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

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Ascending Single Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 157 in Healthy Subjects and Subjects With Moderate to Severe Atopic Dermatitis

Conditions
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Atopic Dermatitis, Healthy Volunteers

Intervention / Treatment
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* Drug: Tezepelumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Escalating dose cohorts will be enrolled sequentially based on a blinded review of safety data up to day 15 of the previous dose cohort with consideration of predefined stopping rules. The first 2 participants in Cohort 1 will be a sentinel pair, randomized at a 1:1 ratio to receive either tezepelumab or placebo and monitored for safety and tolerability. Once the safety in the sentinel pair is confirmed the subsequent six participants will be randomized at a 5:1 ratio for tezepelumab or placebo treatment. In cohorts 2 through 8 (escalating doses, healthy subjects), participants will be randomized to receive tezepelumab or placebo at a 6:2 ratio. In cohort 9 (700 mg IV, atopic dermatitis subjects),a sentinel pair will again be used to first establish safety, and the subsequent 10 participants will be randomized to receive tezepelumab or placebo at a ratio of 8:2, for a total of 12 evaluable participants in this cohort.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tezepelumab<br>Participants will receive a single dose of tezepelumab administered subcutaneously or intravenously. The starting dose will be 2.1 mg tezepelumab. | Drug: Tezepelumab<br>* Administered by subcutaneous or intravenous injection<br>* Other names: Tezspire;|
| Placebo Comparator: Placebo<br>Participants will receive matching placebo administered subcutaneously or intravenously. | Drug: Placebo<br>* Matching placebo administered by subcutaneous or intravenous injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | 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. | 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 | 
| Number of Participants Who Developed Anti-tezepelumab Antibodies | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Time of Maximum Observed Concentration (Tmax) of Tezepelumab | 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. | 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. | 
| Part A: Maximum Observed Concentration (Cmax) of Tezepelumab | 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. | 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. | 
| Part A: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Tezepelumab | 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. | 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. | 
| Part A: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Tezepelumab | 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. | 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. | 
| Part A: Elimination Half-life (t1/2) of Tezepelumab | 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. | 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. | 
| Part B: Time of Maximum Observed Concentration (Tmax) of Tezepelumab | 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. | 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. | 
| Part B: Maximum Observed Concentration (Cmax) of Tezepelumab | 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. | 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. | 
| Part B: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Tezepelumab | 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. | 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. | 
| Part B: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUCinf) of Tezepelumab | 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. | 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. | 
| Part B: Elimination Half-life (t1/2) of Tezepelumab | 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. | 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. | 
| Part B: Percentage of Participants Achieving at Least a 50% Reduction From Baseline in Eczema Area and Severity Index (EASI 50) Score | 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. | Baseline and days 15, 29, 43, 57, 85, and 113 | 
| Part B: Percentage of Participants Achieving at Least a 75% Reduction From Baseline in Eczema Area and Severity Index (EASI 75) Score | 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. | Baseline and days 15, 29, 43, 57, 85, and 113 | 
| Part B: Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score | 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. | Baseline and days 15, 29, 43, 57, 85, and 113 | 
| Part B: Change From Baseline in Investigator's Global Assessment (IGA) | 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; (almost clear) = just perceptible erythema and just perceptible papulation/infiltration; (mild) = mild erythema and mild papulation and infiltration; (moderate) = moderate erythema and moderate papulation and infiltration; (severe) = severe disease with severe erythema and severe papulation and infiltration; (very severe) = severe disease with severe erythema and severe papulation and infiltration with oozing/crusting. A negative change from baseline indicates improvement. | Baseline and days 15, 29, 43, 57, 85, and 113 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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atopic dermatitis, skin diseases, healthy volunteer