Pharmacodynamic Biomarkers to Support Biosimilar Development: Interleukin-5 Antagonists

NCT04183192 | Completed Phase 1 Results FDA Drug

• 1 other identifier: SCR-006
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Subjects; Pharmacokinetics; Pharmacodynamics

Keywords

Pharmacokinetics; Pharmacodynamics

Outcome Measures

Primary Outcomes (2)

• Area Under Effect Curve (AUEC) for Eosinophils for Mepolizumab and Reslizumab

  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.

  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.

• Maximum Change From Baseline for Eosinophils for Mepolizumab and Reslizumab

  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.

  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.

Secondary Outcomes (8)

• 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.

• 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.

• 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.

• 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.

• 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.

Study Arms (9)

Arm A: Mepolizumab low dose

EXPERIMENTAL

Single dose of mepolizumab 3 mg SC

Biological: Mepolizumab

Arm B: Mepolizumab low intermediate dose

EXPERIMENTAL

Single dose of mepolizumab 6 mg SC

Biological: Mepolizumab

Arm C: Mepolizumab high intermediate dose

EXPERIMENTAL

Single dose of mepolizumab 12 mg SC

Biological: Mepolizumab

Arm D: Mepolizumab high dose

EXPERIMENTAL

Single dose of mepolizumab 24 mg SC

Biological: Mepolizumab

Arm E: Reslizumab low dose

EXPERIMENTAL

Single dose of reslizumab 0.1 mg/kg IV

Biological: Reslizumab

Arm F: Reslizumab intermediate low dose

EXPERIMENTAL

Single dose of reslizumab 0.2 mg/kg IV

Biological: Reslizumab

Arm G: Reslizumab high intermediate dose

EXPERIMENTAL

Single dose of reslizumab 0.4 mg/kg IV

Biological: Reslizumab

Arm H: Reslizumab high dose

EXPERIMENTAL

Single dose of reslizumab 0.8 mg/kg IV

Biological: Reslizumab

Arm I: Placebo

PLACEBO COMPARATOR

Single dose of placebo

Biological: Placebo

Interventions

Mepolizumab BIOLOGICAL

Mepolizumab 3 mg administered SC

Arm A: Mepolizumab low dose

Reslizumab BIOLOGICAL

Reslizumab 0.1 mg/kg administered IV

Arm E: Reslizumab low dose

Placebo BIOLOGICAL

Placebo (administered either IV or SC)

Arm I: Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Food and Drug Administration (FDA): lead
• Spaulding Clinical Research LLC: collaborator

Study Sites (1)

Spaulding Clinical Research

West Bend, Wisconsin, 53095, United States

Location

MeSH Terms

Interventions

mepolizumab; reslizumab

Results Point of Contact

• Title: David Strauss, MD, PhD
• Organization: U.S. Food and Drug Administration

David.Strauss@fda.hhs.gov

3017966323

Study Officials

• Jennifer Deering, MSN, APNP

  Spaulding Clinical Research LLC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: The pharmacist (and designated staff member responsible for confirmation of study drug dose) will be unblinded to subject treatment assignment; however, the pharmacist will not perform any study procedures other than study drug preparation and dispensing. Subjects and staff will be blinded to treatment assignment during confinement, but route of administration will not be blinded. The blind will be maintained through a randomization schedule held by the dispensing pharmacist. Subjects and staff will be informed of a subject's end of study day when discharged from confinement. Subjects and staff will not be informed of the specific treatment arm assignment. The clinical research nurse will administer the study drugs in unit dose containers that are not transparent.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: Subjects will be randomized to one of four dose groups (low, intermediate low, intermediate high, and high) of each drug (mepolizumab or reslizumab) or placebo

Study Record Dates

• First Submitted: November 27, 2019
• First Posted: December 3, 2019
• Study Start: February 17, 2020
• Primary Completion: April 4, 2021
• Study Completion: April 4, 2021
• Last Updated: April 22, 2024
• Results First Posted: April 22, 2024

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: April, 2022. Materials will be available indefinitely.

Locations

US (1)