PCSK9 Monoclonal Antibodies Have Come a Long Way.

PURPOSE OF THE REVIEW: This review examines the pivotal role of monoclonal antibodies against PCSK9 in lipid-lowering therapy, emphasizing their biological and clinical impact. RECENT FINDINGS: Randomized controlled trials have validated that PCSK9 monoclonal antibodies (Mabs) effectively reduce LDL-c levels by approximately 50%, even when added to maximal statin therapy. They moreover produce a notable 15-20% relative decrease in major cardiovascular events, with a greater reduction among high-risk patients and no evidence for serious adverse effects, assuaging previous concerns. 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.

PCSK9 inhibitors and inclisiran with or without statin therapy on incident muscle symptoms and creatine kinase: a systematic review and network meta-analysis.

Background: Atherosclerotic cardiovascular disease (ASCVD), a leading cause of global fatalities, has inconsistent findings regarding the impact of muscle symptoms despite promising clinical trials involving PCSK9 inhibitors (PCSK9i) and siRNA as potential therapeutic options. Methods: The databases EMBASE, PubMed, Web of Science, Cochrane, and ClinicalTrials.gov were thoroughly searched without any restrictions on language. Review Manager 5.3 software was utilized to calculate relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences or standardized mean differences with 95%CIs for continuous data. To evaluate publication bias, Egger's test was employed using Stata/SE software. Results: This analysis included 26 studies comprising 28 randomized controlled trials (RCTs) involving a total of 100,193 patients, and 4 different lipid-lowering therapy combinations. For events with creatine kinase >3ULN, evolocumab and alirocumab demonstrated significant advantages compared to inclisiran. Evolocumab showed the best results in terms of both new muscle symptom events and creatine kinase >3ULN. Conclusions: 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. Systematic Review Registration: PROSPERO [CRD42023459558].

Safety of PCSK9 inhibitors.

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). This protein is responsible for reducing the density of LDL receptors on the surface of hepatocytes, which increases the value of LDL-C. 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. In addition to the mechanism of action of PCSK9 inhibitors, resulting in lowering LDL-C level, a number of pleiotropic mechanisms have also been identified, including effects on metabolic processes and inflammation. 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.

PCSK9 Monoclonal Antibodies: An Overview.

PCSK9 monoclonal antibodies are novel lipid-lowering therapy that have been extensively studied in patients with hypercholesterolemia either as monotherapy or as an add-on to other LLTs. PCSK9 monoclonal antibodies have significantly reduced the low-density lipoprotein cholesterol (LDL-C) plasma level resulting in a better LDL-C goal attainment. The commercially available PCSK9 monoclonal antibodies, alirocumab and evolocumab, have demonstrated reductions in major adverse cardiovascular events such as myocardial infarction, stroke, unstable angina, and the need for coronary revascularization but not mortality. PCSK9 monoclonal antibodies have demonstrated a favorable safety profile. The most reported side effects are mild injection site with no causal relationship proven between the inhibition of PCSK9 and neurocognitive or glycemic adverse events. In this overview, the efficacy and safety of PCSK9 monoclonal antibodies in the treatment of primary and familial hypercholesterolemia will be discussed.

Efficacy and safety of PCSK9 monoclonal antibodies: an evidence-based review and update.

OBJECTIVE: Treatment of dyslipidemia lowers cardiovascular (CV) risk. Although statin use is a cornerstone therapy, many patients are not achieving their risk-specific low-density lipoprotein cholesterol (LDL-C) goals. The proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies have been extensively studied as lipid-lowering therapy (LLT). Herein, we present an updated evidence-based review of the efficacy and safety of PCSK9 monoclonal antibodies in the treatment of familial and non-familial hypercholesterolemia. METHODS: PubMed database was searched to review Phase III studies on PCSK9 monoclonal antibodies. Then, the US National Institutes of Health Registry and the WHO International Clinical Trial Registry Platform were searched to identify and present the ongoing research. RESULTS: PCSK9 monoclonal antibodies were investigated for the treatment of dyslipidemia, as a single therapeutic agent or as an add-on therapy to the traditional LLT. They proved effective and safe in the treatment of familial and non-familial hypercholesterolemia, and in the prevention of adverse CV events. CONCLUSIONS: The use of PCSK9 monoclonal antibodies in the treatment of dyslipidemia is currently recommended to achieve risk-specific LDL-C goal to reduce adverse CV events. Future results of the ongoing research might expand their clinical generalizability to broader patient populations.

Late-Stage Failures of Monoclonal Antibody Drugs: A Retrospective Case Study Analysis.

AIM: To analyze the late-stage failures of monoclonal antibody drugs. The later a drug fails in development, the more time and expense is incurred by the sponsor. METHODS: We review the late stage, Phase III, failures of 21 monoclonal antibody drugs between 2014 and 2019 using published and publicly available information to characterize the reasons for these failures. RESULTS: In some cases, the failures are unavoidable due to the lack of adequate science, but in others, we characterize the causes of such failures and recommend how such failures may have been avoided. CONCLUSION: 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.

PCSK9 inhibitors and cardiovascular outcomes.

Introduction: Dyslipidemia, particularly elevated low-density lipoprotein cholesterol (LDL-C), is a key risk factor for atherosclerotic cardiovascular disease (ASCVD), and lipid-lowering drugs are beneficial for the primary and secondary prevention of cardiovascular (CV) disease. While statins are clear first-line drugs, new drug developments such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to improve cardiovascular outcomes when added to statins. Evolocumab reduced the risk of cardiovascular events in patients with ASCVD when added to maximally tolerated statin therapy (± ezetimibe), and recent data from the ODYSSEY OUTCOMES trial indicate that alirocumab added to maximally tolerated statin therapy (± other lipid-lowering drugs) reduces the risk of cardiovascular events in patients with a recent acute coronary syndrome. In this article the authors review the available data on the effect of PCSK9 inhibitors on cardiovascular outcomes.Areas covered: This article reviews the available data on the effect of PCSK9 inhibitors on CV outcomes. Relevant papers were identified from a search of PubMed/Medline and the Cochrane Central Register of Controlled Trials (CENTRAL).Expert opinion: The authors conclude that PCSK9 inhibitors provide substantial and durable reductions in LDL-C levels and improve cardiovascular outcomes.

Efficacy and safety of PCSK9 monoclonal antibodies.

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have been developed since the discovery of the PCSK9 protein in 2003. In addition to background statin treatment, they reduce low-density lipoprotein cholesterol (LDL-C) to unprecedented levels and have shown encouraging results in improving cardiovascular events. Concerns regarding the safety of PCSK9 inhibitors and very low LDL-C have somewhat been allayed after several longer-term prospective studies.Areas covered: A comprehensive literature search was carried out including article searches in electronic databases (EMBASE, PUBMED, OVID) and reference lists of relevant articles. This review examines novel research concerning PCSK9 monoclonal antibodies and cardiovascular outcomes with a special focus on their safety and tolerability. The safety of very low LDL-C concentrations and the link between LDL-C lowering and diabetes is also discussed.Expert opinion: PCSK9 monoclonal antibodies when added to background statin therapy, lowers LDL-C to previously unattainable levels. This is safe with little undesirable effects and impacts positively on cardiovascular disease. Current guidance limits their use to primary prevention. Cost effectiveness should be taken into consideration before allowing a wider use of this new class of cholesterol lowering therapy and more data on their long-term safety is welcome.

Discontinued Drugs for the Treatment of Cardiovascular Disease from 2016 to 2018.

Cardiovascular drug research and development (R&D) has been in active state and continuously attracts attention from the pharmaceutical industry. However, only one individual drug can eventually reach the market from about the 10,000 compounds tested. It would be useful to learn from these failures when developing better strategies for the future. Discontinued drugs were identified from a search performed by Thomson Reuters Integrity. Additional information was sought through PubMed, ClinicalTrials.gov, and pharmaceutical companies search. Twelve compounds discontinued for cardiovascular disease treatment after reaching Phase I-III clinical trials from 2016 to 2018 are detailed in this manuscript, and the reasons for these failures are reported. Of these, six candidates (MDCO-216, TRV027, ubenimex, sodium nitrite, losmapimod, and bococizumab) were dropped for lack of clinical efficacy, the other six for strategic or unspecified reasons. In total, three candidates were discontinued in Phase I trials, six in Phase II, and three in Phase III. It was reported that the success rate of drug R&D utilizing selection biomarkers is higher. Four candidate developments (OPC-108459, ONO-4232, GSK-2798745, and TAK-536TCH) were run without biomarkers, which could be used as surrogate endpoints in the 12 cardiovascular drugs discontinued from 2016 to 2018. This review will be useful for those involved in the field of drug discovery and development, and for those interested in the treatment of cardiovascular disease.

Comments on the most important and recent studies involving PCSK9i.

The paper provides a brief overview of the key studies focused on PCSK9 inhibitors. It mainly examines positive results of the FOURIER studies on evolocumab, the SPIRE study on boccocizumab and the ODYSSEY Outcomes study on alirocumab. All these studies have not only shown a significant decrease in LDL-cholesterol levels, but also the reduction of cardiovascular events just correlating with these levels. The treatment leading to a dramatic drop in LDL-cholesterol levels was safe and well tolerated by patients. All the studies provided with comments demonstrate a positive impact of biological treatment of hypercholesterolemia on cardiovascular disease and confirm validity of the hypothesis saying “the lower the better”, at least for LDL-cholesterol. In conclusion, Professor Braunwalds hypothesis is mentioned saying that this treatment might eventually lead to as much as eradication of atherothrombotic cardiovascular diseases. Key words: alirocumab - bococizumab - evolocumab - FOURIER - cardiovascular disease - LDL-cholesterol - ODYSSEY Outcomes - SPIRE.

Comparative Pharmacokinetics and Pharmacodynamics of Bococizumab Following a Single Subcutaneous Injection Using Drug Substance Manufactured at Two Sites or Administration via Two Different Devices.

The pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, were compared following a single 150-mg subcutaneous dose administered to healthy subjects (n = 156-158/arm) via: (1) a prefilled syringe (PFS) using drug substance (DS) manufactured by Pfizer, (2) a PFS using DS manufactured by Boehringer Ingelheim Pharma, (3) a prefilled pen using DS manufactured by Pfizer (NCT02458209). Blood samples were collected for 12 weeks postdose. Safety was monitored throughout. Mean maximum plasma concentration (Cmax ) ranged between 11.0 and 11.3 µg/mL, and area under the plasma concentration-time curve (AUCinf ) ranged between 177.6 and 185.0 µg·day/mL across treatments. The 90% confidence intervals for the ratios of adjusted geometric means for Cmax and AUCinf fell within the 80%-125% range for both DS and delivery device comparisons. Comparable low-density lipoprotein cholesterol profiles were observed, with nadir values of 54.3-56.1 mg/dL across treatments. Similar PCSK9 responses were also observed. Safety profiles were similar across treatments, and the majority of adverse events (AEs) were mild. Three subjects reported serious AEs. The most frequently reported AEs were headache, injection-site reaction, and upper respiratory tract infection, with no clear differences across treatments. Comparable PK, PD, and safety were observed following a single bococizumab 150-mg subcutaneous injection regardless of site of DS manufacture or delivery device used.

Pharmacology of PCSK9 Inhibitors: Current Status and Future Perspectives.

Protein Convertase Subtilisin/Kexin type 9 (PCSK9) is a serine protease primarily expressed in the liver, which represents the main source of the plasma enzyme. The best characterized function of PCSK9 relates to the binding to Low-Density Lipoprotein Receptor (LDL-R) in hepatocytes, increasing its endosomal and lysosomal degradation. This results in the inhibition of LDL-R recycling to the cell surface and therefore the reduction of the hepatic uptake of LDL, leading to the increase in plasma levels of LDL-cholesterol, a major risk factor of Cardiovascular Diseases (CVD). Therefore, PCSK9 is an important therapeutic target to reduce LDLcholesterol levels. PCSK9 inhibition can occur at the level of its interaction with LDL-R as well as at several sites across the pathway of its intracellular synthesis and secretion. Two fully human mAbs, Alirocumab and Evolocumab, that selectively bind to PCSK9 and prevent its interaction with the LDL-R, are currently used in the clinical practice. These mAbs are the most potent cholesterol-lowering agents available today and can decrease LDLcholesterol levels up to 73% while they also reduce the risk of atherosclerotic CVD. Ongoing research has led to the development of new PCSK9 inhibitors through genome editing technology (CRISPR-Cas9), siRNA or antisense oligonucleotide silencing agents, vaccines, mimetic peptides, adnectins, and inhibitors of PCSK9 secretion. The above inhibitors have been studied in vitro, in animal models in vivo, as well as in phase I and II trials and have demonstrated an important efficacy profile. Future studies with these agents will demonstrate their possible clinical value and will further enlighten the various targets and activities of PCSK9 intracellularly and extracellularly, the underlying mechanisms, as well as the clinical significance of these actions beyond the inhibition of LDL-R recycling.

The effects of single- and multiple-dose administration of bococizumab (RN316/PF-04950615), a humanized IgG2Δa monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin: Results from four phase I studies.

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 (0.5 or 4 mg/kg; no placebo) added to ongoing atorvastatin 40 mg/day (N = 24); (3) single, fixed, subcutaneous (SC) bococizumab (100 or 200 mg), or IV bococizumab (200 mg; no placebo; N = 49; baseline LDL-C ≥130 mg/dL); and (4) weekly IV bococizumab (0.25, 0.5, 1, or 1.5 mg/kg) or placebo for 4 weeks (N = 67; baseline LDL-C ≥130 mg/dL). RESULTS: Bococizumab pharmacokinetics were well characterized following single IV or SC doses and following multiple IV doses. Exposure to single-dose bococizumab increased slightly greater than dose-proportionally and clearance decreased with increasing dose. In the single-dose studies, maximal mean percent reductions from baseline in LDL-C ranged from 43% (0.3 mg/kg) to 84% (18 mg/kg) in bococizumab-treated subjects, compared with 2% for placebo. For the multiple-dose study, maximal reductions in LDL-C ranged from 55% (0.25 mg/kg) to 66% (1 mg/kg) in bococizumab-treated subjects, compared with 9% for placebo. In all studies, adverse events were infrequent, transient, and not dose-related. CONCLUSIONS: Bococizumab was generally safe and well tolerated. Bococizumab lowered LDL-C levels substantially in all four studies.

Pharmacokinetics, pharmacodynamics, and safety of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, in healthy subjects when administered in co-mixture with recombinant human hyaluronidase: A phase 1 randomized trial.

AIM: Prior to the discontinuation of bococizumab's clinical development, it was considered advantageous to develop an infrequent dosing regimen (eg, monthly). Therefore, we conducted a phase 1 study to evaluate the pharmacokinetics, pharmacodynamics, and safety of bococizumab when administered in co-mixture with recombinant human hyaluronidase (rHuPH20). METHOD: Healthy subjects (N = 60) were randomized equally among 4 groups that received a single subcutaneous dose of either bococizumab 150, 300, or 450 mg co-mixed with rHuPH20 or bococizumab 300 mg alone. Bioavailability and lipid-lowering effect of bococizumab were evaluated by using ANCOVA models. RESULTS: In the groups administered bococizumab co-mixed with rHuPH20, dose-normalized C max and AUCinf were 26.6 to 39.1% and 18.3 to 36.6% greater, respectively, compared with bococizumab 300 mg alone. Despite these increases, mean percent reductions from baseline in low-density lipoprotein cholesterol were smaller in the bococizumab 300 mg + rHuPH20 group than in the bococizumab 300-mg group at Day 21 (52.2% and 59.5%, respectively) and were similar at Day 29 (51.7% and 49.6%, respectively). Compared with the group administered bococizumab 300 mg alone, the bococizumab 300 mg + rHuPH20 group did not show a significantly altered AUEC85 (ratio of adjusted means: 102.5%, 90% confidence interval: 96.1-109.3%) but did show a higher MaxELDL-C (ratio of adjusted means: 125.4%, 90% confidence interval: 103.3-152.2%), indicating diminution of efficacy. The most frequent adverse events were injection-site erythema, injection-site bruising, and nasopharyngitis; all injection-site adverse events were mild. CONCLUSION: Co-mixture with rHuPH20 increased the bioavailability of bococizumab without proportional increase in pharmacodynamic effect. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02667223.

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.

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 0.25, 1, 3, or 6 mg/kg. In Study 2, 45 subjects with LDL-C ≥80 mg/dL received IV placebo or bococizumab 1 or 3 mg/kg. Subjects were treated every 4 weeks for 12 weeks. Dosing was interrupted if LDL-C dipped to ≤25 mg/dL and resumed if LDL-C returned to ≥40 mg/dL. The primary endpoint was percent LDL-C reduction from baseline at Week 12. RESULTS: At Week 12, the reductions from baseline in LDL-C vs placebo in the bococizumab 0.25, 1, 3, and 6 mg/kg groups were 9.3%, 10.2%, 41.6%, and 52.0%, respectively (P < .001 vs placebo for all). LDL-C reductions were greater (69.9%) in subjects who received all three doses of bococizumab 6 mg/kg (P < .001 vs placebo). Pharmacogenomic analysis revealed that 15% of hyperlipidemic subjects carried polymorphisms associated with familial hypercholesterolemia, with maximal LDL-C reductions being similar between carriers and noncarriers. Adverse events were mild, unrelated to bococizumab, and resolved by Week 12. CONCLUSIONS: These studies demonstrated that bococizumab safely and effectively lowered LDL-C in hypercholesterolemic subjects on high doses of statin.

Effects of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibition with Bococizumab on Lipoprotein Particles in Hypercholesterolemic Subjects.

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. In study 1, a total of 67 hypercholesterolemic subjects received IV placebo or bococizumab 0.25, 0.5, 1, or 1.5 mg/kg weekly for 4 weeks. In studies 2 and 3, a total of 135 hypercholesterolemic subjects taking statins received IV placebo or bococizumab 0.25, 1, 3, or 6 mg/kg monthly for 12 weeks. Lipoprotein particle concentration and size were measured by using nuclear magnetic resonance spectroscopy. FINDINGS: Overall, the majority of subjects were men (51.9%) aged >50 years of age and of white ethnic origin. In total, 189 subjects with both baseline and 2-week posttreatment data were included in the analysis. After PCSK9 inhibition with bococizumab 0.5, 1, 1.5, 3, and 6 mg/kg, concentrations of total LDL, total small LDL, and small VLDL particles decreased significantly versus baseline and placebo (P < 0.05), whereas concentrations of HDL particles increased (P < 0.05). The size of the LDL, VLDL, and HDL particles increased after PCSK9 inhibition. Reductions in LDL-C and total LDL particle concentrations were highly correlated. IMPLICATIONS: The effect of inhibiting PCSK9 with bococizumab on lipoprotein particle concentration and size are consistent with the general mechanism of PCSK9 inhibitors in blocking PCSK9-mediated downregulation of LDL receptors. PCSK9 inhibition has the potential to provide a clinical benefit through the modulation of atherogenic lipoprotein particles in addition to LDL-C lowering, and this effect will likely be assessed in future analyses of data from cardiovascular outcomes trials of PCSK9 monoclonal antibodies that are currently being conducted. ClinicalTrials.gov identifiers: NCT01243151, NCT01342211, and NCT01350141.

Novel treatment options for the management of heterozygous familial hypercholesterolemia.

INTRODUCTION: Even though statins represent the mainstay of treatment of heterozygous familial hypercholesterolemia (FH), their low-density lipoprotein cholesterol (LDL-C) lowering efficacy is finite and most patients with FH will not achieve LDL-C targets with statin monotherapy. Addition of ezetimibe with or without bile acid sequestrants will also not lead to treatment goals in many of these patients, particularly in those with established cardiovascular disease. In this selected subgroup of the FH population, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors provide substantial reductions in LDL-C levels, reduce cardiovascular morbidity and appear to be safe. Mipomersen, an antisense single-strand oligonucleotide that inhibits the production of apoB by binding to the mRNA that encodes the synthesis of apoB, and lomitapide, an inhibitor of microsomal triglyceride transfer protein, also reduce LDL-C levels but are currently indicated only for the management of homozygous FH. Areas covered: In the present review, the role of PCSK9 inhibitors, mipomersen and lomitapide in the management of FH is briefly discussed. Other LDL-C-lowering agents under evaluation include inclisiran, a small interference RNA molecule that induces long-term inhibition of PSCK9 synthesis, anacetrapib, a cholesterol ester-transfer protein inhibitor, ETC-1002 (bempedoic acid), an inhibitor of adenosine triphosphate citrate lyase, and gemcabene, which reduces hepatic apolipoprotein C-III mRNA. The safety and efficacy of these agents are also reviewed. Expert Commentary: Even though several novel treatment options for heterozygous FH are under development, it remains to be shown whether these treatments will also reduce cardiovascular morbidity in these high-risk patients.

Pharmacokinetics and pharmacodynamics of bococizumab, a monoclonal antibody to PCSK9, after single subcutaneous injection at three sites [NCT 02043301].

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. Blood samples for bococizumab and lipids were collected for 12 weeks postdose. RESULTS: Plasma bococizumab concentration-time profiles and PK parameters were generally similar across injection sites. Mean maximum observed concentration (Cmax ) ranged from 8.14 to 11.9 µg/mL, and area under the concentration-time curve (AUCinf ) ranged from 160.3 to 198.9 µg∙day/mL. The median time to Cmax (Tmax ) ranged from 4.25 to 6.93 days. Similar LDL-C concentration-time profiles were observed across injection sites, with mean (% coefficient of variation) maximum reductions in LDL-C of -57.5% (15.8), -57.0% (25.9), and -55.0% (24.1) for the abdomen, thigh, and upper arm, respectively. Adverse events (AEs) were mostly mild and generally similar across injection sites. Commonly reported AEs were upper respiratory tract infection (9.3%), headache (6.7%), and injection site reaction (6.7%). One serious AE was reported (ischemic colitis), which was not considered related to study drug. CONCLUSIONS: Similar PK profiles and robust LDL-C reductions were observed following a single 150-mg s.c. injection of bococizumab administered to the abdomen, thigh, or upper arm in untreated subjects with LDL-C ≥130 mg/dL. Bococizumab was generally well tolerated following a single 150-mg s.c. administration in this subject population.

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-Controlled, Dose-Ranging Study.

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). Subjects within each study population were randomized to bococizumab 50, 100, or 150 mg, or placebo, q14D for 16 weeks; an open-label ezetimibe 10 mg daily arm was also included for the atorvastatin-treated population. Significant, dose-dependent reductions in fasting LDL-C levels were observed in all bococizumab arms of both study populations at Weeks 12 and 16 (adjusted mean percent changes from baseline: 54.1-76.7% for atorvastatin-treated subjects and 47.7-66.8% for treatment-naive subjects; P<0.001 vs. placebo for all). Bococizumab also caused dose-dependent changes in other lipid parameters in both study populations at Weeks 12 and 16. No serious adverse events (AEs) related to bococizumab treatment occurred and all treatment-emergent AEs were mild or moderate in severity. No dose-dependent relationship between bococizumab treatment and development of anti-drug antibodies was observed. CONCLUSIONS: Bococizumab was well tolerated and significantly reduced fasting LDL-C in atorvastatin-treated and treatment-naive hypercholesterolemic Japanese subjects. (Clinicaltrials.gov identifier: NCT02055976.).

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.

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. First, simulations performed with this model demonstrated that the conventional method of the area-under-the-curve ratio for bioavailability determination underestimated the subcutaneous bioavailability of bococizumab due to its target-mediated disposition. Second, a covariate model component for statin effects on bococizumab PK/PD was characterized, including a description of the decreased baseline LDL-C, increased baseline PCSK9, and increased LDL-C lowering with concomitant use of statins. Last, the impact of the dosing regimens with and without a dose holiday on bococizumab's LDL-C-lowering effectiveness was shown to be predictable due to the well-characterized PK-PD relationship.