Healthy Subjects, Pharmacodynamics, Pharmacokinetics
Conditions
Keywords
Pharmacokinetics, Pharmacodynamics
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.
Detailed description
This study is designed to assess pharmacokinetics and pharmacodynamics of evolocumab and alirocumab, two monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), 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 or alirocumab) or placebo. Evolocumab doses are 21, 35, 70, and 140 mg. Reslizumab doses are 15, 25, 50, and 100 mg . 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 one week and continue follow-up through day 42, 56, or 84. 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 lipid analysis and determination of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) (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.
Interventions
BIOLOGICALEvolocumab
Evolocumab 21 mg administered SC
BIOLOGICALAlirocumab
Alirocumab 15 mg administered SC
BIOLOGICALPlacebo
Placebo administered SC
Sponsors
Spaulding Clinical Research LLC
Food and Drug Administration (FDA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Masking description
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.
Intervention model description
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
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. 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. 2. 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. 3. Subject has a LDL-C level \>=100 and \<=190 mg/dL inclusive, at Screening. 4. 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). 5. Subject must have a negative test result for alcohol and drugs of abuse at screening and Check-in (Day -1). 6. 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. 7. 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. 8. Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures as to complete the study.
Exclusion criteria
1. Subject is taking cholesterol medication (e.g. statins). 2. 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. 3. Subject has had previous exposure to the biologic evolocumab or alirocumab. 4. Subject has a history of asthma. 5. Subject has a history of anaphylaxis from environmental exposures such as peanuts or bee stings. 6. Subject has an allergic history that includes urticaria, angioedema or respiratory coughing or bronchospasm. 7. Subject has a history of severe local reactions or generalized erythema from skin allergen testing. 8. 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. 9. 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. 10. Subject has used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks of Screening. 11. 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. 12. 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 (BMI of 40 or higher) * People with diabetes * People with chronic kidney disease undergoing dialysis * People with liver disease 13. 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. 14. Subject tests positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by a molecular diagnostic test performed prior to admission. 15. Subject has known or suspected allergies or sensitivities to any study drug. 16. Subject has clinical laboratory test results (hematology, serum chemistry lipid panel and comprehensive metabolic panel) at Screening that are outside the reference ranges provided by the clinical laboratory and considered clinically significant by the investigator. 17. Subject has a positive test result at Screening for human immunodeficiency virus (HIV) 1 or 2 antibody, hepatitis C virus load, hepatitis C virus antibodies, or hepatitis B surface antigen. 18. Subject is unable or unwilling to undergo multiple venipunctures for blood sample collection because of poor tolerability or poor venous access. 19. Female subjects are pregnant or lactating before enrollment in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline-adjusted Area Under Effect Curve (AUEC) for LDL-C 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. | 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. |
| Maximum Change From Baseline for LDL-C 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. | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | The values and variability of Cmax at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab |
| 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. | The values and variability of AUC at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab |
| 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. | The values and variability of AUEC for ApoB at low, intermediate-low, intermediate-high, and high doses of evolocumab and alirocumab. AUEC was calculated as the baseline-subtracted area under the ApoB concentration-time curve expressed in units of mg/(dL\*day). More negative AUEC values represent greater reductions in ApoB exposure from baseline. The standard deviation is noted in parentheses. For each subject and dose, the maximum decrease from baseline ApoB 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. |
| Pharmacodynamic Model Parameter, Maximum Effect (Emax), for LDL-C Maximum Change From Baseline Models With 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. | Model parameter (Emax) for LDL-C maximum change from baseline curve models calculated after combining data from low, intermediate low, intermediate high, and high doses of evolocumab or alirocumab with placebo data. |
| Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for LDL-C Maximum Change From Baseline Models With 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. | Model parameter (ED50) for LDL-C maximum change from baseline curve models calculated after combining data from low, intermediate low, intermediate high, and high doses of evolocumab or alirocumab with placebo data. |
| 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. | Model parameter (slope) for LDL-C area under the effect curve model: Mean slope value calculated after combining data from low, intermediate low, intermediate high, and high doses of evolocumab or alirocumab with placebo data. The units of measure for slope are mg/dL•day / (mg dose). |
| 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. | The values and variability of maximal difference at a single time-point for ApoB at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Evolocumab Low Dose Single dose of evolocumab 21 mg subcutaneous (SC)
Evolocumab: Evolocumab 21 mg administered SC | 8 |
| Arm B: Evolocumab Intermediate Low Dose Single dose of evolocumab 35 mg SC
Evolocumab: Evolocumab 35 mg administered SC | 8 |
| Arm C: Evolocumab Intermediate High Dose Single dose of evolocumab 70 mg SC
Evolocumab: Evolocumab 70 mg administered SC | 8 |
| Arm D: Evolocumab High Dose Single dose of evolocumab 140 mg SC
Evolocumab: Evolocumab 140 mg administered SC | 8 |
| Arm E: Alirocumab Low Dose Single dose of alirocumab 15 mg SC
Alirocumab: Alirocumab 15 mg administered SC | 8 |
| Arm F: Alirocumab Intermediate Low Dose Single dose of alirocumab 25 mg SC
Alirocumab: Alirocumab 25 mg administered SC | 8 |
| Arm G: Alirocumab Intermediate High Dose Single dose of alirocumab 50 mg SC
Alirocumab: Alirocumab 50 mg administered SC | 8 |
| Arm H: Alirocumab High Dose Single dose of alirocumab 100 mg SC
Alirocumab: Alirocumab 100 mg administered SC | 8 |
| Arm I: Placebo Single dose of placebo SC
Placebo: Placebo administered SC | 8 |
| Total | 72 |
Baseline characteristics
| Characteristic | Arm B: Evolocumab Intermediate Low Dose | Arm C: Evolocumab Intermediate High Dose | Arm D: Evolocumab High Dose | Arm E: Alirocumab Low Dose | Arm F: Alirocumab Intermediate Low Dose | Arm A: Evolocumab Low Dose | Arm G: Alirocumab Intermediate High Dose | Arm H: Alirocumab High Dose | Arm I: Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 37 years | 40 years | 33 years | 39 years | 31 years | 36 years | 36 years | 40 years | 41 years | 36 years |
| Body mass index | 27.0 kg/m^2 | 28.7 kg/m^2 | 29.5 kg/m^2 | 30.1 kg/m^2 | 27.9 kg/m^2 | 27.7 kg/m^2 | 28.6 kg/m^2 | 25.8 kg/m^2 | 26.8 kg/m^2 | 28.3 kg/m^2 |
| Body weight | 67 kg | 84 kg | 88 kg | 85 kg | 79 kg | 82 kg | 86 kg | 78 kg | 76 kg | 83 kg |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants | 3 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 7 Participants | 8 Participants | 7 Participants | 7 Participants | 8 Participants | 7 Participants | 4 Participants | 5 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 2 Participants | 4 Participants | 5 Participants | 4 Participants | 2 Participants | 2 Participants | 2 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 3 Participants | 6 Participants | 4 Participants | 2 Participants | 4 Participants | 6 Participants | 5 Participants | 5 Participants | 41 Participants |
| Region of Enrollment United States | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants | 72 participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 28 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 6 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 5 Participants | 44 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 | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 5 / 8 | 1 / 8 | 5 / 8 | 3 / 8 | 4 / 8 | 3 / 8 | 1 / 8 | 5 / 8 | 4 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
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.
Time frame: 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.
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Evolocumab Low Dose | Baseline-adjusted Area Under Effect Curve (AUEC) for LDL-C for Evolocumab and Alirocumab | -380 mg/dL*day | Standard Deviation 228 |
| Arm B: Evolocumab Intermediate Low Dose | Baseline-adjusted Area Under Effect Curve (AUEC) for LDL-C for Evolocumab and Alirocumab | -754 mg/dL*day | Standard Deviation 573 |
| Arm C: Evolocumab Intermediate High Dose | Baseline-adjusted Area Under Effect Curve (AUEC) for LDL-C for Evolocumab and Alirocumab | -866 mg/dL*day | Standard Deviation 658 |
| Arm D: Evolocumab High Dose | Baseline-adjusted Area Under Effect Curve (AUEC) for LDL-C for Evolocumab and Alirocumab | -1832 mg/dL*day | Standard Deviation 806 |
| Arm E: Alirocumab Low Dose | Baseline-adjusted Area Under Effect Curve (AUEC) for LDL-C for Evolocumab and Alirocumab | -580 mg/dL*day | Standard Deviation 360 |
| Arm F: Alirocumab Intermediate Low Dose | Baseline-adjusted Area Under Effect Curve (AUEC) for LDL-C for Evolocumab and Alirocumab | -581 mg/dL*day | Standard Deviation 319 |
| Arm G: Alirocumab Intermediate High Dose | Baseline-adjusted Area Under Effect Curve (AUEC) for LDL-C for Evolocumab and Alirocumab | -668 mg/dL*day | Standard Deviation 828 |
| Arm H: Alirocumab High Dose | Baseline-adjusted Area Under Effect Curve (AUEC) for LDL-C for Evolocumab and Alirocumab | -1902 mg/dL*day | Standard Deviation 361 |
| Arm I: Placebo | Baseline-adjusted Area Under Effect Curve (AUEC) for LDL-C for Evolocumab and Alirocumab | -350 mg/dL*day | Standard Deviation 881 |
Primary
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
Time frame: 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.
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Evolocumab Low Dose | Maximum Change From Baseline for LDL-C for Evolocumab and Alirocumab | -27.7 mg/dL | Standard Deviation 11.8 |
| Arm B: Evolocumab Intermediate Low Dose | Maximum Change From Baseline for LDL-C for Evolocumab and Alirocumab | -45.1 mg/dL | Standard Deviation 26.9 |
| Arm C: Evolocumab Intermediate High Dose | Maximum Change From Baseline for LDL-C for Evolocumab and Alirocumab | -49.9 mg/dL | Standard Deviation 26.2 |
| Arm D: Evolocumab High Dose | Maximum Change From Baseline for LDL-C for Evolocumab and Alirocumab | -70.1 mg/dL | Standard Deviation 25 |
| Arm E: Alirocumab Low Dose | Maximum Change From Baseline for LDL-C for Evolocumab and Alirocumab | -35.8 mg/dL | Standard Deviation 16.3 |
| Arm F: Alirocumab Intermediate Low Dose | Maximum Change From Baseline for LDL-C for Evolocumab and Alirocumab | -40.6 mg/dL | Standard Deviation 8.1 |
| Arm G: Alirocumab Intermediate High Dose | Maximum Change From Baseline for LDL-C for Evolocumab and Alirocumab | -47.9 mg/dL | Standard Deviation 18.8 |
| Arm H: Alirocumab High Dose | Maximum Change From Baseline for LDL-C for Evolocumab and Alirocumab | -54.6 mg/dL | Standard Deviation 12.1 |
| Arm I: Placebo | Maximum Change From Baseline for LDL-C for Evolocumab and Alirocumab | -30.1 mg/dL | Standard Deviation 18.7 |
Secondary
Area Under the Curve (AUC) for Evolocumab and Alirocumab
The values and variability of AUC at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab
Time frame: 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.
Population: Analysis population includes all subjects who did not discontinue before the end of study with at least one PK sample above the lower limit of quantification.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Evolocumab Low Dose | Area Under the Curve (AUC) for Evolocumab and Alirocumab | 2.4 mg/dL*day | Geometric Coefficient of Variation 67 |
| Arm B: Evolocumab Intermediate Low Dose | Area Under the Curve (AUC) for Evolocumab and Alirocumab | 0.8 mg/dL*day | Geometric Coefficient of Variation 91 |
| Arm C: Evolocumab Intermediate High Dose | Area Under the Curve (AUC) for Evolocumab and Alirocumab | 12.9 mg/dL*day | Geometric Coefficient of Variation 71 |
| Arm D: Evolocumab High Dose | Area Under the Curve (AUC) for Evolocumab and Alirocumab | 65.7 mg/dL*day | Geometric Coefficient of Variation 57 |
| Arm E: Alirocumab Low Dose | Area Under the Curve (AUC) for Evolocumab and Alirocumab | 8.3 mg/dL*day | Geometric Coefficient of Variation 55 |
| Arm F: Alirocumab Intermediate Low Dose | Area Under the Curve (AUC) for Evolocumab and Alirocumab | 17.1 mg/dL*day | Geometric Coefficient of Variation 57 |
| Arm G: Alirocumab Intermediate High Dose | Area Under the Curve (AUC) for Evolocumab and Alirocumab | 38.5 mg/dL*day | Geometric Coefficient of Variation 92 |
| Arm H: Alirocumab High Dose | Area Under the Curve (AUC) for Evolocumab and Alirocumab | 107.9 mg/dL*day | Geometric Coefficient of Variation 58 |
Secondary
Baseline-adjusted AUEC for Apolipoprotein B (ApoB) for Evolocumab and Alirocumab
The values and variability of AUEC for ApoB at low, intermediate-low, intermediate-high, and high doses of evolocumab and alirocumab. AUEC was calculated as the baseline-subtracted area under the ApoB concentration-time curve expressed in units of mg/(dL\*day). More negative AUEC values represent greater reductions in ApoB exposure from baseline. The standard deviation is noted in parentheses. For each subject and dose, the maximum decrease from baseline ApoB 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.
Time frame: 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.
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Evolocumab Low Dose | Baseline-adjusted AUEC for Apolipoprotein B (ApoB) for Evolocumab and Alirocumab | -207 mg/dL*day | Standard Deviation 313 |
| Arm B: Evolocumab Intermediate Low Dose | Baseline-adjusted AUEC for Apolipoprotein B (ApoB) for Evolocumab and Alirocumab | -482 mg/dL*day | Standard Deviation 434 |
| Arm C: Evolocumab Intermediate High Dose | Baseline-adjusted AUEC for Apolipoprotein B (ApoB) for Evolocumab and Alirocumab | -676 mg/dL*day | Standard Deviation 453 |
| Arm D: Evolocumab High Dose | Baseline-adjusted AUEC for Apolipoprotein B (ApoB) for Evolocumab and Alirocumab | -1094 mg/dL*day | Standard Deviation 952 |
| Arm E: Alirocumab Low Dose | Baseline-adjusted AUEC for Apolipoprotein B (ApoB) for Evolocumab and Alirocumab | -469 mg/dL*day | Standard Deviation 290 |
| Arm F: Alirocumab Intermediate Low Dose | Baseline-adjusted AUEC for Apolipoprotein B (ApoB) for Evolocumab and Alirocumab | -462 mg/dL*day | Standard Deviation 231 |
| Arm G: Alirocumab Intermediate High Dose | Baseline-adjusted AUEC for Apolipoprotein B (ApoB) for Evolocumab and Alirocumab | -128 mg/dL*day | Standard Deviation 536 |
| Arm H: Alirocumab High Dose | Baseline-adjusted AUEC for Apolipoprotein B (ApoB) for Evolocumab and Alirocumab | -1087 mg/dL*day | Standard Deviation 707 |
| Arm I: Placebo | Baseline-adjusted AUEC for Apolipoprotein B (ApoB) for Evolocumab and Alirocumab | -428 mg/dL*day | Standard Deviation 560 |
Secondary
Dose-response Parameters (Slope) for LDL-C Area Under the Effect Curve Models for Evolocumab and Alirocumab
Model parameter (slope) for LDL-C area under the effect curve model: Mean slope value calculated after combining data from low, intermediate low, intermediate high, and high doses of evolocumab or alirocumab with placebo data. The units of measure for slope are mg/dL•day / (mg dose).
Time frame: 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.
Population: Analysis population for each group was limited to those subjects administered evolocumab or placebo (the evolocumab group) or administered alirocumab or placebo (alirocumab) who completed the study. Results from subjects administered placebo were used in all analyses. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 10000 repetitions.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Evolocumab Low Dose | Dose-response Parameters (Slope) for LDL-C Area Under the Effect Curve Models for Evolocumab and Alirocumab | -11 mg/dL•day / (mg dose) |
| Arm B: Evolocumab Intermediate Low Dose | Dose-response Parameters (Slope) for LDL-C Area Under the Effect Curve Models for Evolocumab and Alirocumab | -15 mg/dL•day / (mg dose) |
Secondary
Maximum Change From Baseline for apoB for Evolocumab and Alirocumab
The values and variability of maximal difference at a single time-point for ApoB at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab
Time frame: 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.
Population: Analysis population includes all subjects who did not discontinue before the end of study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Evolocumab Low Dose | Maximum Change From Baseline for apoB for Evolocumab and Alirocumab | 24 mg/dL | Standard Deviation 12 |
| Arm B: Evolocumab Intermediate Low Dose | Maximum Change From Baseline for apoB for Evolocumab and Alirocumab | 32 mg/dL | Standard Deviation 17 |
| Arm C: Evolocumab Intermediate High Dose | Maximum Change From Baseline for apoB for Evolocumab and Alirocumab | 36 mg/dL | Standard Deviation 15 |
| Arm D: Evolocumab High Dose | Maximum Change From Baseline for apoB for Evolocumab and Alirocumab | 46 mg/dL | Standard Deviation 16 |
| Arm E: Alirocumab Low Dose | Maximum Change From Baseline for apoB for Evolocumab and Alirocumab | 23 mg/dL | Standard Deviation 9 |
| Arm F: Alirocumab Intermediate Low Dose | Maximum Change From Baseline for apoB for Evolocumab and Alirocumab | 29 mg/dL | Standard Deviation 6 |
| Arm G: Alirocumab Intermediate High Dose | Maximum Change From Baseline for apoB for Evolocumab and Alirocumab | 28 mg/dL | Standard Deviation 8 |
| Arm H: Alirocumab High Dose | Maximum Change From Baseline for apoB for Evolocumab and Alirocumab | 37 mg/dL | Standard Deviation 7 |
| Arm I: Placebo | Maximum Change From Baseline for apoB for Evolocumab and Alirocumab | 17 mg/dL | Standard Deviation 7 |
Secondary
Maximum Concentration (Cmax) for Evolocumab and Alirocumab
The values and variability of Cmax at low, intermediate low, intermediate high, and high doses of evolocumab and alirocumab
Time frame: 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.
Population: Analysis population includes all subjects who did not discontinue before the end of study with at least one pharmacokinetic (PK) sample above the lower limit of quantification.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A: Evolocumab Low Dose | Maximum Concentration (Cmax) for Evolocumab and Alirocumab | 0.7 ug/mL | Geometric Coefficient of Variation 28 |
| Arm B: Evolocumab Intermediate Low Dose | Maximum Concentration (Cmax) for Evolocumab and Alirocumab | 0.5 ug/mL | Geometric Coefficient of Variation 62 |
| Arm C: Evolocumab Intermediate High Dose | Maximum Concentration (Cmax) for Evolocumab and Alirocumab | 2.0 ug/mL | Geometric Coefficient of Variation 54 |
| Arm D: Evolocumab High Dose | Maximum Concentration (Cmax) for Evolocumab and Alirocumab | 6.2 ug/mL | Geometric Coefficient of Variation 36 |
| Arm E: Alirocumab Low Dose | Maximum Concentration (Cmax) for Evolocumab and Alirocumab | 0.8 ug/mL | Geometric Coefficient of Variation 27 |
| Arm F: Alirocumab Intermediate Low Dose | Maximum Concentration (Cmax) for Evolocumab and Alirocumab | 1.7 ug/mL | Geometric Coefficient of Variation 73 |
| Arm G: Alirocumab Intermediate High Dose | Maximum Concentration (Cmax) for Evolocumab and Alirocumab | 2.9 ug/mL | Geometric Coefficient of Variation 61 |
| Arm H: Alirocumab High Dose | Maximum Concentration (Cmax) for Evolocumab and Alirocumab | 6.9 ug/mL | Geometric Coefficient of Variation 41 |
Secondary
Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for LDL-C Maximum Change From Baseline Models With Evolocumab and Alirocumab
Model parameter (ED50) for LDL-C maximum change from baseline curve models calculated after combining data from low, intermediate low, intermediate high, and high doses of evolocumab or alirocumab with placebo data.
Time frame: 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.
Population: Analysis population for each group was limited to those subjects administered evolocumab or placebo (the evolocumab group) or administered alirocumab or placebo (alirocumab) who completed the study. Results from subjects administered placebo were used in all analyses. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 10000 repetitions.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Evolocumab Low Dose | Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for LDL-C Maximum Change From Baseline Models With Evolocumab and Alirocumab | 32 mg |
| Arm B: Evolocumab Intermediate Low Dose | Pharmacodynamic Model Parameter, ED50 (Half Maximal Effect Dose), for LDL-C Maximum Change From Baseline Models With Evolocumab and Alirocumab | 14 mg |
Secondary
Pharmacodynamic Model Parameter, Maximum Effect (Emax), for LDL-C Maximum Change From Baseline Models With Evolocumab and Alirocumab
Model parameter (Emax) for LDL-C maximum change from baseline curve models calculated after combining data from low, intermediate low, intermediate high, and high doses of evolocumab or alirocumab with placebo data.
Time frame: 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.
Population: Analysis population for each group was limited to those subjects administered evolocumab or placebo (the evolocumab group) or administered alirocumab or placebo (alirocumab) who completed the study. Results from subjects administered placebo were used in all analyses. Confidence intervals for model parameters were generated using bootstrapping of the estimated model with 10000 repetitions.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Evolocumab Low Dose | Pharmacodynamic Model Parameter, Maximum Effect (Emax), for LDL-C Maximum Change From Baseline Models With Evolocumab and Alirocumab | 84 mg/dL |
| Arm B: Evolocumab Intermediate Low Dose | Pharmacodynamic Model Parameter, Maximum Effect (Emax), for LDL-C Maximum Change From Baseline Models With Evolocumab and Alirocumab | 62 mg/dL |