Dose Ranging Pharmacokinetics and Pharmacodynamics Study With Mepolizumab in Asthma Patients With Elevated Eosinophils

Study Overview
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Brief Summary
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A multi-center, randomized, open-label, parallel-group, repeat dose study in asthma patients with elevated eosinophils. Eligible subjects will receive 3 doses (28 days apart) of mepolizumab given intravenous (IV) or subcutaneously (SC). Blood samples for safety, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity analysis, as well as safety/tolerability assessments will be collected throughout the study

Detailed Description
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Mepolizumab (SB-240563) is a humanized monoclonal antibody that blocks human interleukin 5 (IL-5) from binding to its receptor. Mepolizumab is currently under development for severe refractory asthma and a Phase IIB dose-ranging study using the IV route of administration is currently on-going. This study will be a multi-center, randomized, open-label, parallel-group, repeat dose study conducted in approximately 65 subjects with established asthma and elevated blood eosinophil levels. Dosing will occur on three occasions, every four weeks [Day 1, Day 28 (+/- 3 days) and Day 56 (+/- 3 days)]. Blood samples for safety, pharmacodynamics (PD), pharmacokinetics (PK) and immunogenicity analysis, as well safety and tolerability assessments will be collected/assessed throughout the study. Each subject will participate in the study for up to approximately 22 weeks, including screening, dosing and follow-up.

Official Title
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A Multicenter, Open-label, Dose Ranging Study to Determine the Pharmacokinetics and Pharmacodynamics of Mepolizumab Administered Intravenously or Subcutaneously to Adult Asthmatic Subjects With Elevated Blood Eosinophil Levels

Conditions
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Asthma

Intervention / Treatment
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* Biological: Mepolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or eligible females between 18 and 65 years of age inclusive, at the time of signing the informed consent; Non-childbearing potential is defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L) is confirmatory]. To be eligible for entry into the study, females of child-bearing potential and females whose menopausal status is in question must commit to consistent and correct use of an acceptable method of birth control as defined in Section 7.1.1 from one month prior to the first dose of investigational product until 4 months after the last dose of investigational product. History of asthma for at least one year. Subjects must be on a stable dose of an inhaled corticosteroid or combination (ICS+LABA) therapy for at least 12 weeks prior to screening. FEV1≥45% and <90 % of predicted normal value during screening (obtained between 6:00 AM and 1:00 PM). Evidence of airway reversibility (FEV1≥12%) within 30 minutes of inhalation of albuterol OR airway hyperresponsiveness (PC20 of <8mg/mL or PD20 of <7.8 µ mol methacholine/histamine) documented in the 12 months prior to randomization. Subjects with documented evidence of elevated blood eosinophilia levels (>0.3 cells 109/L) within 12 months of screening and evidence of elevated blood eosinophilia levels (>0.3 cells 109/L) at screening. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Exclusion Criteria: QTcF ≥450 msec; or QTcF ≥ 480 msec in subjects with Bundle Branch Block. AST, ALT, alkaline phosphatase and bilirubin ≥ 1.5xULN (isolated bilirubin <1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin ≥35%). Subjects with elevated blood eosinophil levels which is not related to asthma Current smokers (any subject who has smoked within the six months prior to screening or has a positive urine cotinine at screening) or subjects with a smoking history of >10 pack years calculated as follows: Number of cigarettes per day X number of years smoked 20 Presence of a clinically important lung condition other than asthma including current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, Churg-Strauss syndrome, or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer. An asthma exacerbation or respiratory tract infection within six weeks prior to screening (an exacerbation is defined as worsening asthma requiring the use of systemic corticosteroids and/or emergency department visit, hospitalisation). Subjects with a parasitic infestation within six months of screening. A current malignancy or previous history of cancer in remission for less than five years prior screening (except for localized carcinoma of the skin that has been resected for cure). Subjects who have clinically significant cardiovascular, endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Subjects with a known immunodeficiency (e.g. human immunodeficiency virus - HIV). A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within three months of screening. Subjects who have received omalizumab [Xolair] within 130 days of administration of the first dose of study medication. Subjects with recent history (within two years prior to screening) of alcohol misuse or substance abuse prior screening. A positive pre-study drug/alcohol test at screening. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, five half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Subjects who have previously participated in a study of mepolizumab and received study medication within 90 days prior to screening. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within seven days (or 14 days if the drug is a potential enzyme inducer) or five half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. Exposure to live vaccine within the four weeks prior to screening and no intention to receive live vaccine during the study. History of sensitivity to the study medications (or components thereof) or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. Pregnant or lactating females; pregnancy as determined by positive pregnancy test at screening or prior to dosing.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mepolizumab 250 mg subcutaneous (SC)<br>250 mg subcutaneous (SC) | Biological: Mepolizumab<br>* Monoclonal antibody<br>|
| Experimental: Mepolizumab 125 mg subcutaneous (SC)<br>125 mg subcutaneous (SC) | Biological: Mepolizumab<br>* Monoclonal antibody<br>|
| Experimental: Mepolizumab 12.5 mg subcutaneous (SC)<br>12.5 mg subcutaneous (SC) | Biological: Mepolizumab<br>* Monoclonal antibody<br>|
| Experimental: Mepolizimab 75 mg intravenously (I.V.)<br>75 mg intravenously (I.V.) | Biological: Mepolizumab<br>* Monoclonal antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Blood Eosinophil Levels at Week 12 (Day 84) | Change from Baseline in blood eosinophils was calculated as the post-Baseline value minus the Baseline value. The change from Baseline in log-transformed blood eosinophil levels at Week 12 was analyzed using both a linear and non-linear (Imax) dose response models. The dose response was found to be non-linear and hence only the results of the non-linear model are presented. Mepolizumab 75mg IV assumed to equate to 100 mg SC within model. Prior to log10-transformation, zero values were imputed with half the minimum value across all dose groups and time points. An adjustment for Baseline eosinophil count was also incorporated into the model. | Baseline (Day 1 pre-dose) and Week 12 | 
| Area Under the Blood Eosinophil Time Curve (AUEC) up to Day 84 | Area under the absolute blood eosinophil time curve to Day 84 (AUECeos[0-day 84]) determined using the linear trapezoidal rule for subset of participants with blood eosinophil data to Day 84. Blood samples for the analyses of AUEC(eos) (0-day 84) were collected at Days 1, 3, 7, 28, 56, 70 and 84. | Days 1, 3, 7, 28, 56, 70 and 84 | 
| Maximum Change From Baseline in Blood Eosinophils (Emax) | Blood samples were collected at Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 to assess the maximum reduction from Baseline in blood eosinophils between Day 1 pre-dose and last quantifiable study measurement. Change from Baseline was calculated as the ratio of the post-Baseline value divided by the Baseline value. The maximum reduction from Baseline in eosinophils is represented by the minimum ratio to Baseline. | Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 | 
| Time to Maximum Change in Blood Eosinophils Levels (Tmaxeos) | Blood samples were collected at Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 to assess the time to first occurrence of maximum reduction from baseline in blood eosinophil levels between Day 1 pre-dose and last quantifiable study measurement. | Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 | 
| Number of Participants Who Achieved >=50% Eosinophil Repletion by Day 140 | This summarizes the number of participants who returned to at least 50% of their Baseline blood eosinophil levels after maximum inhibition had been achieved and without any subsequent decrease in blood eosinophil levels. Blood samples were collected at Days 1, 3, 7, 28, 56, 70, 84, 112 and 140. | Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 | 
| Mean Area Under the Plasma-concentration Time Curve (AUC) Following SC and IV Administration of Mepolizumab | AUC of mepolizumab was estimated by population modeling techniques using non-linear mixed effect methods for the individual and population pharmacokinetic parameters from the sparse sampling. Individual cumulative plasma of mepolizumab AUC to Day 84 (cumAUC(0-day 84)), is the sum of the AUCs over each dosing interval after each of the three doses administered, for those participants with data up to Day 84. Individual cumulative plasma of mepolizumab AUC to Day 140 (cumAUC(0-day 140) is the sum of the AUCs over each dosing interval after each of the three doses administered plus the AUC post the last dose interval up to Day 140 (i.e. from Day 84 to Day 140). Blood samples for PK analyses were collected on dosing days (Days 1, 28 and 56) at pre-dose and 0.5 hour (h), 1 h and 2 h post-dose (time was relative to the end of infusion in the IV cohort) as well as on Days 3, 7, 70, 84, 112 and 140 (follow-up visit). | Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 | 
| Maximum Plasma Concentration (Cmax) From Pre-dose (Day 1) to Day 140 for Mepolizumab | Maximum plasma concentration was estimated by population modelling techniques using non-linear mixed effect methods for the individual and population pharmacokinetic parameters from the sparse sampling. Blood samples for PK analyses of mepolizumab were collected on dosing days (Days 1, 28 and 56) at pre-dose and 0.5 h, 1 h and 2 h post-dose (time was relative to the end of infusion in the IV cohort) as well as on Days 3, 7, 70, 84, 112 and 140 (follow-up visit). | Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 | 
| Time to Maximum Plasma Concentration (Tmax) From Pre-dose (Day 1) to Day 140 for Mepolizumab | Time to maximum plasma concentration was estimated by population modelling techniques using non-linear mixed effect methods for the individual and population pharmacokinetic parameters from the sparse sampling. Blood samples for PK analyses of mepolizumab were collected on dosing days (Days 1, 28 and 56) at pre-dose and 0.5 h, 1 h and 2 h post-dose (time was relative to the end of infusion in the IV cohort) as well as on Days 3, 7, 70, 84, 112 and 140 (follow-up visit). | Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 | 
| Terminal Half-life (t½) From Pre-dose (Day 1) to Day 140 for Mepolizumab | Terminal half-life (t1/2) was estimated by modelling techniques using non-linear mixed effect methods for the individual and population pharmacokinetic parameters for mepolizumab from the sparse sampling. Blood samples for PK analyses of mepolizumab were collected on dosing days (Days 1, 28 and 56) at pre-dose and 0.5 h, 1 h and 2 h post-dose (time was relative to the end of infusion in the IV cohort) as well as on Days 3, 7, 70, 84, 112 and 140 (follow-up visit). | Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Chemistry Parameters Outside the Normal Range Following Treatment | Clinical chemistry laboratory parameters included blood urea nitrogen (BUN), potassium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB) and direct bilirubin, creatinine, chloride, uric acid, glucose, total carbondioxide (CO2), gamma glutamyltransferase (GGT), albumin, sodium, calcium, alkaline phosphatase (ALP) and total protein assessed at Baseline, Weeks 4, 8, 12 and 20. Laboratory abnormalities outside the normal range (high and low values) at any time post-Baseline are presented. | Baseline (Day 1 pre-dose), Weeks 4, 8, 12 and 20 | 
| Number of Participants With Hematology Laboratory Parameters Outside the Normal Range at Following Treatment | Hematology laboratory parameters included platelet count, red blood cells (RBC) count, white blood cell (WBC) count, hemoglobin, hematocrit, reticulocyte count, mean corpuscle volume (MCV), mean corpuscle hemoglobin (MCH), mean corpuscle hemoglobin concentration (MCHC), neutrophils, segmented neutrophils (SN), total neutrophils (TN), lymphocytes, monocytes, eosinophils and basophils assessed at Baseline, Weeks 4, 8, 12 and 20. Hematology abnormalities outside the normal range (high and low values) at any time post-Baseline are presented. | Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 (follow-up visit) | 
| Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Assessed at Baseline, Day 1, Day 28, Day 56, Day 84, Day 112 and Day 140 | Vital sign measurements including systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured at Baseline (pre-dose Day 1), Day 1 (30 minutes, 1 h, 2 h), Day 28 (pre-dose, 30 minutes, 1 h, 2 h), Day 56 (pre-dose, 30 minutes, 1 h, 2 h), Day 84, Day 112 and follow-up (Day 140). | Baseline (Day 1 pre-dose) and at Day 1, Day 28, Day 56, Day 84, Day 112 and Day 140 | 
| Change From Baseline in Heart Rate Assessed at Baseline, Day 1, Day 28, Day 56, Day 84, Day 112 and Day 140 | Vital sign measurements including heart rate (HR) was measured at Baseline (Pre-dose Day 1), Day 1 (30 minutes, 1 h, 2 h), Day 28 (pre-dose, 30 minutes, 1 h, 2 h), Day 56 (pre-dose, 30 minutes, 1 h, 2 h), Day 84, Day 112 and follow-up (Day 140). | Baseline (Day 1 pre-dose) and at Day 1, Day 28, Day 56, Day 84, Day 112 and Day 140 | 
| Number of Participants With Levels of Anti-mepolizumab Antibodies at Indicated Time Points | Blood samples were collected for the determination of anti-mepolizumab antibodies by antibody detection (AD) and antibody neutralisation (AN) assay. For participants who prematurely withdrew from the study and had been dosed, immunogenicity testing occurred (if possible) at the time of premature withdrawal and at 16 weeks after dosing (or the end of the study, whichever came first). Serum was tested for the presence of anti-mepolizumab antibodies using the currently approved analytical methodology incorporating screening, confirmation and titration steps. Samples confirmed positive for the presence of anti-mepolizumab antibodies in the original assay were tested for the presence of neutralizing antibodies. | Day 1, Day 112 and Day 140 | 
| Number of Participants With the Indicated Electrocardiogram (ECG) Findings at Screening and Day 3 | The number of participants with normal, abnormal - clinically significant (CS), and abnormal - not clinically significant (NCS) ECG findings, as well as the number of participants with no results (NR), at Screening (SCR) and Day 3 are presented. Findings were determined to be normal, abnormal CS, and NCS by the investigator. | Screening (SCR) and at Day 3 | 
| Mean AUC to Assess the Absolute Bioavailability of SC Mepolizumab | Population modelling techniques using non-linear mixed effect methods were used to estimate individual and population pharmacokinetic parameters from the sparse sampling. Log-transformed individual clearance estimates were analysed using an analysis of variance (ANOVA) model. The absolute bioavailability for each SC dose group and across SC doses will be estimated from the model together with associated 90% confidence intervals. Blood samples for PK analyses were collected on dosing days (Days 1, 28 and 56) at pre-dose and 0.5 h, 1 h and 2 h post-dose (time was relative to the end of infusion in the IV cohort) as well as on Days 3, 7, 70, 84, 112 and 140 (follow-up visit). | Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 | 
| Mean Dose Normalized Cmax Ratio to Assess the Relative Bioavailability of SC Mepolizumab as Compared With IV Mepolizumab | Maximum plasma concentration was estimated by population modelling techniques using non-linear mixed effect methods for the individual and population pharmacokinetic parameters from the sparse sampling. Log-transformed dose-normalized (DM) Cmax were be analyzed using an analysis of variance (ANOVA) model. The ratio for each SC dose group versus IV and across SC doses versus IV will be estimated from the model together with associated 90% confidence intervals. Blood samples for PK analyses of mepolizumab were collected on dosing days (Days 1, 28 and 56) at pre-dose and 0.5 h, 1 h and 2 h post-dose (time was relative to the end of infusion in the IV cohort) as well as on Days 3, 7, 70, 84, 112 and 140 (follow-up visit). | Days 1, 3, 7, 28, 56, 70, 84, 112 and 140 |