to 3 (severe).; The percent affected area for each of the 4 body areas is assessed on a 6-point scale from 0 (0%) to 6 (90% to 100%). The total score for each body region is obtained by multiplying the sum of the severity scores of the 4 clinical signs by the area score, with adjustment for the proportion of the body region to the whole body.; The total EASI score is the sum of the scores for each body region, and ranges from 0 to 72, with higher scores indicating greater disease severity.; Percent change from baseline = \[(Post-baseline Value - Baseline Value) / Baseline Value\] x 100.; A negative change from baseline indicates improvement.
Part B: Change From Baseline in Investigator's Global Assessment (IGA)	Baseline and days 15, 29, 43, 57, 85, and 113	IGA score is a static 6-point measure of disease activity based on an overall assessment of skin lesions. The IGA was scored on a scale of 0 to 5, where 0 (clear) = no inflammatory signs of AD; 1. (almost clear) = just perceptible erythema and just perceptible papulation/infiltration; 2. (mild) = mild erythema and mild papulation and infiltration; 3. (moderate) = moderate erythema and moderate papulation and infiltration; 4. (severe) = severe disease with severe erythema and severe papulation and infiltration; 5. (very severe) = severe disease with severe erythema and severe papulation and infiltration with oozing/crusting.; A negative change from baseline indicates improvement.