Healthy Volunteers
Conditions
Keywords
healthy volunteers
Brief summary
The primary objective is to evaluate the safety, tolerability, and immunogenicity of multiple-dose administration of tezepelumab in healthy adults.
Detailed description
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).
Interventions
DRUGPlacebo
Administered by subcutaneous or intravenous injection.
DRUGTezepelumab
Administered by subcutaneous or intravenous injection
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events | From first dose of study drug up to day 169 | 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 After Initiation of Treatment | For Q28D groups: Days 28, 56, 85, 113, and 169; For Q14D and Q7D groups: Days 29, 57, 85, 113, 141, and 169 | 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
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | 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 | 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. |
| Time of Maximum Observed Concentration (Tmax) of Tezepelumab | 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 | 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. |
| Accumulation Ratio Based on Cmax | 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 calculated as Cmax after last dose / Cmax after first dose |
| Accumulation Ratio Based on AUCtau | 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 (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. |
| Maximum Observed Concentration (Cmax) of Tezepelumab | 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 | 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. |
Participant flow
Recruitment details
This study was conducted at a single center in the United States.
Pre-assignment details
Participants were enrolled into 1 of 6 cohorts. In the first 5 cohorts escalating subcutaneous doses of tezepelumab were compared with placebo and in cohort 6 a regimen of intravenous tezepelumab was compared with placebo. Within each cohort, healthy participants were randomized at a 6:2 ratio to receive either tezepelumab or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Tezepelumab 35 mg Q28D Participants received 35 mg tezepelumab by subcutaneous injection once every 28 days (Q28D) for 3 doses. | 6 |
| Tezepelumab 105 mg Q28D Participants received 105 mg tezepelumab by subcutaneous injection once every 28 days for 3 doses. | 6 |
| Tezepelumab 210 mg Q28D Participants received 210 mg tezepelumab by subcutaneous injection once every 28 days for 3 doses. | 6 |
| Tezepelumab 210 mg Q14D Participants received 210 mg tezepelumab by subcutaneous injection once every 14 days (Q14D) for 6 doses. | 6 |
| Tezepelumab 210 mg Q7D Participants received 210 mg tezepelumab by subcutaneous injection once every 7 days (Q7D) for 12 doses. | 7 |
| Tezepelumab 700 mg Q28D IV Participants received 700 mg tezepelumab by intravenous injection once every 28 days for 3 doses. | 6 |
| Placebo Participants received matching placebo administered subcutaneously (Cohorts 1-5) or intravenously (Cohort 6), matching the treatment regimen of tezepelumab. | 12 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Administrative Decision | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 3 | 1 |
| Overall Study | Noncompliance | 1 | 0 | 0 | 0 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 0 | 1 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Tezepelumab 35 mg Q28D | Tezepelumab 105 mg Q28D | Tezepelumab 210 mg Q28D | Tezepelumab 210 mg Q14D | Tezepelumab 210 mg Q7D | Tezepelumab 700 mg Q28D IV | Placebo | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 29.8 year STANDARD_DEVIATION 9.3 | 34.8 year STANDARD_DEVIATION 5.8 | 32.3 year STANDARD_DEVIATION 5.3 | 31.5 year STANDARD_DEVIATION 5.6 | 36.1 year STANDARD_DEVIATION 7.7 | 27.7 year STANDARD_DEVIATION 4.1 | 34.1 year STANDARD_DEVIATION 5.2 | 32.6 year STANDARD_DEVIATION 6.4 |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 3 Participants | 6 Participants | 4 Participants | 5 Participants | 3 Participants | 1 Participants | 7 Participants | 29 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 4 Participants | 3 Participants | 4 Participants | 17 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 1 Participants | 0 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 6 Participants | 2 Participants | 6 Participants | 6 Participants | 10 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 6 | 4 / 6 | 2 / 6 | 6 / 6 | 5 / 7 | 3 / 6 | 24 / 37 | 10 / 12 |
| serious Total, serious adverse events | 1 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 6 | 1 / 37 | 0 / 12 |
Outcome results
Primary
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.
Time frame: For Q28D groups: Days 28, 56, 85, 113, and 169; For Q14D and Q7D groups: Days 29, 57, 85, 113, 141, and 169
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tezepelumab 35 mg Q28D | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab binding antibodies | 0 Participants |
| Tezepelumab 35 mg Q28D | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab neutralizing antibodies | 0 Participants |
| Tezepelumab 105 mg Q28D | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab binding antibodies | 0 Participants |
| Tezepelumab 105 mg Q28D | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab neutralizing antibodies | 0 Participants |
| Tezepelumab 210 mg Q28D | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab binding antibodies | 0 Participants |
| Tezepelumab 210 mg Q28D | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab neutralizing antibodies | 0 Participants |
| Tezepelumab 210 mg Q14D | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab binding antibodies | 0 Participants |
| Tezepelumab 210 mg Q14D | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab neutralizing antibodies | 0 Participants |
| Tezepelumab 210 mg Q7D | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab binding antibodies | 0 Participants |
| Tezepelumab 210 mg Q7D | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab neutralizing antibodies | 0 Participants |
| Tezepelumab 700 mg Q28D IV | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab binding antibodies | 0 Participants |
| Tezepelumab 700 mg Q28D IV | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab neutralizing antibodies | 0 Participants |
| Placebo | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab binding antibodies | 0 Participants |
| Placebo | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab neutralizing antibodies | 0 Participants |
Primary
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.
Time frame: From first dose of study drug up to day 169
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tezepelumab 35 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation of study drug | 0 Participants |
| Tezepelumab 35 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 1 Participants |
| Tezepelumab 35 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Any adverse event | 4 Participants |
| Tezepelumab 35 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation from study | 0 Participants |
| Tezepelumab 35 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Grade 3 adverse events | 1 Participants |
| Tezepelumab 35 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Grade 4 adverse events | 0 Participants |
| Tezepelumab 35 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Fatal (grade 5) adverse events | 0 Participants |
| Tezepelumab 35 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Any treatment-related adverse event | 2 Participants |
| Tezepelumab 105 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Tezepelumab 105 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Any treatment-related adverse event | 0 Participants |
| Tezepelumab 105 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation of study drug | 0 Participants |
| Tezepelumab 105 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation from study | 0 Participants |
| Tezepelumab 105 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Grade 3 adverse events | 0 Participants |
| Tezepelumab 105 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Grade 4 adverse events | 0 Participants |
| Tezepelumab 105 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Fatal (grade 5) adverse events | 0 Participants |
| Tezepelumab 105 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Any adverse event | 4 Participants |
| Tezepelumab 210 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation of study drug | 0 Participants |
| Tezepelumab 210 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Any treatment-related adverse event | 1 Participants |
| Tezepelumab 210 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation from study | 0 Participants |
| Tezepelumab 210 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Grade 3 adverse events | 0 Participants |
| Tezepelumab 210 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Grade 4 adverse events | 0 Participants |
| Tezepelumab 210 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Fatal (grade 5) adverse events | 0 Participants |
| Tezepelumab 210 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Tezepelumab 210 mg Q28D | Number of Participants With Treatment-emergent Adverse Events | Any adverse event | 2 Participants |
| Tezepelumab 210 mg Q14D | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Tezepelumab 210 mg Q14D | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation from study | 0 Participants |
| Tezepelumab 210 mg Q14D | Number of Participants With Treatment-emergent Adverse Events | Any treatment-related adverse event | 1 Participants |
| Tezepelumab 210 mg Q14D | Number of Participants With Treatment-emergent Adverse Events | Grade 3 adverse events | 1 Participants |
| Tezepelumab 210 mg Q14D | Number of Participants With Treatment-emergent Adverse Events | Grade 4 adverse events | 0 Participants |
| Tezepelumab 210 mg Q14D | Number of Participants With Treatment-emergent Adverse Events | Fatal (grade 5) adverse events | 0 Participants |
| Tezepelumab 210 mg Q14D | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation of study drug | 0 Participants |
| Tezepelumab 210 mg Q14D | Number of Participants With Treatment-emergent Adverse Events | Any adverse event | 6 Participants |
| Tezepelumab 210 mg Q7D | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation from study | 0 Participants |
| Tezepelumab 210 mg Q7D | Number of Participants With Treatment-emergent Adverse Events | Grade 4 adverse events | 1 Participants |
| Tezepelumab 210 mg Q7D | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation of study drug | 0 Participants |
| Tezepelumab 210 mg Q7D | Number of Participants With Treatment-emergent Adverse Events | Any treatment-related adverse event | 3 Participants |
| Tezepelumab 210 mg Q7D | Number of Participants With Treatment-emergent Adverse Events | Any adverse event | 5 Participants |
| Tezepelumab 210 mg Q7D | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Tezepelumab 210 mg Q7D | Number of Participants With Treatment-emergent Adverse Events | Fatal (grade 5) adverse events | 0 Participants |
| Tezepelumab 210 mg Q7D | Number of Participants With Treatment-emergent Adverse Events | Grade 3 adverse events | 1 Participants |
| Tezepelumab 700 mg Q28D IV | Number of Participants With Treatment-emergent Adverse Events | Fatal (grade 5) adverse events | 0 Participants |
| Tezepelumab 700 mg Q28D IV | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation from study | 0 Participants |
| Tezepelumab 700 mg Q28D IV | Number of Participants With Treatment-emergent Adverse Events | Grade 4 adverse events | 0 Participants |
| Tezepelumab 700 mg Q28D IV | Number of Participants With Treatment-emergent Adverse Events | Grade 3 adverse events | 1 Participants |
| Tezepelumab 700 mg Q28D IV | Number of Participants With Treatment-emergent Adverse Events | Any treatment-related adverse event | 0 Participants |
| Tezepelumab 700 mg Q28D IV | Number of Participants With Treatment-emergent Adverse Events | Any adverse event | 3 Participants |
| Tezepelumab 700 mg Q28D IV | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Tezepelumab 700 mg Q28D IV | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation of study drug | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation from study | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Grade 3 adverse events | 2 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Grade 4 adverse events | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Any adverse event | 10 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Serious adverse events | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | AE Leading to discontinuation of study drug | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Fatal (grade 5) adverse events | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Any treatment-related adverse event | 2 Participants |
Secondary
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.
Time frame: 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
Population: Participants who received tezepelumab and had a sufficient number of serum concentration measurements for computing the PK parameter after first dose and after last dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tezepelumab 35 mg Q28D | Accumulation Ratio Based on AUCtau | 1.82 ratio | Standard Deviation 0.262 |
| Tezepelumab 105 mg Q28D | Accumulation Ratio Based on AUCtau | 1.64 ratio | Standard Deviation 0.0883 |
| Tezepelumab 210 mg Q28D | Accumulation Ratio Based on AUCtau | 1.59 ratio | Standard Deviation 0.242 |
| Tezepelumab 210 mg Q14D | Accumulation Ratio Based on AUCtau | 2.89 ratio | Standard Deviation 0.892 |
| Tezepelumab 210 mg Q7D | Accumulation Ratio Based on AUCtau | 8.23 ratio | Standard Deviation 1.93 |
| Tezepelumab 700 mg Q28D IV | Accumulation Ratio Based on AUCtau | 1.34 ratio | Standard Deviation 0.314 |
Secondary
Accumulation Ratio Based on Cmax
Accumulation ratio based on Cmax calculated as Cmax after last dose / Cmax after first dose
Time frame: 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
Population: Participants who received tezepelumab and had a sufficient number of serum concentration measurements for computing the PK parameter after first dose and after last dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tezepelumab 35 mg Q28D | Accumulation Ratio Based on Cmax | 1.79 ratio | Standard Deviation 0.392 |
| Tezepelumab 105 mg Q28D | Accumulation Ratio Based on Cmax | 1.66 ratio | Standard Deviation 0.0901 |
| Tezepelumab 210 mg Q28D | Accumulation Ratio Based on Cmax | 1.59 ratio | Standard Deviation 0.288 |
| Tezepelumab 210 mg Q14D | Accumulation Ratio Based on Cmax | 2.84 ratio | Standard Deviation 0.965 |
| Tezepelumab 210 mg Q7D | Accumulation Ratio Based on Cmax | 6.74 ratio | Standard Deviation 1.69 |
| Tezepelumab 700 mg Q28D IV | Accumulation Ratio Based on Cmax | 1.30 ratio | Standard Deviation 0.176 |
Secondary
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.
Time frame: 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
Population: Participants who received tezepelumab and had a sufficient number of serum concentration measurements for computing the PK parameter after first dose and after last dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tezepelumab 35 mg Q28D | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | First dose | 78.9 days*µg/mL | Standard Deviation 23.4 |
| Tezepelumab 35 mg Q28D | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | Last dose | 136 days*µg/mL | Standard Deviation 35.9 |
| Tezepelumab 105 mg Q28D | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | First dose | 237 days*µg/mL | Standard Deviation 50.5 |
| Tezepelumab 105 mg Q28D | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | Last dose | 333 days*µg/mL | Standard Deviation 28.8 |
| Tezepelumab 210 mg Q28D | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | First dose | 481 days*µg/mL | Standard Deviation 171 |
| Tezepelumab 210 mg Q28D | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | Last dose | 799 days*µg/mL | Standard Deviation 338 |
| Tezepelumab 210 mg Q14D | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | First dose | 263 days*µg/mL | Standard Deviation 49.2 |
| Tezepelumab 210 mg Q14D | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | Last dose | 787 days*µg/mL | Standard Deviation 180 |
| Tezepelumab 210 mg Q7D | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | First dose | 84.3 days*µg/mL | Standard Deviation 34.9 |
| Tezepelumab 210 mg Q7D | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | Last dose | 732 days*µg/mL | Standard Deviation 224 |
| Tezepelumab 700 mg Q28D IV | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | First dose | 2980 days*µg/mL | Standard Deviation 395 |
| Tezepelumab 700 mg Q28D IV | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | Last dose | 4050 days*µg/mL | Standard Deviation 1270 |
Secondary
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.
Time frame: 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
Population: Participants who received tezepelumab and had a sufficient number of serum concentration measurements for computing the PK parameter after first dose and after last dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tezepelumab 35 mg Q28D | Maximum Observed Concentration (Cmax) of Tezepelumab | Last dose | 6.29 µg/mL | Standard Deviation 2.02 |
| Tezepelumab 35 mg Q28D | Maximum Observed Concentration (Cmax) of Tezepelumab | First dose | 3.70 µg/mL | Standard Deviation 1.16 |
| Tezepelumab 105 mg Q28D | Maximum Observed Concentration (Cmax) of Tezepelumab | Last dose | 16.6 µg/mL | Standard Deviation 2.02 |
| Tezepelumab 105 mg Q28D | Maximum Observed Concentration (Cmax) of Tezepelumab | First dose | 10.7 µg/mL | Standard Deviation 3.13 |
| Tezepelumab 210 mg Q28D | Maximum Observed Concentration (Cmax) of Tezepelumab | First dose | 23.6 µg/mL | Standard Deviation 9.5 |
| Tezepelumab 210 mg Q28D | Maximum Observed Concentration (Cmax) of Tezepelumab | Last dose | 37.4 µg/mL | Standard Deviation 17.5 |
| Tezepelumab 210 mg Q14D | Maximum Observed Concentration (Cmax) of Tezepelumab | First dose | 23.8 µg/mL | Standard Deviation 5.4 |
| Tezepelumab 210 mg Q14D | Maximum Observed Concentration (Cmax) of Tezepelumab | Last dose | 63.8 µg/mL | Standard Deviation 13.5 |
| Tezepelumab 210 mg Q7D | Maximum Observed Concentration (Cmax) of Tezepelumab | First dose | 18.0 µg/mL | Standard Deviation 4.58 |
| Tezepelumab 210 mg Q7D | Maximum Observed Concentration (Cmax) of Tezepelumab | Last dose | 117 µg/mL | Standard Deviation 45.6 |
| Tezepelumab 700 mg Q28D IV | Maximum Observed Concentration (Cmax) of Tezepelumab | Last dose | 370 µg/mL | Standard Deviation 74.9 |
| Tezepelumab 700 mg Q28D IV | Maximum Observed Concentration (Cmax) of Tezepelumab | First dose | 294 µg/mL | Standard Deviation 48.2 |
Secondary
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.
Time frame: 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
Population: Participants who received tezepelumab and had a sufficient number of serum concentration measurements for computing the PK parameter after first dose and after last dose.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tezepelumab 35 mg Q28D | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | Last dose | 166 hours |
| Tezepelumab 35 mg Q28D | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | First dose | 160 hours |
| Tezepelumab 105 mg Q28D | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | Last dose | 71.8 hours |
| Tezepelumab 105 mg Q28D | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | First dose | 71.5 hours |
| Tezepelumab 210 mg Q28D | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | First dose | 118 hours |
| Tezepelumab 210 mg Q28D | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | Last dose | 167 hours |
| Tezepelumab 210 mg Q14D | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | First dose | 70.7 hours |
| Tezepelumab 210 mg Q14D | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | Last dose | 66.5 hours |
| Tezepelumab 210 mg Q7D | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | First dose | 164 hours |
| Tezepelumab 210 mg Q7D | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | Last dose | 74.4 hours |
| Tezepelumab 700 mg Q28D IV | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | Last dose | 3.97 hours |
| Tezepelumab 700 mg Q28D IV | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | First dose | 4.00 hours |