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We evaluated the pharmacokinetics, pharmacodynamics, and safety of evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open-label, parallel-design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140-mg dose of evolocumab. The effects of evolocumab treatment on low-density lipoprotein cholesterol (LDL-C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups. Geometric mean C max and AUC last values in the severe RI and ESRD hemodialysis groups compared with the normal renal function group were lower but within 37% of the normal renal function group (Jonckheere-Terpstra trend test; C max , P = .23; AUC last , P = .22) and within 26% after adjusting for body weight (mean body weight was approximately 9% higher in the renally impaired groups compared with the normal renal function group). No correlations were observed between exposure and baseline creatinine clearance. No adverse event was determined by the investigators to be related to evolocumab, and there were no trends indicative of clinically important effects on laboratory variables or vital signs. Overall, there were no meaningful differences in evolocumab exposure, as assessed by C max and AUC last , in patients with severe RI and ESRD hemodialysis compared with patients with normal renal function, and LDL-C-lowering effects were similar across groups. These results support the use of evolocumab without dose adjustment in patients who have severe RI or ESRD., (© 2019 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) relationship of a therapeutic monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) exhibiting target-mediated drug disposition (TMDD) is critical for selecting optimal dosing regimens. We describe the PK/PD relationship of evolocumab using a mathematical model that captures evolocumab binding and removal of unbound PCSK9 as well as reduction in circulating low-density lipoprotein cholesterol (LDL-C). Data were pooled from 2 clinical studies: a single-dose escalation study in healthy subjects (7-420 mg SC; n = 44) and a multiple-dose escalation study in statin-treated hypercholesterolemic patients (14 mg weekly to 420 mg monthly [QM] SC; n = 57). A TMDD model described the time course of unbound evolocumab concentrations and removal of unbound PCSK9. The estimated linear clearance and volume of evolocumab were 0.256 L/day and 2.66 L, respectively, consistent with other monoclonal antibodies. The time course of LDL-C reduction was described by an indirect response model with the elimination rate of LDL-C being modulated by unbound PCSK9. The concentration of unbound PCSK9 associated with half-maximal inhibition (IC 50 ) of LDL-C elimination was 1.46 nM. Based on simulations, 140 mg every 2 weeks (Q2W) and 420 mg QM were predicted to achieve a similar time-averaged effect of 69% reduction in LDL-C in patients on statin therapy, suggesting that an approximate 3-fold dose increase is required for a 2-fold extension in the dosing interval. Evolocumab dosing regimens of 140 mg Q2W or 420 mg QM were predicted to result in comparable reductions in LDL-C over a monthly period, consistent with results from recently completed phase 3 studies., (© 2016, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Evolocumab binds PCSK9, increasing low-density lipoprotein cholesterol (LDL-C) receptors and lowering LDL-C. Target-mediated evolocumab elimination is attributable to PCSK9 binding. As circulating PCSK9 and LDL-C levels are primarily regulated by the liver, we compared evolocumab pharmacokinetics, pharmacodynamics, and safety in individuals with and without hepatic impairment. An open-label, parallel-group study evaluated the pharmacokinetics of evolocumab in hepatic-impaired (Child-Pugh Class A or B) or healthy adults. Participants were classified as having no, mild, or moderate hepatic impairment (n = 8/group) and received a single 140-mg evolocumab dose. Assessments of unbound evolocumab and PCSK9 were made predose and postdose. Adverse events were monitored throughout the study. No significant association was observed between baseline PCSK9 and increasing level of hepatic impairment. No difference in extent and time course of PCSK9 or LDL-C reduction was observed despite an apparent decrease in mean unbound evolocumab exposure with increasing hepatic impairment (Jonckheere-Terpstra trend test; maximum serum concentration P = .18; area under the curve P = .09). Maximum reductions were observed in moderately impaired subjects vs healthy individuals: mean maximum serum concentration -34%; mean area under the concentration-time curve (AUC) -47%. On average, unbound PCSK9 serum concentrations fell by >80% at 4 hours after a single evolocumab dose. Mean (95% confidence interval) maximum LDL-C reductions in the healthy, mild, and moderate groups were -57% (-64% to -48%), -70% (-75% to -63%), and -53% (-61% to -43%), respectively. No safety risks were identified. These results support evolocumab use without dose adjustment in patients with active liver disease and mild or moderate hepatic impairment., (© 2016, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors, and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all-cause mortality, cause-specific mortality, relevant non-fatal morbidity (e.g., all-cause and cause-specific hospitalization), composites capturing both morbidity and mortality, safety, symptoms, functional capacity, and patient-reported outcomes. Each of these endpoints has strengths and weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consistency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronic heart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA-ESC) convened a group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12-13 February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. This report summarizes the group's recommendations for achieving common views on heart failure endpoints in clinical trials.

Anemia is common in heart failure (HF) patients. A prespecified pooled analysis of 2 randomized, double-blind, placebo-controlled studies evaluated darbepoetin alfa (DA) in 475 anemic patients with HF (hemoglobin [Hb], 9.0-12.5 g/dL). DA was administered subcutaneously every 2 weeks and titrated to achieve and maintain a target Hb level of 14.0+/-1.0 g/dL. By week 27, mean (SD) Hb concentrations did not increase with placebo but increased with DA from 11.5 (0.7) to 13.3 (1.3) g/dL. Hazard ratios (HRs) for DA compared with placebo for all-cause death or first HF hospitalization (composite end point), all-cause death, and HF hospitalization by month 12 were 0.67 (95% confidence interval [CI], 0.44-1.03; P=.067), 0.76 (95% CI, 0.39-1.48; P=.419), and 0.66 (95% CI, 0.40-1.07; P=.093), respectively. Incidence of adverse events was similar in both groups. In post hoc analyses, improvement in the composite end point was significantly associated with the mean Hb change from baseline (adjusted HR, 0.40; P=.017) with DA treatment. There was no increased risk of all-cause mortality or first HF hospitalization with DA in patients with reduced renal function or elevated baseline B-type natriuretic peptide, a biomarker of worse HF. These results suggest that DA is well tolerated, corrects HF-associated anemia, and may have favorable effects on clinical outcomes., ((c) 2010 Wiley Periodicals, Inc.)

Aims: To assess the safety and tolerability of darbepoetin alfa (DA) in the treatment of anaemia in heart failure (HF)., Methods and Results: In this pooled analysis of three randomized, double-blind, placebo-controlled studies of anaemic [haemoglobin (Hb) < or =12.0 g/dL or < or =12.5 g/dL] symptomatic HF subjects, DA was administered subcutaneously once every 2 weeks and titrated to achieve and maintain a target Hb of 14.0 +/- 1.0 g/dL. In total, 516 subjects were randomized; 231 (44.8%) to placebo, 285 (55.2%) to DA. Darbepoetin alfa was well tolerated, with an adverse event (AE) profile similar to placebo. Most subjects (placebo, 85%; DA, 87%) experienced at least one AE. There was a lower incidence of serious AEs in the DA group (placebo, 43%; DA, 37%) with the most frequent being worsening HF (placebo, 19%; DA, 11%). Treatment-related AEs were reported for 9% and 12% in placebo and DA subjects, respectively. Fewer deaths were reported in DA group (6%) vs. placebo (8%)., Conclusion: Darbepoetin alfa was well tolerated with an AE profile similar to placebo in HF subjects treated to a target Hb of 14.0 +/- 1.0 g/dL. Contrary to recent data in other patient populations, there was no evidence of increased risk of mortality or cardiovascular events.

Background: Patients with heart failure (HF) and anaemia have greater functional impairment, worse symptoms, increased rates of hospital admission, and a higher risk of death, compared with non-anaemic HF patients. Whether correcting anaemia can improve outcomes is unknown., Objective: The Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF; Clinical Trials.gov NCT 003 58215) was designed to evaluate the effect of the long-acting erythropoietin-stimulating agent darbepoetin alfa on mortality and morbidity (and quality of life) in patients with HF and anaemia., Methods: Approximately 2600 patients with New York Heart Association class II-IV, an ejection fraction < or =40%, and a haemoglobin (Hb) consistently < or =12.0 g/dL but > or =9.0 g/dL will be enrolled. Patients are randomized 1:1 to double-blind subcutaneous administration of darbepoetin alfa or placebo. Investigators are also blinded to Hb measurements and darbepoetin alfa is dosed to achieve an Hb concentration of 13.0 g/dL (but not exceeding 14.5 g/dL) with sham adjustments of the dose of placebo. The primary endpoint is the time to death from any cause or first hospital admission for worsening HF, whichever occurs first. The study will complete when approximately 1150 subjects experience a primary endpoint.