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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
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
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
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
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...
November 17, 2016: Clinical and Translational Science
Paul M Ridker, Pierre Amarenco, Robert Brunell, Robert J Glynn, J Wouter Jukema, John J P Kastelein, Wolfgang Koenig, Steven Nissen, James Revkin, Raul D Santos, Pamela F Schwartz, Carla Yunis, Jean-Claude Tardif
BACKGROUND: Although statins significantly reduce vascular event rates, residual cholesterol risk remains high in many patient groups, including those with known vascular disease as well as in the setting of high-risk primary prevention. Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), prolongs the half-life of hepatic low-density lipoprotein (LDL) receptors, and reduces circulating atherogenic cholesterol levels. DESIGN: The SPIRE program comprises 6 lipid-lowering studies and 2 cardiovascular outcomes trials, each comparing bococizumab (150 mg subcutaneously every 2 weeks) to matching placebo...
August 2016: American Heart Journal
Bryce Chackerian, Alan Remaley
PURPOSE OF REVIEW: mAbs targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have the potential to become groundbreaking therapies for the treatment of hypercholesterolemia. However, one major drawback of mAb-based therapy for a chronic condition like dyslipidemia is its relatively high cost. This review summarizes two recent studies describing novel vaccine approaches for lowering LDL-cholesterol by active immunization against PCSK9. RECENT FINDINGS: PCSK9 is a plasma protein secreted by the liver that controls cholesterol homeostasis by enhancing endosomal and lysosomal degradation of the LDL receptor...
August 2016: Current Opinion in Lipidology
K Yadav, M Sharma, K C Ferdinand
AIMS: Our comprehensive review highlights the drug development and pharmacogenomics leading to the recent approval of PCSK9 inhibitors. We also review the anticipated future advances into the uses of PCSK9 inhibition. BACKGROUND: Despite the present advances in pharmacotherapy, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide. Low density lipoprotein-cholesterol (LDL-C) lowering is the primary target for ASCVD risk reduction, showing demonstrable benefits in mortality...
October 2016: Nutrition, Metabolism, and Cardiovascular Diseases: NMCD
Matthew K Ito, Raul D Santos
Current guidelines for hypercholesterolemia treatment emphasize lifestyle modification and lipid-modifying therapy to reduce the risk for cardiovascular disease. Statins are the primary class of agents used for the treatment of hypercholesterolemia. Although statins are effective for many patients, they fail to achieve optimal reduction in lipids for some patients, including those who have or are at high risk for cardiovascular disease. The PCSK9 gene was identified in the past decade as a potential therapeutic target for the management of patients with hypercholesterolemia...
January 2017: Journal of Clinical Pharmacology
Barbara Cybulska, Zbigniew Gaciong, Piotr Hoffman, Piotr Jankowski, Longina Kłosiewicz-Latoszek, Jarosław Kaźmierczak, Katarzyna Mitręga, Grzegorz Opolski, Andrzej Pająk, Piotr Ponikowski, Andrzej Rynkiewicz, Janina Stępińska, Beata Średniawa, Zbigniew Kalarus
The severe hypercholesterolaemia can be recognised when low density lipoprotein cholesterol (LDL-C) serum levels are equal to or above 5 mmol/L (≥ 190 mg/dL). The prevalence of LDL-C ≥ 5 mmol/L is 3.8% in Polish population aged 18-79 years. Among these adults there are patients with familial hypercholesterolaemia (FH). According to meta-analysis of 6 Polish population surveys prevalence of heterozygous FH (HeFH) diagnosed using Dutch Lipid Clinic criteria is 0.4% (95% Cl 0.28-0.53%) in men and women aged 20-74 years, i...
2016: Kardiologia Polska
Alexandra M Sible, James J Nawarskas, Joe R Anderson
Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are novel agents indicated for the treatment of hyperlipidemia. Inhibition of PCSK9 produces an increase in surface low-density lipoprotein (LDL) receptors and increases removal of LDL from the circulation. Alirocumab (Praluent; Sanofi/Regeneron, Bridgewater, NJ) and evolocumab (Repatha; Amgen, Thousand Oaks, CA) are currently available and approved for use in patients with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, and clinical atherosclerotic cardiovascular disease...
May 2016: Cardiology in Review
Andrea Denegri, Iveta Petrova-Slater, Elena Pasotti, Maria Grazia Rossi, Giovanni Battista Pedrazzini, Tiziano Moccetti, Marco Moccetti
Atherosclerosis is characterized by cholesterol deposition in the arterial intima, with subsequent plaque formation and arterial disease. Low-density lipoprotein cholesterol (LDL-C) plays the most important role in the atherogenesis process, which is the substrate of cardiovascular disease and is the leading cause of death worldwide. Several studies show that a strict control of risk factors, particularly the reduction of LDL-C levels, is a cornerstone in primary and secondary prevention of coronary heart disease...
April 2016: Journal of Cardiovascular Medicine
Janice M Reichert
The number of novel antibody therapeutics that received first marketing approvals in 2015 met expectations, with 6 (alirocumab (Praluent®), evolocumab (Repatha®), daratumumab (Darzalex®), dinutuximab (Unituxin®), idarucizumab (Praxbind®), mepolizumab (Nucala®)) granted first approvals as of mid-November*. Seven novel antibody therapeutics (begelomab, brodalumab, elotuzumab, ixekizumab, necitumumab, obiltoxaximab, reslizumab) are in regulatory review, and thus a similar number, if not more, are projected to gain first approvals in 2016...
2016: MAbs
Sanjiv Gupta
Reduction of low density lipoprotein cholesterol (LDLc) is of vital importance for the prevention of atherosclerotic cardiovascular disease (ASCVD). Statin is the most effective therapy today to lower LDLc by inhibiting HMG-CoA-reductase. However despite intensive statin therapy, there remains a residual risk of recurrent myocardial infarction in about 20-30% cases. Moreover a few patients develop statin intolerance. For severe hypercholesterolemia, statins alone or in combination of ezetimibe, niacin and fenofibrate have been advocated...
September 2015: Indian Heart Journal
Sarah N Campion, Bora Han, Gregg D Cappon, Elise M Lewis, Eugenia Kraynov, Hong Liang, Christopher J Bowman
Bococizumab is a humanized monoclonal IgG2Δa antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) for the treatment of hyperlipidemia. The evaluation of potential effects on embryo-fetal development was conducted in the rat. In a pharmacokinetic/pharmacodynamic study bococizumab was administered intravenously to pregnant Sprague-Dawley (SD) rats (n = 8/group) at 0, 10, 30, and 100 mg/kg during organogenesis. Maternal and fetal bococizumab, total cholesterol and HDL concentrations were determined...
November 2015: Regulatory Toxicology and Pharmacology: RTP
Željko Reiner
Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular disease (CVD) morbidity and mortality. Statins are the treatment of choice for lowering LDL-C but a considerable number of patients treated with statins are unable to achieve LDL-C target values and many are statin-intolerant. New LDL-C-lowering drugs--antibodies to PCSK9 (alirocumab, evolocumab and bococizumab)--have been developed and are being tested in large clinical trials. They further reduce LDL-C above maximally tolerated statin therapy by up to > 70%; they also reduce Lp(a), non-HDL-C, apolipoprotein-B, and modestly increase HDL-C...
2015: Expert Opinion on Drug Metabolism & Toxicology
Željko Reiner
Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular disease (CVD) morbidity and mortality. Statins are the treatment of choice for lowering LDL-C but a considerable number of patients treated with statins are unable to achieve LDL-C target values and many are statin-intolerant. New LDL-C-lowering drugs - antibodies to PCSK9 (alirocumab, evolocumab and bococizumab) - have been developed and are being tested in large clinical trials. They further reduce LDL-C above maximally tolerated statin therapy by up to > 70%; they also reduce Lp(a), non-HDL-C, apolipoprotein-B, and modestly increase HDL-C...
August 3, 2015: Expert Opinion on Drug Metabolism & Toxicology
Christie M Ballantyne, Joel Neutel, Anne Cropp, William Duggan, Ellen Q Wang, David Plowchalk, Kevin Sweeney, Nitin Kaila, John Vincent, Harold Bays
Bococizumab is a humanized monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, which may be a potential therapeutic option for reducing low-density lipoprotein cholesterol (LDL-C) levels in patients with hypercholesterolemia. In this 24-week, multicenter, double-blind, placebo-controlled, dose-ranging study (NCT01592240), subjects with LDL-C levels≥80 mg/dl on stable statin therapy were randomized to Q14 days subcutaneous placebo or bococizumab 50, 100, or 150 mg or Q28 days subcutaneous placebo or bococizumab 200 or 300 mg...
May 1, 2015: American Journal of Cardiology
Nihar R Desai, Marc S Sabatine
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that plays an important role in modulating low-density lipoprotein cholesterol (LDL-C) levels by targeting LDL-C receptors for lysosomal degradation. Genetic association studies have demonstrated that loss-of-function mutations in PCSK9 are associated with low plasma LDL-C levels and a reduction in the incidence of adverse cardiovascular events. Monoclonal antibodies directed against PCSK9 have been developed and have been shown in phase 1, 2, and 3 trials to dramatically reduce LDL-C regardless of background lipid-lowering therapy, including in clinically challenging populations such as patients intolerant to statin therapy and those with familial hypercholesterolemia...
October 2015: Trends in Cardiovascular Medicine
Janice M Reichert
The commercial pipeline of recombinant antibody therapeutics is robust and dynamic. As of early December 2014, a total of 6 such products (vedolizumab, siltuximab, ramucirumab, pembrolizumab, nivolumab, blinatumomab) were granted first marketing approvals in 2014. As discussed in this perspective on antibodies in late-stage development, the outlook for additional approvals, potentially still in 2014 and certainly in 2015, is excellent as marketing applications for 7 antibody therapeutics (secukinumab, evolocumab, mepolizumab, dinutuximab, nivolumab, blinatumomab, necitumumab) are undergoing a first regulatory review in the EU or US...
2015: MAbs
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