Trial Outcomes & Findings for Double-blind, Multiple Dose Study of Tezepelumab (AMG 157) in Adults With Mild Atopic Asthma (NCT NCT01405963)

This proof-of-concept, randomized, double-blind, placebo-controlled study was conducted at 5 centers in Canada.

Participants were randomly assigned in a 1:1 ratio to receive tezepelumab or placebo.

Double-blind, Multiple Dose Study of Tezepelumab (AMG 157) in Adults With Mild Atopic Asthma

Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction (measured by a fall in FEV1). FEV1 was measured prior to the challenge and between 3 to 7 hours post allergen challenge to assess late asthmatic response (LAR). The percent change in FEV1 from pre-challenge was calculated to each time point between 3 to 7 hours post challenge. The maximum percent decrease in FEV1 from pre-allergen challenge is the percent change in FEV1 representing the largest percentage decrease (or minimum percentage increase) from pre-allergen challenge FEV1 during late (3-7 hour) asthmatic response time frame.

Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 3 to 7 hours post challenge to assess late asthmatic response (LAR). The percent change in FEV1 from pre-challenge was calculated to each time point between 3 to 7 hours post challenge. The area under the curve for the percent change at each time point was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated.

A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: * fatal, * life-threatening, * requires in-patient hospitalization or prolongation of existing hospitalization, * results in persistent or significant disability/incapacity, * congenital anomaly/birth defect, and/or * other medically important serious event. The severity of each adverse event was graded by the Investigator as mild, moderate, severe, life-threatening, or fatal according to the Common Terminology Criteria for Adverse Events (Version 4).

Laboratory toxicities were graded according to the Common Terminology Criteria for Adverse Events (Version 4) on a scale from grade 1 (mild) to 5 (death).

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.

Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The maximum percent decrease in FEV1 from pre-allergen challenge is the percent change in FEV1 representing the largest percentage decrease (or minimum percentage increase) from pre-allergen challenge FEV1 during early (0-2 hour) asthmatic response time frame.

Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The percent change in FEV1 from pre-allergen challenge was calculated to each time point between 0 to 2 hours post challenge. The area under the curve for the percent change at each time point was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated.

Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The minimum FEV1 post onset of the allergen challenge for EAR is defined as the smallest value of FEV1 measured during 0 to 2 hours post allergen challenge.

Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The area under the curve for the FEV1 between 0 to 2 hours post allergen challenge was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated.

Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 3 to 7 hours post challenge to assess late asthmatic response (LAR). The minimum FEV1 post allergen challenge for LAR is defined as the smallest value of FEV1 measured during 3 to 7 hours post allergen challenge.

Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 3 to 7 hours post allergen challenge to assess late asthmatic response (LAR). The area under the curve for the FEV1 between 3 to 7 hours post allergen challenge was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated.

The PK parameter 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.

The PK parameter 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.

The PK parameter Cmin 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.

The PK parameter AUCtau was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The dosing interval (tau) was 28 days. 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.

Accumulation ratio (AR) based on AUCtau was calculated as AUCtau after last dose / AUCtau after first dose.

Accumulation ratio based on Cmax calculated as Cmax after last dose / Cmax after first dose.

The PK parameter AUCinf 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.

The PK parameter t1/2,z 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.