Bococizumab

We sought to characterize the population pharmacokinetic/pharmacodynamic (PK/PD) relationship of bococizumab (RN316/PF-04950615), a humanized IgG2Δa monoclonal antibody that binds to secreted human proprotein convertase subtilisin kexin type 9 (PCSK9), using data derived from 16 phase I, II, and III clinical studies (36,066 bococizumab observations, 46,790 low-density lipoprotein cholesterol [LDL-C] measurements, 3499 participants). A two-compartment disposition model with parallel linear and Michaelis-Menten elimination and an indirect response model was used to characterize the population PK and LDL-C response of bococizumab...

Therapeutic antibodies sometimes elicit anti-drug antibodies (ADAs) that can affect efficacy and safety. Engineered antibodies that contain artificial amino acid sequences are potentially highly immunogenic, but this is currently difficult to predict. Therefore, it is important to efficiently assess immunogenicity during the development of complex antibody-based formats. Here, we present an in vitro peripheral blood mononuclear cell-based assay that can be used to assess immunogenicity potential within 3 days...

Historically, the biopharmaceutical industry has used titer to characterize the magnitude of an anti-drug antibody (ADA) response. While reporting levels of antibodies in terms of titer is generally understood and accepted by regulatory and medical communities, titer values are inherently variable given the multiple serial dilutions and reporting a value either directly before or interpolated at the assay cut point on the lower plateau of the assay curve range. Using S/N is an appealing alternative approach to titer as it simplifies analysis with less dilutions, significantly reducing testing, time, and resources and provides a more precise value potentially differentiating low-level ADA responses...

Mammalian display enables the selection of biophysically favorable antibodies from a large IgG antibody library displayed on the plasma membrane of mammalian cells. We constructed and validated a novel mammalian display platform utilizing the commercially available Flp-In CHO cell line as a starting point. We introduced a single copy of a landing pad for Bxb1 integrase-driven recombinase-mediated cassette exchange into the FRT site of the Flp-In CHO line to facilitate the efficient single-copy integration of an antibody display cassette into the genome of the cell line...

Osteoporosis and hyperlipidemia are closely correlated and statins might be associated with a decreased risk of fracture. We aimed to investigate the association between proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) therapy and the risk of fracture. The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to October 22, 2022. Randomized clinical trials (RCTs) that addressed to fracture events of participants using alirocumab, evolocumab, bococizumab or inclisiran, with a follow-up of ≥ 24 weeks were included...

Cardiovascular disease causes significant personal, financial, and societal burden and is a major cause of mortality and morbidity globally. Dyslipidemia has proven to be a major factor that contributes to its increased incidence; thus, since a long time, low-density lipoprotein cholesterol-lowering therapies have been employed to reduce coronary artery disease-associated mortality. The first-line therapy for hyperlipidemia and dyslipidemia is statins. Evidence showed that statins decrease the level of LDL-C resulting in a lower risk of CVD (20-25% for every decrease of 1 mmol/L)...

Self-association governs the viscosity and solubility of therapeutic antibodies in high-concentration formulations used for subcutaneous delivery, yet it is difficult to reliably identify candidates with low self-association during antibody discovery and early-stage optimization. Here, we report a high-throughput protein engineering method for rapidly identifying antibody candidates with both low self-association and high affinity. We find that conjugating quantum dots to IgGs that strongly self-associate (pH 7...

annually in Europe, 4 million people die from cardiovascular diseases, the main cause of which is atherosclerosis. In order to slow down the development of atherosclerotic plaques, the main therapeutic goal is to lower LDL cholesterol (LDL-C) level. Undoubtedly, statins are the basis of lipid-lowering therapy for many years. However, a European study shows that only 43% of statin-taking patients achieved their LDL-C targets. PCSK9 inhibitors are a new group of lipid-lowering drugs whose main point of action is the protein discovered in 2003 - the PCSK9 (proprotein convertase subtilisin/kexin 9)...

Bococizumab is an anti-PCSK9 monoclonal antibody that was intended for the treatment of hypercholesterolemia. After reviewing the 6-month rat toxicity study data, in which there was a low spontaneous tumor incidence, unrelated to bococizumab administration, the U.S. FDA granted a carcinogenicity waiver request based on a weight-of-evidence assessment of low carcinogenic risk. Subsequently, after reviewing 6-month rat toxicity study data from another anti-PCSK9 antibody, RN317, with a similar low tumor incidence (unrelated to RN317), the U...

Objectives: The aim of this study was to provide the first study to systematically analyze the efficacy and safety of PCSK9-mAbs in the treatment of familial hypercholesterolemia (FH). Methods: A computer was used to search the electronic Cochrane Library, PubMed/MEDLINE, and Embase databases for clinical trials using the following search terms: "AMG 145", "evolocumab", "SAR236553/REGN727", "alirocumab", "RG7652", "LY3015014", "RN316/bococizumab", "PCSK9", and "familial hypercholesterolemia" up to November 2020...

BACKGROUND: Safety concerns about proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors make physicians reluctant to prescribe agents for patients. The present aim was to assess the efficacy and safety of alirocumab, evolocumab and bococizumab in patients with atherosclerotic cardiovascular disease (ASCVD). METHODS: Medline, the Cochrane Library and Clinicaltrials.gov were searched for 45 randomized controlled trials, involving 97,297 patients. RESULTS: Compared with the control group, PCSK9 inhibitors could significantly reduce low-density lipoprotein cholesterol, total cholesterol, triglycerides and increase high-density lipoprotein cholesterol...

BACKGROUND: It has been suggested that lipid lowering therapy causes impaired cognitive changes. The association between the use of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk of neurocognitive adverse events remains unclear. This meta-analysis aims to assess neurocognitive safety of PCSK9 inhibitors in randomized controlled trials (RCTs). METHODS AND RESULTS: The research was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)...

Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors are a group of drugs whose main mechanism of action is binding to the PCSK-9 molecule, which reduces the degradation of the low-density lipoprotein receptor (LDL-R) and, hence, increases the uptake of low-density lipoprotein cholesterol (LDLc) from the bloodstream as well as reducing its concentration. The effectiveness of three monoclonal antibodies, namely, alirocumab (human IgG1/κ monoclonal antibody, genetically engineered in Chinese hamster ovary cells), evolocumab (the first fully human monoclonal antibody), and bococizumab (humanized mouse antibody), in inhibiting the action of PCSK-9 and reducing LDLc levels has been confirmed...

PURPOSE: Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors treatment induce large reductions in low-density lipoprotein cholesterol (LDLc) and major cardiovascular events. Clinical trials might have been underpowered to test the effect of PSCK9 inhibitors treatment on myocardial infarction and stroke, two of the most relevant cardiovascular events, since all analyzed a combined endpoint. METHODS: we performed a meta-analysis, with currently available studies involving PCSK9 inhibitors and event rate adjudication, with the aim of assessing treatment effects on myocardial infarction and stroke...

AIMS: The neutrophil-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that may associate with atherosclerosis and predict cardiovascular (CV) events. The aims of this study are to determine whether the NLR predicts incident major adverse cardiovascular events (MACE) and is modified by anti-inflammatory therapy. METHODS AND RESULTS: Baseline and on-treatment NLRs were calculated from complete blood counts among 60 087 participants randomized in the CANTOS, JUPITER, SPIRE-1, SPIRE-2, and CIRT trials to receive placebo or canakinumab, rosuvastatin, bococizumab, or methotrexate, respectively, and followed up for MACE...

INTRODUCTION: The market for monoclonal antibody (mAb) therapies is growing rapidly as the pharmaceutical industry expands its development across a broad spectrum of diseases. Unfortunately, as shown in the recent failure of bococizumab by Pfizer, these treatments often stimulate formation of problematic anti-drug antibodies (ADAs). ADAs can cause side effects and limit efficacy for many patients. To increase efficacy and decrease safety concerns from ADAs, immunogenicity characterization is needed early in the drug development process...

The early phase of protein drug development has traditionally focused on target binding properties leading to a desired mode of therapeutic action. As more protein therapeutics pass through the development pipeline; however, it is clear that non-optimal biophysical properties can emerge, particularly as proteins are formulated at high concentrations, causing aggregation or polyreactivity. Such late-stage "developability" problems can lead to delay or failure in traversing the development process. Aggregation propensity is also correlated with increased immunogenicity, resulting in expensive, late-stage clinical failures...

Validation of key analytical and functional performance characteristics of in vitro immunogenicity risk assessment assays increases our confidence in utilizing them for screening biotherapeutics. Herein, we present a fit-for-purpose (FFP) validation of a dendritic cell (DC) activation assay designed to assess the immunogenicity liability of protein biotherapeutics. Characterization of key assay parameters was achieved using monocyte-derived DCs (MoDCs) treated with cell culture medium only (i.e., background control (BC)), keyhole limpet hemocyanin (KLH) as system positive control (SPC), and 2 therapeutic monoclonal antibodies (mAbs) with known clinical immunogenicity profiles (bococizumab and TAM163) as therapeutic controls (TCs)...

BACKGROUND: Evidence shows a positive association between the use of statins and new-onset diabetes. There is, however, contradictory evidence as to whether a similar association exists for the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. OBJECTIVE: The aim of this study was to investigate the safety of PCSK9 monoclonal antibodies (PCSK9-mAbs) in regard to incident diabetes. METHODS AND RESULTS: Randomized controlled trials that reported data on the incidence of new-onset diabetes mellitus or the worsening of pre-existing diabetes were searched, and risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare the endpoints...

OBJECTIVE: Bococizumab, a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, has been shown to reduce low-density lipoprotein cholesterol (LDL-C). Here, we describe the pharmacokinetics and pharmacodynamics of bococizumab and its effect on lipoprotein particle composition and other biomarkers, based on a double-blind, placebo-controlled, randomized, dose-ranging study. MATERIALS AND METHODS: The study consisted of two populations: Japanese subjects with uncontrolled LDL-C (LDL-C ≥ 100 mg/dL) despite treatment with atorvastatin (n = 121) and Japanese subjects naïve to lipid-lowering agents with LDL-C ≥ 130 mg/dL (n = 97)...