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https://www.readbyqxmd.com/read/29209441/pcsk9-signaling-pathways-and-their-potential-importance-in-clinical-practice
#1
REVIEW
Michał Wiciński, Jarosław Żak, Bartosz Malinowski, Gabriela Popek, Grzegorz Grześk
In the following review, authors described the structure and biochemical pathways of PCSK9, its involvement in LDL metabolism, as well as significances of proprotein convertase subtilisin/kexin type 9 targeted treatment. PCSK9 is a proprotein convertase, which plays a crucial role in LDL receptor metabolism. Transcription and translation of PCSK9 is controlled by different nuclear factors, such as, SREBP and HNF1α. This review focuses on interactions between PCSK9 and LDL receptor, VLDLR, ApoER2, CD36, CD81, and others...
December 2017: EPMA Journal
https://www.readbyqxmd.com/read/29116337/effects-of-monoclonal-antibodies-against-pcsk9-on-clinical-cardiovascular-events-a-meta-analysis-of-randomized-controlled-trials
#2
Y Zhu, X Shen, Q Jiang, Z Wang, Z Wang, X Dong, J Li, Q Han, J Zhao, B Wang, L Liu
BACKGROUND: The present meta-analysis was designed to improve statistical power and review the effects of monoclonal antibodies against PCSK9 on clinical cardiovascular events. METHODS: PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to May 2017. Studies considered to be eligible were randomized controlled trials about the effects of monoclonal antibodies against PCSK9 on clinical cardiovascular events. The primary endpoint was positively adjudicated cardiovascular events; the secondary endpoint comprised cardiac mortality, myocardial infarction (MI), coronary revascularization, stroke, and hospitalization for unstable angina...
November 7, 2017: Herz
https://www.readbyqxmd.com/read/29078037/the-effects-of-single-and-multiple-dose-administration-of-bococizumab-rn316-pf-04950615-a-humanized-igg2%C3%AE-a-monoclonal-antibody-binding-proprotein-convertase-subtilisin-kexin-type-9-in-hypercholesterolemic-subjects-treated-with-and-without-atorvastatin-results
#3
Barry Gumbiner, Tenshang Joh, Hong Liang, Hong Wan, Matteo Levisetti, Alicia M Vana, David L Shelton, Philippe Forgues, Stephan Billotte, Jaume Pons, Charles M Baum, Pamela D Garzone
AIMS: Three single-dose and one multiple-dose phase I studies were conducted in subjects with primary hypercholesterolemia to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. METHODS: The dosing schedules for hypercholesterolemic subjects randomized in the four phase I studies were (1) ascending, single, intravenous (IV) bococizumab (0.3, 1, 3, 6, 12, or 18 mg/kg), or placebo (N = 48; baseline low-density lipoprotein cholesterol [LDL-C] ≥130 mg/dL); (2) single, IV bococizumab (0...
February 2018: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/29057618/effects-of-12-weeks-of-treatment-with-intravenously-administered-bococizumab-a-humanized-monoclonal-antibody-blocking-proprotein-convertase-subtilisin-kexin-type-9-in-hypercholesterolemic-subjects-on-high-dose-statin
#4
Sergio Fazio, David G Robertson, Tenshang Joh, Hong Wan, Tom Riel, Philippe Forgues, Charles M Baum, Pamela D Garzone, Barry Gumbiner
AIMS: Two multiple-dose phase II studies were conducted in subjects with primary hypercholesterolemia to evaluate the LDL-C lowering efficacy, safety, and tolerability of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. METHODS: The results from the two phase II, double-blinded, randomized, placebo-controlled, multicenter studies conducted in the USA and Canada were combined. In Study 1, 90 subjects with LDL-C ≥100 mg/dL received intravenous (IV) placebo or bococizumab 0...
February 2018: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/29037448/effects-of-proprotein-convertase-subtilisin-kexin-type-9-pcsk9-inhibition-with-bococizumab-on-lipoprotein-particles-in-hypercholesterolemic-subjects
#5
Hong Wan, Barry Gumbiner, Tenshang Joh, Tom Riel, Chandrasekhar Udata, Philippe Forgues, Pamela D Garzone
PURPOSE: Monoclonal antibody inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) elicit significant reductions in serum LDL-C levels. However, little is known about their effects on lipoprotein particles. The purpose of this analysis was to evaluate the effect of PCSK9 inhibition with bococizumab (RN316/PF-04950615), a humanized monoclonal antibody to PCSK9, on LDL, VLDL, and HDL particle concentration and size in hypercholesterolemic subjects. METHODS: Data from 3 double-blind, placebo-controlled, randomized studies were analyzed...
November 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28886926/2017-focused-update-of-the-2016-acc-expert-consensus-decision-pathway-on-the-role-of-non-statin-therapies-for-ldl-cholesterol-lowering-in-the-management-of-atherosclerotic-cardiovascular-disease-risk-a-report-of-the-american-college-of-cardiology-task-force
#6
Donald M Lloyd-Jones, Pamela B Morris, Christie M Ballantyne, Kim K Birtcher, David D Daly, Sondra M DePalma, Margo B Minissian, Carl E Orringer, Sidney C Smith
In 2016, the American College of Cardiology published the first expert consensus decision pathway (ECDP) on the role of non-statin therapies for low-density lipoprotein (LDL)-cholesterol lowering in the management of atherosclerotic cardiovascular disease (ASCVD) risk. Since the publication of that document, additional evidence and perspectives have emerged from randomized clinical trials and other sources, particularly considering the longer-term efficacy and safety of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors in secondary prevention of ASCVD...
October 3, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28636184/pharmacokinetics-and-pharmacodynamics-of-bococizumab-a-monoclonal-antibody-to-pcsk9-after-single-subcutaneous-injection-at-three-sites-nct-02043301
#7
Ellen Q Wang, Anna Plotka, Joanne Salageanu, Catherine Sattler, Carla Yunis
AIM: To characterize the single-dose pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a monoclonal antibody inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), administered subcutaneously (s.c.) to the abdomen, thigh, or upper arm (NCT02043301). METHODS: Seventy-five adults with low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL and not on background lipid-lowering therapy were randomized (1:1:1) to a single 150-mg s.c. dose of bococizumab administered to the abdomen, thigh, or upper arm...
October 2017: Cardiovascular Therapeutics
https://www.readbyqxmd.com/read/28617192/emerging-biologic-therapies-for-hypercholesterolaemia
#8
REVIEW
Giacomo Pucci, Arrigo F Cicero, Claudio Borghi, Giuseppe Schillaci
LDL-cholesterol (LDL-C) is one of the most well-established risk factors for CV disease. Indeed, therapies that decrease LDL-C are proven to effectively reduce the risk of atherosclerotic CV disease. Monoclonal antibodies (mAbs) that target proprotein convertase subtilisin/kexin type 9 (PCSK9) have recently gained traction as a promising therapeutic strategy. Areas covered: In this review, the authors discuss the effectiveness of mAbs against PCSK9 in lowering low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipid fractions...
September 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28596304/pcsk9-inhibition-and-atherosclerotic-cardiovascular-disease-prevention-does-reality-match-the-hype
#9
REVIEW
Savvas Hadjiphilippou, Kausik K Ray
Within this review we look at whether the potential provided by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition for prevention of atherosclerotic cardiovascular disease matches the excitement generated. Two fully human monoclonal antibodies to PCSK9 are currently licenced for clinical use both in the USA and the European Union: evolocumab and alirocumab. These reduce low-density lipoprotein cholesterol by over 50% across a range of populations and were generally found to have a safety profile comparable with placebo...
November 2017: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/28552009/bococizumab-for-the-treatment-of-hypercholesterolaemia
#10
Nicola Ferri, Alberto Corsini, Cesare R Sirtori, Massimiliano Ruscica
No abstract text is available yet for this article.
July 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28549755/cholesterol-and-stroke-roll-of-pcsk9-inhibitors
#11
L Castilla-Guerra, M C Fernández-Moreno, M A Rico-Corral
INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the modulation of plasma levels of low density lipoprotein cholesterol (LDLC). PCSK9 binds to the LDL receptor (LDLR), disrupts its endocytic recycling itinerary and directs it to lysosomal degradation. Activation of PCSK9 can thus decrease the expression of LDLR in the liver and inhibit LDL uptake, which leads to hypercholesterolaemia. DEVELOPMENT: Currently we now know that different polymorphisms of PCSK9 are associated with the occurrence of ischaemic stroke...
May 23, 2017: Neurología: Publicación Oficial de la Sociedad Española de Neurología
https://www.readbyqxmd.com/read/28539539/efficacy-and-safety-of-bococizumab-rn316-pf-04950615-a-monoclonal-antibody-against-proprotein-convertase-subtilisin-kexin-type-9-in-hypercholesterolemic-japanese-subjects-receiving-a-stable-dose-of-atorvastatin-or-treatment-naive-results-from-a-randomized-placebo
#12
Koutaro Yokote, Shigeto Kanada, Osamu Matsuoka, Hisakuni Sekino, Keiji Imai, Junichi Tabira, Nobushige Matsuoka, Sandip Chaudhuri, Tamio Teramoto
BACKGROUND: A Phase 2, dose-ranging study of bococizumab, a monoclonal anti-proprotein convertase subtilisin/kexin type 9 antibody, was conducted in Japanese subjects to assess its efficacy, safety, and tolerability in this population.Methods and Results:Two different hypercholesterolemic study populations were enrolled concurrently: Japanese subjects with uncontrolled low-density lipoprotein cholesterol (LDL-C) despite atorvastatin treatment (LDL-C ≥100 mg/dL; n=121), and Japanese subjects naive to lipid-lowering agents and with LDL-C ≥130 mg/dL (n=97)...
September 25, 2017: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/28453187/pcsk9-monoclonal-antibodies-for-the-primary-and-secondary-prevention-of-cardiovascular-disease
#13
REVIEW
Amand F Schmidt, Lucy S Pearce, John T Wilkins, John P Overington, Aroon D Hingorani, Juan P Casas
BACKGROUND: Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for patients who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) may further reduce LDL-C, potentially reducing CVD risk as well...
April 28, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28304242/cardiovascular-efficacy-and-safety-of-bococizumab-in-high-risk-patients
#14
RANDOMIZED CONTROLLED TRIAL
Paul M Ridker, James Revkin, Pierre Amarenco, Robert Brunell, Madelyn Curto, Fernando Civeira, Marcus Flather, Robert J Glynn, Jean Gregoire, J Wouter Jukema, Yuri Karpov, John J P Kastelein, Wolfgang Koenig, Alberto Lorenzatti, Pravin Manga, Urszula Masiukiewicz, Michael Miller, Arend Mosterd, Jan Murin, Jose C Nicolau, Steven Nissen, Piotr Ponikowski, Raul D Santos, Pamela F Schwartz, Handrean Soran, Harvey White, R Scott Wright, Michal Vrablik, Carla Yunis, Charles L Shear, Jean-Claude Tardif
BACKGROUND: Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS: In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo...
April 20, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28304227/lipid-reduction-variability-and-antidrug-antibody-formation-with-bococizumab
#15
RANDOMIZED CONTROLLED TRIAL
Paul M Ridker, Jean-Claude Tardif, Pierre Amarenco, William Duggan, Robert J Glynn, J Wouter Jukema, John J P Kastelein, Albert M Kim, Wolfgang Koenig, Steven Nissen, James Revkin, Lynda M Rose, Raul D Santos, Pamela F Schwartz, Charles L Shear, Carla Yunis
BACKGROUND: Bococizumab, a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), reduces levels of low-density lipoprotein (LDL) cholesterol. However, the variability and durability of this effect are uncertain. METHODS: We conducted six parallel, multinational lipid-lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months; 96% were receiving statin therapy at the time of enrollment...
April 20, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28181260/a-mechanism-based-pharmacokinetic-pharmacodynamic-model-for-bococizumab-a-humanized-monoclonal-antibody-against-proprotein-convertase-subtilisin-kexin-type-9-and-its-application-in-early-clinical-development
#16
Chandrasekhar Udata, Pamela D Garzone, Barry Gumbiner, Tenshang Joh, Hong Liang, Kai-Hsin Liao, Jason H Williams, Xu Meng
Bococizumab (RN316/PF-04950615), a humanized monoclonal antibody, binds to secreted proprotein convertase subtilisin/kexin type 9 (PCSK9) and prevents its downregulation of low-density lipoprotein receptor, leading to improved clearance and reduction of low-density lipoprotein cholesterol (LDL-C) in plasma. A mechanism-based drug-target binding model was developed, accounting for bococizumab, PCSK9, and LDL-C concentrations and the effects of concomitant administration of statins. This model was utilized to better understand the pharmacokinetic/pharmacodynamic (PK/PD) data obtained from 3 phase 1 and 2 phase 2a clinical studies...
February 9, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28060539/bococizumab-for-the-treatment-of-hypercholesterolaemia
#17
REVIEW
Nicola Ferri, Alberto Corsini, Cesare R Sirtori, Massimiliano Ruscica
Low-density lipoprotein cholesterol (LDL-C) remains a well-established risk factor for cardiovascular disease (CVD). LDL-C levels are considered primary targets of therapy. A new series of systemic biomolecules, the monoclonal antibodies (mAbs) of proprotein convertase subtilisin/kexin type 9 (PCSK9), have a higher activity in reducing LDL-C. Areas covered: The authors critically review the current evidence on the efficacy and safety of bococizumab, a humanized mAb against PCSK9, which was surprisingly discontinued in November 2016...
February 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/27888904/-anti-pcsk9-antibodies-in-type-2-diabetes-and-secondary-prevention-of-cardiovascular-diseases
#18
REVIEW
José López-Miranda, Xavier Pintó
Patients with type 2 diabetes are considered to have the same cardiovascular risk as patients with ischemia. However, the degree of lipid control in diabetic and ischemic patients remains highly deficient. The availability of new agents, such as anti-PCSK9 monoclonal antibodies, could represent a notable advance in meeting this unmet need. Alirocumab and evolucumab, followed by bococizumab, are currently under the advanced phase of research. A growing database has demonstrated a relationship between glucose metabolism, body weight and PCSK9 function, but the clinical implications of this relationship have not been well defined...
May 2016: Clínica e Investigación en Arteriosclerosis
https://www.readbyqxmd.com/read/27877050/development-of-proprotein-convertase-subtilisin-kexin-type-9-inhibitors-and-the-clinical-potential-of-monoclonal-antibodies-in-the-management-of-lipid-disorders
#19
REVIEW
Sanjiv Gupta
The aim of this manuscript is to review available data to evaluate the present status of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia. Relevant literature since 2003 is reviewed. The effectiveness of PCSK9 inhibitors in lowering low-density lipoprotein cholesterol and other atherogenic lipid fractions was studied in various Phase 2 and Phase 3 trials of Alirocumab, Evolocumab, and Bococizumab. The results of published long-term ODYSSEY and OSLER studies are summarized...
2016: Vascular Health and Risk Management
https://www.readbyqxmd.com/read/27860267/a-phase-i-randomized-study-of-a-specifically-engineered-ph-sensitive-pcsk9-inhibitor-rn317-pf-05335810-in-hypercholesterolemic-subjects-on-statin-therapy
#20
RANDOMIZED CONTROLLED TRIAL
M Levisetti, T Joh, H Wan, H Liang, P Forgues, B Gumbiner, P D Garzone
This phase I study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of RN317 (PF-05335810), a specifically engineered, pH-sensitive, humanized proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody, in hypercholesterolemic subjects (low-density lipoprotein cholesterol (LDL-C) ≥ 80 mg/dl) 18-70 years old receiving statin therapy. Subjects were randomized to: single-dose placebo, RN317 (subcutaneous (s.c.) 0.3, 1, 3, 6, or intravenous (i.v.) 1, 3, 6 mg/kg), or bococizumab (s...
January 2017: Clinical and Translational Science
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