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Patients with hyperlipidemia were assigned to receive the PCSK9 antibody evolocumab or placebo on a background of lipid-lowering therapy. At 52 weeks, the least-squares mean reduction in LDL cholesterol from baseline for evolocumab versus placebo was 57%. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that is produced predominantly in the liver, is secreted into the plasma and plays a major role in regulating levels of low-density lipoprotein (LDL) cholesterol by binding to hepatic LDL receptors and promoting their degradation. 1 , 2 In short-term (8-to-12-week), placebo-controlled, phase 2 trials, PCSK9 inhibitors have been shown to significantly reduce LDL cholesterol levels. 3 – 9 Four of these trials involved the use of evolocumab (AMG 145), a fully human monoclonal PCSK9 antibody, and assessed different doses and regimens in diverse patient populations with varying lipid phenotypes, cardiovascular disease risks, and baseline . . .

PurposeAMG 986 is a novel apelin receptor (APJ) agonist that improves cardiac contractility in animal models without adversely impacting hemodynamics. This phase 1b study evaluated the safety/tolerability, pharmacokinetics, and pharmacodynamics of AMG 986 in healthy subjects and patients with heart failure (HF).MethodsHealthy adults (Parts A/B) and HF patients (Part C) aged 18–85 years were randomized 3:1 to single-dose oral/IV AMG 986 or placebo (Part A); multiple-dose oral/IV AMG 986 or placebo (Part B); or escalating-dose oral AMG 986 or placebo (Part C). Primary endpoint: treatment-emergent adverse events, laboratory values/vital signs/ECGs; others included AMG 986 pharmacokinetics, left ventricular (LV) function.ResultsOverall, 182 subjects were randomized (AMG 986/healthy: n = 116, placebo, n = 38; AMG 986/HF: n = 20, placebo, n = 8). AMG 986 had acceptable safety profile; no clinically significant dose-related impact on safety parameters up to 650 mg/day was observed. AMG 986 exposures increased nonlinearly with increasing doses; minimal accumulation was observed. In HF with reduced ejection fraction patients, there were numerical increases in percent changes from baseline in LV ejection fraction and stroke volume by volumetric assessment with AMG 986 vs placebo (stroke volume increase not recapitulated by Doppler).ConclusionsIn healthy subjects and HF patients, short-term AMG 986 treatment was well tolerated. Consistent with this observation, clinically meaningful pharmacodynamic effects in HF patients were not observed. Changes in ejection fraction and stroke volume in HF patients suggest additional studies may be needed to better define the clinical utility and optimal dosing for this molecule.Trial Registration NumberClinicalTrials.gov NCT03276728.Date of RegistrationSeptember 8, 2017