Pharmacodynamic Biomarkers to Support Biosimilar Development: Interleukin-5 Antagonists

Phase 1

Completed

Conditions: Healthy Subjects
Pharmacokinetics
Pharmacodynamics

Interventions: Biological: Mepolizumab
Biological: Reslizumab
Biological: Placebo

Registration Number: NCT04183192

Lead Sponsor: Food and Drug Administration (FDA)

Brief Summary: This study is designed to assess pharmacokinetics and pharmacodynamics of mepolizumab and reslizumab across an appropriate dose range to inform clinical trial operating characteristics for future clinical pharmacology pharmacodynamics similarity studies.

This is a randomized, placebo-controlled, single-dose, parallel arm study in 72 healthy subjects assigned to one of four dose groups (low, intermediate low, intermediate high, and high) of each drug (mepolizumab or reslizumab) or placebo.

Detailed Description: This study is designed to assess pharmacokinetics and pharmacodynamics of mepolizumab and reslizumab across an appropriate dose range to inform clinical trial operating characteristics for future clinical pharmacology pharmacodynamics similarity studies.

This is a randomized, placebo-controlled, single-dose, parallel arm study in 72 healthy subjects assigned to one of four dose groups (low, intermediate low, intermediate high, and high) of each drug (mepolizumab or reslizumab) or placebo. Mepolizumab doses are 3, 6, 12, or 24 mg. Reslizumab doses are 0.1, 0.2, 0.4, or 0.8 mg/kg. Each arm will include 8 subjects (4 male and 4 female).

Subjects will be admitted for treatment on day -1 and receive a single dose of study drug or placebo on day 1. Depending on the treatment arm, subjects will remain in confinement for two weeks and continue follow-up through either day 63 or day 123.

Blood samples (approximately 5 mL per sample) will be collected for determination of plasma concentrations for study drug. Additional blood samples will be collected for determination of eosinophil counts (5 mL per sample; pharmacodynamic measure) and exploratory proteomics analyses (5 mL per sample).

Safety evaluations will include adverse event (AE) monitoring, vital sign measurements, and physical examinations. All AEs reported by the subject or observed by the investigator or clinical research unit (CRU) staff will be recorded. Any AE reported after the informed consent is signed and before study drug application will be recorded as medical history.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 72

Inclusion Criteria

Subject signs an institutional review board approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act authorization) before any study related procedures are performed.
Subject is a healthy man or woman, 18 to 55 years of age, inclusive, who has a body mass index of 18.5 to 29.9 kg/m2, inclusive, at Screening.
Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12 lead electrocardiogram (ECG) results, and physical examination findings at screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee).
Subject must have a negative test result for alcohol and drugs of abuse at screening and Check-in (Day -1).
Subject has a peripheral blood eosinophil count of ≥50 and ≤700 cells per microliter of blood as measured by a standard hematology analyzer.
Female subjects must be of non-childbearing potential or, if they are of childbearing potential, they must: 1) have been strictly abstinent for 1 month before Check in (Day -1) and agree to remain strictly abstinent for the duration of the study and for at least 1month after the last application of study drug; OR 2) be practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from at least 1 month before Check in (Day -1) until at least 1 month after the end of the study.
Male subjects must agree to practice 1 highly effective method of birth control (as determined by the investigator or designee) from at least 1 month before Check in (Day -1) until at least 1 month after the end of the study.
Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study

Exclusion Criteria

Subject is taking any medication known to affect leukocyte population numbers.
Subject is anemic (i.e., with Hct or Hgb less than the lower limit of normal) or has any chronic condition(s) that may impact blood sample collection.
Subject has had previous exposure to the biologic mepolizumab or reslizumab.
Subject has a history of asthma.
Subject has a history of anaphylaxis from environmental exposures such as peanuts or bee stings.
Subject has an allergic history that includes urticaria, angioedema or respiratory coughing or bronchospasm.
Subject has a history of severe local reactions or generalized erythema from skin allergen testing.
Subject is anemic or has any chronic condition(s) that may impact blood sample collection.
Subject has used any prescription or nonprescription drugs (including aspirin or NSAIDs and excluding oral contraceptives and acetaminophen) within 14 days or 5 half-lives (whichever is longer) or complementary and alternative medicines within 28 days before the first dose of study drug.
Subjects are currently participating in another clinical study of an investigational drug or are have been treated with any investigational drug within 30 days or 5 half-lives (whichever is longer) of the compound.
Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks of Screening.
Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee, chocolate, cola), caffeine, grapefruit, or grapefruit juice within 48 hours of dosing. Subjects must refrain from ingesting these throughout the study.
Subject has any underlying disease or surgical or medical condition (e.g., cancer, human immunodeficiency virus [HIV], severe hepatic or renal impairment) that could put the subject at risk or would normally prevent participation in a clinical study. This includes subjects with any underlying medical conditions that put subjects at higher risk for coronavirus disease of 2019 (COVID-19) complications; per current Center for Disease Control and Prevention (CDC) recommendations this includes:
- People with chronic lung disease or moderate to severe asthma
- People who have serious heart conditions
- People who are immunocompromised
- Many conditions can cause a person to be immunocompromised, including cancer treatment, smoking, bone marrow or organ transplantation, immune deficiencies, poorly controlled HIV, and prolonged use of corticosteroids and other immune weakening medications
- People with severe obesity (body mass index [BMI] of 40 or higher)
- People with diabetes
- People with chronic kidney disease undergoing dialysis
- People with liver disease
Subject has any signs or symptoms that are consistent with COVID-19. Per current CDC recommendations this includes subjects with the symptoms cough or shortness of breath or difficulty breathing, or at least two of the following symptoms: fever, chills, repeated shaking with chills, muscle pain, headache, sore throat or new loss of taste/smell. In addition, the subject has any other findings suggestive of COVID-19 risk in the opinion of the investigator.
Subject tests positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by a molecular diagnostic test performed prior to admission.
Subject has known or suspected allergies or sensitivities to any study drug.
Subject has clinical laboratory test results (hematology, serum chemistry) at Screening that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator.
Subject has a positive test result at Screening for HIV 1 or 2 antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.
Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or poor venous access.
Female subjects are pregnant or lactating before enrollment in the study.
Subject is known to have, or is suspected to have, a parasitic infection.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A: Mepolizumab low dose	Mepolizumab	Single dose of mepolizumab 3 mg SC
Arm D: Mepolizumab high dose	Mepolizumab	Single dose of mepolizumab 24 mg SC
Arm E: Reslizumab low dose	Reslizumab	Single dose of reslizumab 0.1 mg/kg IV
Arm B: Mepolizumab low intermediate dose	Mepolizumab	Single dose of mepolizumab 6 mg SC
Arm H: Reslizumab high dose	Reslizumab	Single dose of reslizumab 0.8 mg/kg IV
Arm C: Mepolizumab high intermediate dose	Mepolizumab	Single dose of mepolizumab 12 mg SC
Arm I: Placebo	Placebo	Single dose of placebo
Arm F: Reslizumab intermediate low dose	Reslizumab	Single dose of reslizumab 0.2 mg/kg IV
Arm G: Reslizumab high intermediate dose	Reslizumab	Single dose of reslizumab 0.4 mg/kg IV

Primary Outcome Measures

Name	Time	Method
Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab	Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I.	The values and variability of AUEC for eosinophils at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab. AUEC was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Calculations were performed using non-compartmental analysis packages available in R software.
Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab	Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I.	The values and variability of maximal change from baseline for eosinophils at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab. Values are percentage change from baseline.

Secondary Outcome Measures

Name	Time	Method
Area Under the Curve (AUC) for Mepolizumab and Reslizumab	0 (pre-dose), 1, 4, 12, 24, hours post-dose; once daily from Day 3 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, and H.	The values and variability of AUC at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab.
Maximum Concentration (Cmax) for Mepolizumab and Reslizumab	0 (pre-dose), 1, 4, 12, 24, hours post-dose; once daily from Day 3 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, and H.	The values and variability of Cmax at low, intermediate low, intermediate high, and high doses of mepolizumab and reslizumab.
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Area Under the Effect Curve Versus Dose Emax Model for Reslizumab	Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms E, F and until Day 123 post-dose for Arms G, H, and I.	The model parameter (ED50, units mg/kg) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of reslizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Maximum Change From Baseline Curve Versus Dose Emax Model Mepolizumab	Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, and until Day 123 post-dose for Arms C, D, and I.	The model parameter (ED50, units mg) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Maximum Change From Baseline Curve Versus Dose Emax Model Reslizumab	Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms E, F and until Day 123 post-dose for Arms G, H, and I.	The model parameter (ED50, units mg/kg) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of reslizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.
Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Maximum Change From Baseline Versus Dose Emax Models With Mepolizumab or Reslizumab	Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I.	The model parameter (Emax, units percentage change from baseline) from an Emax model for eosinophil maximum change from baseline versus dose was calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab or reslizumab with placebo data. Maximum change from baseline (units of percentage change from baseline) was calculated as percentage change from baseline and considered all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.
Pharmacodynamic Model Parameters (Maximum Effect [Emax]) for Eosinophil Area Under the Effect Curve Versus Dose Emax Models for Mepolizumab or Reslizumab	Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, E, F and until Day 123 post-dose for Arms C, D, G, H, and I.	The model parameter (Emax, units percentage change from baseline \* day) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab or reslizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for Eosinophil Area Under the Effect Curve Versus Dose Emax Model for Mepolizumab	Day -1 and 0h (pre-dose), 24h (post-dose); once daily from Day 2 onwards until Day 14 post-dose; once weekly from Day 21 onwards until Day 63 post-dose for Arms A, B, and until Day 123 post-dose for Arms C, D, and I.	The model parameter (ED50, units mg) from an Emax model for eosinophil area under the effect curve versus dose were calculated after combining data from low, intermediate low, intermediate high, and high doses of mepolizumab with placebo data. AUEC (units of percentage change from baseline \* day) was calculated as percentage change from baseline and used all measures from time zero to the last sample collected on study. Model-analyses were conducted using the DoseFinding package available in R software. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 2500 repetitions.