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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Healthy, Hypercholesterolemia

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, pharmacodynamics, RN316, recombinant human hyaluronidase