Pharmacodynamic Biomarkers to Support Biosimilar Development: PCSK9 Inhibitors

NCT04189484 | Completed Phase 1 Results FDA Drug

• 1 other identifier: SCR-007
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

Brief Summary

This study is designed to assess pharmacokinetics and pharmacodynamics of evolocumab and alirocumab 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 (evolocumab and alirocumab ) or placebo.

Conditions

Healthy Subjects; Pharmacokinetics; Pharmacodynamics

Keywords

Pharmacokinetics; Pharmacodynamics

Outcome Measures

Primary Outcomes (2)

• Baseline-adjusted Area Under Effect Curve (AUEC) for LDL-C for Evolocumab and Alirocumab

  The values and variability of AUEC for LDL-C at low, intermediate-low, intermediate-high, and high doses of evolocumab and alirocumab. AUEC was calculated as the baseline-subtracted area under the LDL-C concentration-time curve expressed in units of mg/(dL\*day). More negative AUEC values represent greater reductions in LDL-C exposure from baseline. The standard deviation is noted in parentheses. For each subject and dose, the maximum decrease from baseline LDL-C was determined using all sampled timepoints. AUEC values were log-transformed and an ANCOVA model was used to calculate geometric means and 90% confidence intervals for each treatment group.

  Day -1 and 0h (pre-dose), 24h (post-dose); once on Day 2, 3, 4, 5, 7, 10, 14, 21, 28, 35, and 42 for all Arms. Additionally, once on Day 56 for Arms C, D, G, H, & I; and once on Day 70 and 84 for Arms D, H, & I.

• Maximum Change From Baseline for LDL-C for Evolocumab and Alirocumab

  The values and variability of maximum change from baseline for LDL-C at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab

  Day -1 and 0h (pre-dose), 24h (post-dose); once on Day 2, 3, 4, 5, 7, 10, 14, 21, 28, 35, and 42 for all Arms. Additionally, once on Day 56 for Arms C, D, G, H, & I; and once on Day 70 and 84 for Arms D, H, & I.

Secondary Outcomes (7)

• Baseline-adjusted AUEC for Apolipoprotein B (ApoB) for Evolocumab and Alirocumab

  Day -1 and 0h (pre-dose), 24h (post-dose); once on Day 2, 3, 4, 5, 7, 10, 14, 21, 28, 35, and 42 for all Arms. Additionally, once on Day 56 for Arms C, D, G, H, & I; and once on Day 70 and 84 for Arms D, H, & I.

• Maximum Change From Baseline for apoB for Evolocumab and Alirocumab

  Day -1 and 0h (pre-dose), 24h (post-dose); once on Day 2, 3, 4, 5, 7, 10, 14, 21, 28, 35, and 42 for all Arms. Additionally, once on Day 56 for Arms C, D, G, H, & I; and once on Day 70 and 84 for Arms D, H, & I.

• Maximum Concentration (Cmax) for Evolocumab and Alirocumab

  0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8,12, 24, hours post-dose; once on Day 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 35, and 42 for all Arms. Additionally, once on Day 56 for Arms C, D, G, H, & I; and once on Day 70 and 84 for Arms D, H, & I.

• Area Under the Curve (AUC) for Evolocumab and Alirocumab

  0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8,12, 24, hours post-dose; once on Day 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 35, and 42 for all Arms. Additionally, once on Day 56 for Arms C, D, G, H, & I; and once on Day 70 and 84 for Arms D, H, & I.

• Dose-response Parameters (Slope) for LDL-C Area Under the Effect Curve Models for Evolocumab and Alirocumab

  Day -1 and 0h (pre-dose), 24h (post-dose); once on Day 2, 3, 4, 5, 7, 10, 14, 21, 28, 35, and 42 for all Arms. Additionally, once on Day 56 for Arms C, D, G, H, & I; and once on Day 70 and 84 for Arms D, H, & I.

Study Arms (9)

Arm A: Evolocumab low dose

EXPERIMENTAL

Single dose of evolocumab 21 mg subcutaneous (SC)

Biological: Evolocumab

Arm B: Evolocumab intermediate low dose

EXPERIMENTAL

Single dose of evolocumab 35 mg SC

Biological: Evolocumab

Arm C: Evolocumab intermediate high dose

EXPERIMENTAL

Single dose of evolocumab 70 mg SC

Biological: Evolocumab

Arm D: Evolocumab high dose

EXPERIMENTAL

Single dose of evolocumab 140 mg SC

Biological: Evolocumab

Arm E: Alirocumab low dose

EXPERIMENTAL

Single dose of alirocumab 15 mg SC

Biological: Alirocumab

Arm F: Alirocumab intermediate low dose

EXPERIMENTAL

Single dose of alirocumab 25 mg SC

Biological: Alirocumab

Arm G: Alirocumab intermediate high dose

EXPERIMENTAL

Single dose of alirocumab 50 mg SC

Biological: Alirocumab

Arm H: Alirocumab high dose

EXPERIMENTAL

Single dose of alirocumab 100 mg SC

Biological: Alirocumab

Arm I: Placebo

PLACEBO COMPARATOR

Single dose of placebo SC

Biological: Placebo

Interventions

Evolocumab BIOLOGICAL

Evolocumab 21 mg administered SC

Arm A: Evolocumab low dose

Alirocumab BIOLOGICAL

Alirocumab 15 mg administered SC

Arm E: Alirocumab low dose

Placebo BIOLOGICAL

Placebo administered 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 (IRB)-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 32 kg/m2, inclusive, at Screening.
• Subject has a LDL-C level \>=100 and \<=190 mg/dL 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).
• 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 1 month 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 last application of study drug.
• 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 last application of study drug.
• Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures as to complete the study.

You may not qualify if:

• Subject is taking cholesterol medication (e.g. statins).
• Subject is anemic (i.e., with hematocrit or hemoglobin 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 evolocumab or alirocumab.
• 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 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

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

evolocumab; alirocumab

Results Point of Contact

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

David.Strauss@fda.hhs.gov

3017966323

Study Officials

• Colleen Nalepinski, MPAS, PA-C

  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. 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 subcutaneous study drug 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 (evolocumab or alirocumab) or placebo

Study Record Dates

• First Submitted: December 2, 2019
• First Posted: December 6, 2019
• Study Start: January 7, 2020
• Primary Completion: April 7, 2021
• Study Completion: April 7, 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)