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Bococizumab (RN316) is a monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9), blocking PCSK-9-mediated down-regulation of liver LDL receptors leading to improved serum clearance of LDL cholesterol. The half-life of bococizumab is approximately 245 hrs. Bococizumab lowers LDL-C by approximately 60% compared to a dieting regimen. In addition to lowering LDL-C, treatment with bococizumab is also associated with lower serum triglycerides and a higher HDL-C. <ref name=circ>Gumbiner B, Udata C, Joh T, Liang H, Wan H, Shelton D, et al. The Effects of Multiple Dose Administration of RN316 (PF-04950615), a Humanized IgG2a Monoclonal Antibody Binding Proprotein Convertase Subtilisin Kexin Type 9, in Hypercholesterolemic Subjects. Circulation 2012; 126: A13524</ref>
Bococizumab (RN316) is a monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9), blocking PCSK-9-mediated down-regulation of liver LDL receptors leading to improved serum clearance of LDL cholesterol. The half-life of bococizumab is approximately 245 hrs. Bococizumab lowers LDL-C by approximately 60% compared to a dieting regimen. In addition to lowering LDL-C, treatment with bococizumab is also associated with lower serum triglycerides and a higher HDL-C. <ref name=circ>Gumbiner B, Udata C, Joh T, Liang H, Wan H, Shelton D, et al. The Effects of Multiple Dose Administration of RN316 (PF-04950615), a Humanized IgG2a Monoclonal Antibody Binding Proprotein Convertase Subtilisin Kexin Type 9, in Hypercholesterolemic Subjects. Circulation 2012; 126: A13524</ref>


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File:PCSK9_function_01.jpg|550px|Biologic function of PCSK9  <font size="1">''Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408''<ref name="Urban-2013">{{Cite journal  | last1 = Urban | first1 = D. | last2 = Pöss | first2 = J. | last3 = Böhm | first3 = M. | last4 = Laufs | first4 = U. | title = Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. | journal = J Am Coll Cardiol | volume = 62 | issue = 16 | pages = 1401-8 | month = Oct | year = 2013 | doi = 10.1016/j.jacc.2013.07.056 | PMID = 23973703 }}</ref></font>
File:PCSK9_function_01.jpg|Biologic function of PCSK9  <font size="1">''Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408''<ref name="Urban-2013">{{Cite journal  | last1 = Urban | first1 = D. | last2 = Pöss | first2 = J. | last3 = Böhm | first3 = M. | last4 = Laufs | first4 = U. | title = Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. | journal = J Am Coll Cardiol | volume = 62 | issue = 16 | pages = 1401-8 | month = Oct | year = 2013 | doi = 10.1016/j.jacc.2013.07.056 | PMID = 23973703 }}</ref></font>
File:Pharmacologic-interventions-for-PCSK9.jpg|550px|Pharmacologic interventions for PCSK9  <font size="1">''Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408''<ref name="Urban-2013">{{Cite journal  | last1 = Urban | first1 = D. | last2 = Pöss | first2 = J. | last3 = Böhm | first3 = M. | last4 = Laufs | first4 = U. | title = Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. | journal = J Am Coll Cardiol | volume = 62 | issue = 16 | pages = 1401-8 | month = Oct | year = 2013 | doi = 10.1016/j.jacc.2013.07.056 | PMID = 23973703 }}</ref></font>]]
File:Pharmacologic-interventions-for-PCSK9.jpg|Pharmacologic interventions for PCSK9  <font size="1">''Adapted from Journal of the American College of Cardiology, 62(16): 1401-1408''<ref name="Urban-2013">{{Cite journal  | last1 = Urban | first1 = D. | last2 = Pöss | first2 = J. | last3 = Böhm | first3 = M. | last4 = Laufs | first4 = U. | title = Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. | journal = J Am Coll Cardiol | volume = 62 | issue = 16 | pages = 1401-8 | month = Oct | year = 2013 | doi = 10.1016/j.jacc.2013.07.056 | PMID = 23973703 }}</ref></font>
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Latest revision as of 18:10, 31 July 2015

For a review of all PCSK9 inhibitors please click here

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Bococizumab (PF-04950615; RN316) is a humanized monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 and is an investigational agent for the reduction of LDL-C levels in patients with hypercholesterolemia.

Properties

Bococizumab (RN316) is a monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9), blocking PCSK-9-mediated down-regulation of liver LDL receptors leading to improved serum clearance of LDL cholesterol. The half-life of bococizumab is approximately 245 hrs. Bococizumab lowers LDL-C by approximately 60% compared to a dieting regimen. In addition to lowering LDL-C, treatment with bococizumab is also associated with lower serum triglycerides and a higher HDL-C. [1]

Major Trials

Phase II Trials [3]

A 24 week, randomized, placebo-controlled, dose-ranging phase IIB trial was conducted in 354 patients to examine two different doses of bococizumab: a twice monthly dose of either 50, 100 or 150 mg; and a once monthly dose of either 200 or 300 mg. A dose reduction was made at week 6 for the twice monthly and at week 8 for the once monthly regimen in patients with LDL-C ≤25 mg/dL. The primary efficacy endpoint was the placebo-adjusted change from baseline in LDL-C at week 12. The study met its primary endpoint across all doses with a safety and tolerability profile equivalent to placebo.

Dosing regimens Mean change from baseline in LDL-C at Week 12 (placebo-adjusted) Maximum mean change from baseline in LDL-C (placebo-adjusted)
150 mg twice monthly -53.4 mg/dL -66.9 mg/dL (week 8)
300 mg once monthly -44.9 mg/dL -54.9 mg/dL (week 4)

Phase III Trials[4]

SPIRE-FH

SPIRE-FH is a phase 3 randomized, double-blind, placebo-controlled trial that aims to evaluate the efficacy and safety of bococizumab vs. placebo among patients with heterozygous familial hypercholesterolemia. Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks for a total of 12 months. The primary endpoint of this trial is the percent change in baseline LDL-C level at 12 weeks. Secondary endpoints include change in baseline serum concentrations of total cholesterol, apolipoprotein B, HDL cholesterol, and triglycerides. The trial is currently recruiting patients and is expected to be completed in April 2016.

SPIRE-HR & SPIRE-LDL

SPIRE-HR and SPIRE-LDL are phase 3 multi-center, randomized, double-blind, placebo-controlled trials that aim to evaluate the efficacy and safety of bococizumab vs. placebo among patients with hypercholesterolemia or mixed dyslipidemia and high cardiovascular risk on statin therapy. Inclusion criteria include high cardiovascular risk, current statin use, fasting LDL-C > 70 mg/dL, and triglycerides ≤ 400 mg/dL. Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks for a total of 12 months. The primary endpoint in both trials is the percent change in baseline LDL-C level at 12 weeks. Secondary endpoints include change in baseline serum concentrations of total cholesterol, apolipoprotein B, HDL cholesterol, and triglycerides. These trials are currently recruiting patients and are expected to be completed by April-June 2016.

SPIRE-1

SPIRE-1 is a phase 3 multi-center, randomized, double-blind, placebo-controlled trial that aims to evaluate the efficacy and safety of bococizumab in the reduction of major cardiovascular events at 5 years (composite of cardiovascular death, myocardial infarction, stroke, and unstable angina requiring urgent revascularization). Inclusion criteria include current background lipid lowering therapy, high cardiovascular risk, and LDL-C ≥ 70 mg/dL (1.8 mmol/L) and < 100 mg/dL (2.6 mmol/L). Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks. The trial is currently recruiting patients and is expected to be completed in March 2018.

SPIRE-2

SPIRE-2 is a phase 3 multi-center, randomized, double-blind, placebo-controlled trial that aims to evaluate the efficacy and safety of bococizumab in the reduction of major cardiovascular events at 5 years (composite of cardiovascular death, myocardial infarction, stroke, and unstable angina requiring urgent revascularization). Inclusion criteria include current background lipid lowering therapy, high cardiovascular risk, and in contrast with SPIRE-1 an LDL-C > 100 mg/dL (2.6 mmol/L). Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks. The trial is currently recruiting patients and is expected to be completed in March 2018.

SPIRE-SI

SPIRE-SI is a phase 3, randomized, double-blind, placebo and active controlled, trial that aims to assess the efficacy, safety and tolerability of bococizumab in subjects with primary hyperlipidemia or mixed dyslipidemia who are intolerant to statins. Inclusion criteria include high cardiovascular risk, current statin use with documented intolerance, fasting LDL-C > 70 mg/dL, and triglycerides ≤ 400 mg/dL. Patients will be administered 150 mg of bococizumab or placebo as a subcutaneous injection every 2 weeks for a total of 24 weeks. The primary endpoint of this trial is the percent change in baseline LDL-C level at 12 weeks. Secondary endpoints include change in baseline serum concentrations of total cholesterol, apolipoprotein B, HDL cholesterol, and triglycerides. The trial is currently recruiting patients and is expected to be completed in November 2015.

References

  1. Gumbiner B, Udata C, Joh T, Liang H, Wan H, Shelton D, et al. The Effects of Multiple Dose Administration of RN316 (PF-04950615), a Humanized IgG2a Monoclonal Antibody Binding Proprotein Convertase Subtilisin Kexin Type 9, in Hypercholesterolemic Subjects. Circulation 2012; 126: A13524
  2. 2.0 2.1 Urban, D.; Pöss, J.; Böhm, M.; Laufs, U. (2013). "Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis". J Am Coll Cardiol. 62 (16): 1401–8. doi:10.1016/j.jacc.2013.07.056. PMID 23973703. Unknown parameter |month= ignored (help)
  3. http://press.pfizer.com/press-release/bococizumab-rn316-significantly-reduced-ldl-cholesterol-statin-treated-adults-high-cho
  4. Dadu RT, Ballantyne CM (2014). "Lipid lowering with PCSK9 inhibitors". Nat Rev Cardiol. 11 (10): 563–75. doi:10.1038/nrcardio.2014.84. PMID 24958078.


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