Safety Study of Tezepelumab (AMG 157) in Healthy Adults

Study Overview
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Brief Summary
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The primary objective is to evaluate the safety, tolerability, and immunogenicity of multiple-dose administration of tezepelumab in healthy adults.

Detailed Description
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This study will follow a randomized, multiple-dose, double-blind, placebo-controlled, sequential dose-escalation study design. The study will consist of five subcutaneous (SC) cohorts and one intravenous (IV) cohort. Each dose cohort is planned to enroll 8 participants, randomized such that 6 participants will receive tezepelumab and 2 will receive placebo (3:1 ratio).

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Ascending Multiple Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of AMG 157 in Healthy Subjects

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Placebo
* Drug: Tezepelumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must sign an Institutional Review Board (IRB) approved informed consent form before any study-specific procedures; Healthy subject, aged between 18 and 45 years, inclusive; Female subject must be of non-reproductive potential (ie, postmenopausal by history - no menses for ≥ 1 year and by follicle-stimulating hormone (FSH) [using local reference ranges]; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); Male subjects with female partner of childbearing potential who agrees to inform their female partner of their participation in this clinical study and use highly effective methods of birth control during the study. (Highly effective methods of birth control may include abstinence, vasectomy, or a condom with spermicide in combination with either hormonal birth control, intra-uterine device, or barrier methods used by the woman); Male subject who agrees to use birth control for five months after last dose of study medication, male subject who agrees not to donate sperm during the study and for five months after last dose of study medication; Healthy subject with a body mass index (BMI) between 18 and 32 kg/m^2, inclusive at screening; Subject must have normal or clinically acceptable physical examination and electrocardiogram (ECG) results prior to Day 1 based on the opinion of the investigator; Subject must have normal or clinically acceptable clinical laboratory tests at screening as determined by Amgen and the investigator; Subject must have adequate renal function (defined as creatinine clearance > 80 mL/min using the Cockcroft Gault equation). Exclusion Criteria: Subject who has history or evidence of a clinically significant disorder, condition or disease (including but not limited to cardiopulmonary, oncologic, immunologic, autoimmune, collagen vascular, renal, metabolic, hematologic or psychiatric), 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 (eg, common cold, viral syndrome, flu-like symptoms). Subject who, in the opinion of the investigator, has a high risk of parasitic disease is also excluded; Subject who has known positive tuberculin skin test (if not treated with appropriate chemoprophylaxis) or recent (within six months from randomization) exposure to an individual with active tuberculosis; Subject who has history of malignancy of any type, other than in situ cervical cancer or surgically excised non-melanomatous skin cancers within five years before randomization of the study; Subject who has known type I/II diabetes; Subject who uses nonprescription drugs within 14 days prior to randomization and for the entire duration of the study. All herbal supplements, vitamins, and nutritional supplements taken within the last 30 days prior to dosing on Day 1 (and continued use, if appropriate), must be reviewed and approved by the PI and Amgen Medical Monitor; Subject who has used any systemic cytotoxic or systemic immunosuppressive medications (other than corticosteroids) within 6 months prior to randomization and for the entire duration of the study or has used any corticosteroid, topical cytotoxic or topical immunosuppressive medications within 30 days or five half-lives (whichever is longer) prior to randomization and for the entire duration of the study; Subject who has previously received any other therapeutic monoclonal antibody; Subject who has previously received any investigational drug (or is currently using an investigational device) within 30 days or five half-lives (whichever is longer) prior to randomization; Subject who has tested positive for drugs and/or alcohol use at screening or before randomization, subject who has consumed alcohol within 48 hours prior to any study visit including screening, and subject with alcohol intake of > 2 drinks/day on average during the study (one drink being equivalent to 12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces of wine or 1.5 ounces of 80 proof distilled spirits); Female subject who is pregnant or lactating; female subject who is of child-bearing potential; Subject who has donated blood (including blood products) or experienced loss of blood ≥ 500 mL within two months of study screening; Subject who is positive for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen, or hepatitis C antibodies; Subject who has regularly used nicotine or tobacco containing products (including but not limited to: snuff, chewing tobacco, cigars, cigarettes, pipes, or nicotine patches) during six months before randomization and during the study; Subject who has any other condition that might reduce the chance of obtaining data (eg, known poor compliance) required by the protocol or that might compromise the ability to give truly informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: The cohorts will enroll sequentially: enrollment to the subsequent cohort (ie, next higher dose) will proceed only after the previous dose is determined to be safe and well tolerated by a blinded review of available safety data conducted on day 43 of the previous cohort. Within each dose cohort, participants will be randomized 3:1 to receive tezepelumab or placebo.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tezepelumab<br>Tezepelumab will be administered subcutaneously (SC) at doses from 35 mg once every 28 days (Q28D) (cohort 1) up to 210 mg once every 7 days (Q7D) (cohort 5) and an intravenous (IV) dose cohort of 700 mg Q28D (cohort 6). | Drug: Tezepelumab<br>* Administered by subcutaneous or intravenous injection<br>* Other names: Tezspire;|
| Placebo Comparator: Placebo<br>Two participants in each cohort (cohorts 1 to 6) will receive matching placebo administered subcutaneously (cohorts 1-5) or intravenously (cohort 6), matching the treatment regiment of tezepelumab. | Drug: Placebo<br>* 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 Treatment-emergent 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. | From first dose of study drug up to day 169 | 
| Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | 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. | For Q28D groups: Days 28, 56, 85, 113, and 169; For Q14D and Q7D groups: Days 29, 57, 85, 113, 141, and 169 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time of Maximum Observed Concentration (Tmax) of Tezepelumab | The pharmacokinetic (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 enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification of the assay was 10 ng/ml. | First dose: Day 1 predose, end of infusion (EOI; IV cohort only), 4 hours, 3, 7, 14 (Q14D & Q28D only) and 28 days (Q28D only) postdose. Last Dose: Day 57 (Q28D), Day 71 (Q14D) and Day 78 (Q7D) predose, EOI (IV cohort), 4 hours, 3, 7, 14, 28 days postdose | 
| Maximum Observed Concentration (Cmax) of Tezepelumab | 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. | First dose: Day 1 predose, end of infusion (EOI; IV cohort only), 4 hours, 3, 7, 14 (Q14D & Q28D only) and 28 days (Q28D only) postdose. Last Dose: Day 57 (Q28D), Day 71 (Q14D) and Day 78 (Q7D) predose, EOI (IV cohort), 4 hours, 3, 7, 14, 28 days postdose | 
| Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | The PK parameter AUCtau was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The dosing interval (tau) was 28 days, 14 days or 7 days depending on the treatment arm. 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. | First dose: Day 1 predose, end of infusion (EOI; IV cohort only), 4 hours, 3, 7, 14 (Q14D & Q28D only) and 28 days (Q28D only) postdose. Last Dose: Day 57 (Q28D), Day 71 (Q14D) and Day 78 (Q7D) predose, EOI (IV cohort), 4 hours, 3, 7, 14, 28 days postdose | 
| Accumulation Ratio Based on AUCtau | Accumulation ratio (AR) based on AUCtau was calculated as AUCtau after last dose / AUCtau after first dose, except for the Q7D cohort where AR was calculated as AUCtau after last dose / area under the concentration-time curve from time 0 to time of last measurable concentration (AUC0-t) after first dose. | First dose: Day 1 predose, end of infusion (EOI; IV cohort only), 4 hours, 3, 7, 14 (Q14D & Q28D only) and 28 days (Q28D only) postdose. Last Dose: Day 57 (Q28D), Day 71 (Q14D) and Day 78 (Q7D) predose, EOI (IV cohort), 4 hours, 3, 7, 14, 28 days postdose | 
| Accumulation Ratio Based on Cmax | Accumulation ratio based on Cmax calculated as Cmax after last dose / Cmax after first dose | First dose: Day 1 predose, end of infusion (EOI; IV cohort only), 4 hours, 3, 7, 14 (Q14D & Q28D only) and 28 days (Q28D only) postdose. Last Dose: Day 57 (Q28D), Day 71 (Q14D) and Day 78 (Q7D) predose, EOI (IV cohort), 4 hours, 3, 7, 14, 28 days postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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healthy volunteers