Pharmacokinetic and Pharmacodynamic Study of Bococizumab Alone and When Combined With Recombinant Human Hyaluronidase

A Phase 1, Open Label, Randomized, Single Dose, Dose Escalation Study To Assess The Subcutaneous Pharmacokinetics And Pharmacodynamics Of Bococizumab (pf 04950615) Alone And In Co Mixture With Recombinant Human Hyaluronidase (rhuph20, Pf 06744547) In Healthy And Hypercholesterolemic Adult Subjects

This is a Phase 1, open-label, single-dose, randomized, dose escalation study in healthy and hypercholesterolemic subjects. Each subject will receive 1 of 5 treatments as a single subcutaneous injection. Subjects will remain confined at the research clinic for approximately 2 days. After discharge, subjects will return to the research clinic 15 times during 12 weeks.

Study Overview

• Status: Terminated
• Conditions: Healthy; Hypercholesterolemia
• Intervention / Treatment: Biological: Cohort 1: bococizumab 150 mg + rHuPH20; Biological: Cohort 2: bococizumab 300 mg; Biological: Cohort 3: bococizumab 300 mg + rHuPH20; Biological: Cohort 5: bococizumab 450 mg + rHuPH20; Biological: Cohort 4: bococizumab 300 mg + rHuPH20

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, B-1070
    • Pfizer Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy and hypercholesterolemic subjects between the ages of 18 and 65 years.
• Healthy subjects must have fasting LDL-C >/= 70 to </= 190 mg/dL at two qualifying visits.
• Hypercholesterolemic subjects must be on a stable daily dose of statin for at least 45 days before dosing and fasting LDL-C must be >/= 70 mg/dL.

Exclusion Criteria:

• Use of prescription or non-prescription drugs within 7 days or 5 half-lives (whichever) is longer prior to the first dose of study medication. For hypercholesterolemic subjects the use of statin class medication is allowed.
• Prior exposure to bococizumab (also known as PF-04950615 or RN316) or other investigational PCSK9 inhibitors.
• Treatment with monoclonal antibodies within 6 months or 5 half-lives (whichever is longer) before dosing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: bococizumab 150 mg + rHuPH20; bococizumab 150 mg co-mixed with rHuPH20 and administered subcutaneously to healthy volunteers	Biological: Cohort 1: bococizumab 150 mg + rHuPH20; bococizumab 150 mg + rHuPH20 administered SC to healthy volunteers
Active Comparator: Cohort 2: bococizumab 300 mg; bococizumab 300 mg administered subcutaneously to healthy volunteers	Biological: Cohort 2: bococizumab 300 mg; bococizumab 300 mg administered SC to healthy volunteers
Experimental: Cohort 3: bococizumab 300 mg + rHuPH20; bococizumab 300 mg co-mixed with rHuPH20 and administered subcutaneously to healthy volunteers	Biological: Cohort 3: bococizumab 300 mg + rHuPH20; bococizumab 300 mg + rHuPH20 administered SC to healthy volunteers
Experimental: Cohort 5: bococizumab 450 mg + rHUPH20; bococizumab 450 mg co-mixed with rHuPH20 and administered subcutaneously to healthy volunteers	Biological: Cohort 5: bococizumab 450 mg + rHuPH20; bococizumab 450 mg + rHuPH20 administered SC to healthy volunteers
Experimental: Cohort 4: bococizumab 300 mg + rHuPH20; bococizumab 300 mg co-mixed with rHuPH20 and administered subcutaneously to subjects with hypercholesterolemia receiving a statin	Biological: Cohort 4: bococizumab 300 mg + rHuPH20; bococizumab 300 mg + rHuPH20 administered SC to subjects with hypercholesterolemia receiving a statin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUCinf of bococizumab	Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞), if data permits (otherwise AUClast will be used).	Day 1 - Day 85
Cmax of bococizumab	Maximum Observed Plasma Concentration (Cmax)	Day 1 - Day 85

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tmax	Time to Reach Maximum Observed Plasma Concentration (Tmax)	Day 1 - Day 85
CL/F	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance is influenced by the fraction of the dose absorbed. Clearance is estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.	Day 1 - Day 85
Vz/F	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after dose (Vz/F) is influenced by the fraction absorbed.	Day 1 - Day 85
t1/2	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	Day 1 - Day 85
LDL-C at Week 4	Absolute value, and absolute change and % change in LDL cholesterol at Week 4 following bococizumab administration alone and when co-mixed with rHuPH20.	Baseline to Week 4
MaxELDL-C	Maximum LDL-C lowering calculated using absolute LDL-C values	Baseline up to Day 85
Tmax, LDL-C	Time to MaxELDL-C calculated using absolute LDL-C values	Baseline up to Day 85
AUEC85	Area under the LDL-C concentration-time curve calculated using absolute LDL-C values	Baseline up to Day 85
AEs	Incidence, severity, and causal relationship of treatment-emergent adverse events (TEAEs)	Baseline up to Day 85
Laboratory tests	Incidence of abnormal and clinically relevant safety laboratory tests including clinical chemistry and hematology	Baseline up to Day 85
Vital signs	Incidence of abnormal and clinically relevant vital signs	Baseline up to Day 85
AUClast of bococizumab	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)	Day 1 - Day 85
ADA	Incidence and titer of Anti-Drug Antibodies (ADA) following administration of bococizumab alone and when co-mixed with rHuPH20.	Day 1 - Day 85
nAb	Incidence and titer of neutralizing antibodies (nAb), if applicable, following administration of bococizumab alone and when co-mixed with rHuPH20.	Day 1- Day 85

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Halozyme Therapeutics

Publications and helpful links

General Publications

• Bass A, Plotka A, Mridha K, Sattler C, Kim AM, Plowchalk DR. Pharmacokinetics, pharmacodynamics, and safety of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, in healthy subjects when administered in co-mixture with recombinant human hyaluronidase: A phase 1 randomized trial. Health Sci Rep. 2018 Jul 18;1(9):e61. doi: 10.1002/hsr2.61. eCollection 2018 Sep.

Helpful Links

• To obtain contact information for a study center near you, click here.
• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: January 6, 2016
• First Submitted That Met QC Criteria: January 25, 2016
• First Posted (Estimate): January 28, 2016

Study Record Updates

• Last Update Posted (Estimate): October 21, 2016
• Last Update Submitted That Met QC Criteria: October 19, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: pharmacokinetics; pharmacodynamics; RN316; recombinant human hyaluronidase
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Bococizumab
• Other Study ID Numbers: B1481051; 2015-003568-36 (EudraCT Number)