bococizumab (RN316) / Pfizer - LARVOL DELTA

COMPARATIVE EFFICACY, SAFETY, AND LONG-TERM OUTCOMES OF INJECTABLE CHOLESTEROL-LOWERING AGENTS: A NETWORK META-ANALYSIS OF ALIROCUMAB, EVOLOCUMAB, INCLISIRAN, AND MIPOMERSEN - Rakhshanda Khan (ACC 2025) - "Risk of bias was assessed using ROB 2.0. PCSK9 inhibitors, including Alirocumab, Evolocumab, Bococizumab, and Inclisiran, significantly reduced LDL-C levels, with reductions over 60%. PCSK9 inhibitors, particularly alirocumab and evolocumab, significantly reduce LDL-C and lower the risk of myocardial infarction, stroke, and revascularization. These agents provide a promising adjunct to statin therapy in high-risk patients with a favorable safety profile, supporting their role in improving long-term CV outcomes. Further research is needed on their long-term cost-effectiveness and clinical impact."

Retrospective data • Atherosclerosis • Cardiovascular • Myocardial Infarction

PCSK9 Inhibitors: The Evolving Future. (PubMed, Health Sci Rep) - "In the FOURIER trial, evolocumab reduced LDL-C by 59% and major cardiovascular events by 15%-20%. The SPIRE-2 trial, despite early termination, showed a 21% risk reduction in the primary composite endpoint with bococizumab. The ODYSSEY Outcomes trial reported a 57% LDL-C reduction with alirocumab, alongside a 15% reduction in adverse events. Emerging treatments like Inclisiran offer long-term LDL-C control with fewer doses...PCSK9 inhibitors significantly lower LDL-C and reduce cardiovascular events, offering promising therapies for high-risk patients, including those with familial hypercholesterolemia (FH) and those who cannot tolerate statins. Future research will focus on optimizing these inhibitors, integrating complementary therapies, and exploring gene-editing technologies to improve patient outcomes."

Journal • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Metabolic Disorders

PCSK9 Monoclonal Antibodies Have Come a Long Way. (PubMed, Curr Atheroscler Rep) - "This review highlights the benefits of PCSK9 Mabs in high cardiovascular risk patients. Despite their efficacy and safety, these therapies are hindered by limited access, and require broader integration into clinical practice to optimize therapeutic outcomes."

Journal • Review • Cardiovascular

Effects of lipid-lowering therapies on lipoprotein(a) levels in patients with dyslipidemia: a systematic review and network meta-analysis of 64 randomised controlled trials (ESC 2024) - "The percentage change of serum Lp(a) levels, cardiovascular and safety outcomes were compared among statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin), fibrates, ezetimibe, niacin, PCSK9 inhibitors (alirocumab, evolocumab, bococizumab) and inclisiran, in patients with primary dyslipidemia... PCSK9 inhibitors produced the greatest effect on Lp(a) levels, compared with other lipid-lowering therapies. Further studies into PCSK9 inhibitors are necessary to characterise their efficacy and safety specifically for Lp(a)-lowering, and elucidate the impact of Lp(a) reduction on cardiovascular risk."

Retrospective data • Review • Cardiovascular • Dyslipidemia

Efficacy of lipid lowering therapy beyond statins to prevent cardiovascular events (ESC 2024) - " We performed a systematic search using the Pubmed, Cochrane, SCOPUS, and Web of Science databases for studies, evaluating the impact of an intensified lipid lowering therapy via ezetimibe, bempedoic acid, Bococizumab, Alirocumab, Evolocumab, Inclisiran in addition to statin therapy compared to statin therapy alone. Intensified LDL-lowering therapy with ezetimibe, bempedoic acic or PCSK-9 inhibitors, in addition to statins, reduces the risk of myocardial infarction and stroke, however, does not impact overall mortality. A potential survival benefit was also not observed in studies with follow-up duration of ≥ 3 years."

Clinical • Cardiovascular • Coronary Artery Disease • Ischemic stroke • Myocardial Infarction

PCSK9 inhibitors and inclisiran with or without statin therapy on incident muscle symptoms and creatine kinase: a systematic review and network meta-analysis. (PubMed, Front Cardiovasc Med) - "For events with creatine kinase >3ULN, evolocumab and alirocumab demonstrated significant advantages compared to inclisiran...Based on this network meta-analysis (NMA) results, evolocumab has emerged as a promising treatment option for patients with hyperlipidemia and muscle disorders compared to other PCSK9 inhibitors and inclisiran. PROSPERO [CRD42023459558]."

Journal • Retrospective data • Review • Atherosclerosis • Cardiovascular • Dyslipidemia

Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG1 antibodies. (PubMed, MAbs) - "A panel of related monospecific and bispecific IgG1 antibodies was constructed and assessed for immunogenicity risk by comparison with benchmark antibodies with known low (Avastin and Herceptin) or high (bococizumab and ATR-107) clinical incidence of anti-drug antibodies. Comparable or slightly higher immunogenicity risk assessment data were obtained for research-grade preparations of trastuzumab and bevacizumab versus Herceptin and Avastin, respectively. These data provide experimental support for the common practice of using research-grade preparations of IgG1 as surrogates for immunogenicity risk assessment of their corresponding pharmaceutical counterparts."

Journal

Rapid in vitro assessment of the immunogenicity potential of engineered antibody therapeutics through detection of CD4 T cell interleukin-2 secretion. (PubMed, MAbs) - "Seven antibodies with known rates of immunogenicity (etanercept, emicizumab, abciximab, romosozumab, blosozumab, humanized anti-human A33 antibody, and bococizumab) induced responses in 1.9%, 3.8%, 6.4%, 10.0%, 29.2%, 43.8%, and 89.5% of donors, respectively. These data are comparable with ADA incidences in clinical settings. Our results show that this assay can contribute to the swift assessment and mechanistic understanding of the immunogenicity of therapeutic antibodies."

Journal • Preclinical • CD4 • IL2

Anti-drug Antibody Magnitude and Clinical Relevance Using Signal to Noise (S/N): Bococizumab Case Study. (PubMed, AAPS J) - "The impact of anti-bococizumab antibodies on pharmacokinetic (PK) and pharmacodynamic (PD) endpoints was originally assessed using titer. Retrospective analysis of anti-bococizumab ADA responses using S/N ratios illustrates that S/N is an acceptable alternative to titer for characterizing the magnitude of ADA response and interpretation of clinically relevant ADA."

Journal • Dyslipidemia

The effect of proprotein convertase subtilisin/kexin type 9 inhibition on the plasma proteome: a SPIRE sub-study (ESC 2023) - "Methods In 190 patients participating in the SPIRE-1/2 trials, 184 targeted proteins were measured at baseline and after 12 months of bococizumab treatment using the Cardiovascular II and III panels (Sweden)...The local effects on cellular and vascular inflammation by PCSK9 inhibition observed in earlier studies most likely reflect a direct consequence of a reduced cholesterol content in inflammatory cells and plaques, subsequently leading to a local anti-inflammatory effect. These findings support the combination of targeted anti-inflammatory therapies on top of potent LDL-C lowering in order to further reduce the residual inflammatory risk."

Cardiovascular • Dyslipidemia • CRP

Selection of biophysically favorable antibody variants using a modified Flp-In CHO mammalian display platform. (PubMed, Front Bioeng Biotechnol) - "Enrichment of bococizumab variants via fluorescence-activated cell sorting selections was followed by next generation sequencing and thorough characterization of biophysical properties of 10 bococizumab variants that subsequently allowed attribution of the mutations to the biophysical properties of the antibody variants. The mammalian displayed variants exhibited reduced aggregation propensity and polyreactivity, while critically retaining its target binding thereby demonstrating the utility of this valuable tool."

Journal

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and the Risk of Fracture: A Systematic Review and Meta-analysis of Randomized Controlled Trials. (PubMed, Calcif Tissue Int) - "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. No significant associations were detected in any of the sensitivity analyses and subgroup analyses stratified by the type of PCSK9i, follow-up duration, age, sex, sample size, and patient profile. Pooled results of our meta-analysis showed that exposure to PCSK9i was not associated with reduced risks of fracture in the short term."

Clinical • Journal • Retrospective data • Review • Dyslipidemia • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology

Genetics, Safety, Cost-Effectiveness, and Accessibility of Injectable Lipid-Lowering Agents: A Narrative Review. (PubMed, J Lipids) - "Moreover, bococizumab was recently suspended due to its higher immunogenicity with time, resulting in less efficacy with long-term use. Current data from phase 2 and 3 trials (ORION, ODYSSEY, and FOURIER) suggest a favorable profile for evolocumab, alirocumab, and inclisiran with minimal tolerable side effects and superior efficacy in statin-intolerant patients. Their cost-effectiveness has not yet been established clearly, but future outcomes seem promising."

Clinical • Cost effectiveness • HEOR • Journal • Review • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Metabolic Disorders

Reduction of therapeutic antibody self-association using yeast-display selections and machine learning. (PubMed, MAbs) - "We find that conjugating quantum dots to IgGs that strongly self-associate (pH 7.4, PBS), such as lenzilumab and bococizumab, results in immunoconjugates that are highly sensitive for detecting other high self-association antibodies. Moreover, negatively charged mutations in the heavy chain CDR2 of bococizumab, adjacent to its paratope, were effective at reducing self-association without reducing affinity. Interestingly, most of the bococizumab variants with reduced self-association also displayed improved folding stability and reduced nonspecific binding, revealing that this approach may be particularly useful for identifying antibody candidates with attractive combinations of drug-like properties.Abbreviations: AC-SINS: affinity-capture self-interaction nanoparticle spectroscopy; CDR: complementarity-determining region; CS-SINS: charge-stabilized self-interaction nanoparticle spectroscopy; FACS: fluorescence-activated cell sorting; Fab: fragment antigen binding; Fv:..."

Journal • CDR2

Safety of PCSK9 inhibitors. (PubMed, Biomed Pharmacother) - "The discovery of this protein was soon after the basis for the start of research, thanks to which three monoclonal antibodies against PCSK9 were developed - evolocumab, alirocumab, bococizumab - and inclisiran, an inhibitor of PCSK9 synthesis in the liver. Until the registration and introduction of above-mentioned drugs into everyday clinical practice, many studies were carried out, in which, in addition to assessing the effectiveness of treatment, the safety and tolerability of the drug were also examined. The purpose of this review is to summarize information on the safety profile of PCSK9 inhibitors, which may help in making therapeutic decision."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Immunology • Inflammation

Regulatory Experience Assessing the Carcinogenic Potential of a Monoclonal Antibody Inhibiting PCSK9, Bococizumab, Including a 2-Year Carcinogenicity Study in Rats. (PubMed, Int J Toxicol) - "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.S. FDA rescinded the bococizumab carcinogenicity study waiver and requested a full 2-year rat carcinogenicity study be conducted. The resulting 2-year carcinogenicity study demonstrated no bococizumab-related increase in tumors, confirming the weight-of-evidence evaluation and alleviating concerns regarding the carcinogenic potential. Here we report the scientific and regulatory background that led to the request for a rat carcinogenicity study, the feedback on the design of the carcinogenicity study, and the results from this study which affirmed the original weight-of-evidence assessment of low carcinogenic risk."

Journal • Preclinical • Dyslipidemia • Metabolic Disorders • Oncology

Genome-wide pharmacogenetics of anti-drug antibody response to bococizumab highlights key residues in HLA DRB1 and DQB1. (PubMed, Sci Rep) - P3 | "Two clusters of missense variants at DRB1 were associated with general ADA measures (residues 9, 11, 13; and 96, 112, 120, 180) and a third cluster of missense variants in DQB1 was associated with ADA measures including neutralizing antibody (NAb) titers (residues 66, 67, 71, 74, 75). The structural disposition of the missense substitutions implicates peptide antigen binding and CD4 effector function, mechanisms that are potentially generalizable to other therapeutic mAbs.Clinicaltrials.gov: NCT01968954, NCT01968967, NCT01968980, NCT01975376, NCT01975389, NCT02100514."

Biomarker • Journal • Cardiovascular • CD4 • HLA-DRB1

A Systematic Review and Meta-Analysis of Therapeutic Efficacy and Safety of Alirocumab and Evolocumab on Familial Hypercholesterolemia. (PubMed, Biomed Res Int) - "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. Moreover, no significant difference was found between PCSK9-mAbs treatment and placebo in common adverse events, serious events, and laboratory adverse events. PCSK9-mAbs significantly decreased LDL-C and other lipid levels with satisfactory safety and tolerability in FH treatment."

Journal • Retrospective data • Review • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Metabolic Disorders • APOA1 • APOB

Efficacy and safety of PCSK9 inhibition in cardiovascular disease: a meta-analysis of 45 randomized controlled trials. (PubMed, Cardiol J) - "Alirocumab and evolocumab could ameliorate lipid profile and reduce the risk of cardiac disorders and stroke with satisfactory safety and tolerability. However, injection-site reactions should be paid attention to."

Journal • Retrospective data • Atherosclerosis • Cardiovascular • Dyslipidemia • Myocardial Infarction

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk for neurocognitive adverse events: A systematic review, meta-analysis and meta-regression. (PubMed, Int J Cardiol) - "Pooled results of our meta-analysis and meta-regression show that exposure to PCSK9 inhibitors is not associated with an increased risk of neurocognitive adverse effects."

Adverse events • Journal • Retrospective data • Review

Pleiotropic Effects of PCSK-9 Inhibitors. (PubMed, Int J Mol Sci) - "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...They are currently used both as monotherapy and in combination with statins and ezetimibe to intensify therapy and achieve therapeutic goals following the American Heart Association (AHA) and European Society of Cardiology (ESC) guidelines...The article focuses on activities other than lipid-lowering, such as the anti-atherosclerotic effect and stabilization of atherosclerotic plaque, the anti-aggregation effect, the anticoagulant effect, the antineoplastic effect, and the ability to influence the course of bacterial infections. In this publication, we try to systematically review the current scientific data, both from our own..."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Infectious Disease • Metabolic Disorders • Oncology

Prevention of myocardial infarction and stroke with PCSK9 inhibitors treatment: a metanalysis of recent randomized clinical trials. (PubMed, J Diabetes Metab Disord) - "We included 81,700 patients, 41,979 treated with a PSCK9 inhibitors: 17,244 with evolocumab; 13,720 with bococizumab and 11,015 with alirocumab. PCSK9 inhibitors treatment had no effect on mortality (RR: 0.95, 95% CI 0.86-1.04). PCSK9 inhibitors reduce the incidence of myocardial infarction by 19% and stroke by 25%."

Clinical • Journal • Acute Coronary Syndrome • Cardiovascular • Dyslipidemia • Myocardial Infarction

The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials. (PubMed, Eur Heart J) - "The NLR, an easily obtained inflammatory biomarker, independently predicts CV risk and all-cause mortality, and is reduced by interleukin-1β blockade with canakinumab."

Clinical • Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Hematological Disorders • Immunology • Inflammation • Thrombosis

Epitope Characterization of Anti-drug Antibodies-A Tool for Discovery and Health An overview of the necessity of early epitope characterization to avoid anti-drug antibodies and promote patient health. (PubMed, Expert Opin Biol Ther) - "Unfortunately, as shown in the recent failure of bococizumab by Pfizer, these treatments often stimulate formation of problematic anti-drug antibodies (ADAs)...We propose using high-information assays to characterize epitopes to help mAb therapy engineering and potentially improve individual patient outcomes. To understand this, we will discuss three different aspects of ADAs: (1) the problem of ADAs and what is currently being done about them, (2) the current state of epitope characterization and how it's being utilized, and (3) how early epitope characterization can advance drug discovery and improve outcomes for patients taking mAb therapies."

Clinical • Journal

Late-Stage Failures of Monoclonal Antibody Drugs: A Retrospective Case Study Analysis. (PubMed, Pharmacology) - "By learning from previous mistakes and adhering to the principles and recommendations provided, it is possible to avoid these common pitfalls, increasing the likelihood of success in phase III clinical trials, and thus securing regulatory approval."

Journal • Retrospective data • Review