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Among 65 patients with homozygous familial hypercholesterolemia, the use of evinacumab, a monoclonal antibody against ANGPTL3, resulted in a reduction from baseline in the LDL cholesterol level, as compared with a small increase with placebo, for a between-group difference of 49.0 percentage points at 24 weeks.

Evinacumab, a monoclonal antibody that blocks ANGPTL3, was administered to nine adults with homozygous familial hypercholesterolemia. At 4 weeks, LDL cholesterol was reduced by a mean of 49%, with a mean absolute change from baseline of −157 mg per deciliter.

Evinacumab, an angiopoietin‐like 3 (ANGPTL3) inhibitor, significantly reduces low‐density lipoprotein cholesterol (LDL‐C), independent of low‐density lipoprotein receptor, in patients with homozygous familial hypercholesterolemia (HoFH). A population pharmacokinetic (PK)/pharmacodynamic (PD) model was previously developed to characterize evinacumab exposure and LDL‐C response in adolescents and adults. In this analysis, the PK/PD model was refined to include children aged 5 to < 12 years and to characterize the lipoprotein apheresis effect on LDL‐C reduction. The PK of evinacumab was characterized by a two‐compartment model with parallel linear and non‐linear elimination. Linear disposition parameters were allometrically scaled by body weight. Baseline ANGPTL3 concentrations and disease status (non‐HoFH vs. HoFH) influenced the maximum target‐mediated rate of elimination but had a minimal effect on evinacumab exposures at 15 mg/kg intravenous doses every 4 weeks across weight/age groups. In patients with HoFH, the LDL‐C reduction was adequately described by an indirect response model in which evinacumab inhibits the formation of LDL‐C and that includes a secondary elimination process quantifying the lipoprotein apheresis effect. Older age was associated with a decrease in baseline LDL‐C. An increase in body weight was associated with a reduction in the maximum inhibitory effect of evinacumab. Model‐based simulations showed that while evinacumab exposure is reduced with decreasing age/body weight, younger patients are predicted to have a comparable or greater magnitude of LDL‐C reduction than older patients at a dose of 15 mg/kg. Overall, the model adequately predicted the evinacumab exposure and LDL‐C reduction in children, adolescents, and adults with HoFH, aligning with clinically relevant observations.

Reduction in low-density lipoprotein cholesterol (LDL-C) is associated with decreased risk for cardiovascular disease. Alirocumab, an antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduces LDL-C. Here, we report development of a quantitative systems pharmacology (QSP) model integrating peripheral and liver cholesterol metabolism, as well as PCSK9 function, to examine the mechanisms of action of alirocumab and other lipid-lowering therapies, including statins. The model predicts changes in LDL-C and other lipids that are consistent with effects observed in clinical trials of single or combined treatments of alirocumab and other treatments. An exploratory model to examine the effects of lipid levels on plaque dynamics was also developed. The QSP platform, on further development and qualification, may support dose optimization and clinical trial design for PCSK9 inhibitors and lipid-modulating drugs. It may also improve our understanding of factors affecting therapeutic responses in different phenotypes of dyslipidemia and cardiovascular disease.

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations ( n  = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations ( n  = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations ( n  = 19). Fifty-one patients (males, n  = 27; females, n  = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg −1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of −27.1% (37.4) (95% confidence interval −71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 . The potential of evinacumab, a monoclonal antibody targeting angiopoietin-like 3, for reducing triglyceride levels was tested in patients with severe hypertriglyceridemia due to differing genetic etiologies.

Loss-of-function variants in ANGPTL3 were associated with lower plasma levels of lipids and lower rates of coronary disease. A monoclonal antibody against ANGPTL3 reduced the atherosclerotic lesion area in mice and reduced levels of triglycerides and LDL cholesterol in human volunteers.

Persistent chylomicronemia is caused by lipoprotein lipase deficiency (LPLD) or lack of lipoprotein lipase (LPL) bioavailability. This disorder is characterized by plasma triglyceride (TG) levels above 10 mmol/L, increased acute pancreatitis risk, and features of familial chylomicronemia syndrome (FCS). Evinacumab is an angiopoietin-like protein 3 (ANGPTL3) monoclonal antibody, and its efficacy in decreasing plasma TG levels depends on LPL bioavailability. To identify FCS-causing pathogenic variants in patients with persistent chylomicronemia treated with evinacumab. A phase II clinical trial was conducted with evinacumab in patients with severe hypertriglyceridemia. Plasma TG values were measured at baseline and every 2 weeks for 24 weeks. Three FCS patients homozygotes for a P234L pathogenic variant in the LPL gene (HoLPL P234L) known to be associated with low postheparin LPL activity (proven LPLD) participated in the study and were used as tracers. The genotype-specific efficacy of evinacumab to decrease TG levels in other participants was compared to that achieved in HoLPL P234L patients. After 24 weeks of evinacumab treatment, TG levels decreased <20% in HoLPL P234L patients known to lack LPL. Similarly, a participant homozygote for a E282X variant in the exon 6 of the LPL gene that was suspected to be pathogenic due to its location did not respond to evinacumab (TG decreased <10% and remained >10 mmol/L). The efficacy of ANGPTL3 inhibitors in decreasing TG levels is LPL-dependent. Poor response to evinacumab supports the evidence that the E282X variant in the LPL gene is pathogenic and associated with persistent chylomicronemia (FCS phenotype).

Association studies are used to identify genetic determinants of complex human traits of medical interest. With the large number of validated single nucleotide polymorphisms (SNPs) currently available, two limiting factors in association studies are genotyping capability and costs. Pooled DNA genotyping has been proposed as an efficient means of screening SNPs for allele frequency differences in case-control studies and for prioritising them for subsequent individual genotyping analysis. Here, we apply quantitative pooled genotyping followed by individual genotyping and replication to identify associations with human serum high-density lipoprotein (HDL) cholesterol levels. The DNA from individuals with low and high HDL cholesterol levels was pooled separately, each pool was amplified by polymerase chain reaction in triplicate and each amplified product was separately hybridised to a high-density oligonucleotide array. Allele frequency differences between case and control groups with low and high HDL cholesterol levels were estimated for 7,283 SNPs distributed across 71 candidate gene regions spanning a total of 17.1 megabases. A novel method was developed to take advantage of independently derived haplotype map information to improve the pooled estimates of allele frequency differences. A subset of SNPs with the largest estimated allele frequency differences between low and high HDL cholesterol groups was chosen for individual genotyping in the study population, as well as in a separate replication population. Four SNPs in a single haplotype block within the cholesteryl ester transfer protein (CETP) gene interval were significantly associated with HDL cholesterol levels in both populations. Our study is among the first to demonstrate the application of pooled genotyping followed by confirmation with individual genotyping to identify genetic determinants of a complex trait.

Background The effect of alirocumab on potentially atherogenic lipoprotein subfractions was assessed in a post ho c analysis using the vertical auto profile (VAP) method. Methods Patients from three Phase II studies with low-density lipoprotein cholesterol (LDL-C) ≥2.59 mmol/L (100 mg/dL) at baseline on stable statin therapy were randomised to receive subcutaneous alirocumab 50–150 mg every 2 weeks (Q2W) or 150–300 mg every 4 weeks (according to study) or placebo for 8–12 weeks. Samples from patients treated with alirocumab 150 mg Q2W ( n  = 74; dose common to all three trials) or placebo ( n  = 71) were analysed by VAP. Percent change in lipoprotein subfractions with alirocumab vs. placebo was analysed at Weeks 6, 8 or 12 using analysis of covariance. Results Alirocumab significantly reduced LDL-C and the cholesterol content of subfractions LDL 1 , LDL 2 and LDL 3+4 . Significant reductions were also observed in triglycerides, apolipoproteins CII and CIII and the cholesterol content of very low-density, intermediate-density, and remnant lipoproteins. Conclusion Alirocumab achieved reductions across a spectrum of atherogenic lipoproteins in patients receiving background statin therapy. Trial registration Clinicaltrials.gov identifiers: NCT01288443 , NCT01288469 , NCT01266876

Purpose To investigate the plasma levels of amyloid beta (Aβ) and select inflammatory mediators in patients with various stages of AMD compared to that of age-matched controls, and discern a relationship to disease severity. Methods Plasma samples were obtained from AMD subjects at various stages of disease—early (drusen only), geographic atrophy (GA), neovascular AMD (CNV)—and from controls of similar age without AMD. Samples were analyzed using a commercially available ELISA kit (sixteen cytokines) or LC/MS/MS (Aβ isotypes). Descriptive statistics were compiled on all analytes. Analysis of covariance (ANCOVA) was conducted to compare each analyte across AMD groups while adjusting for sex and age of the patients, and in comparison to the control group. Receiver operating characteristics plots were generated for the strongest predictor variables. Results Levels of alternative spliced CC3 proteins were significantly different between controls and CNV groups ( p  < 0.05), with median levels almost twice higher in CNV than in controls. There was an increasing trend for plasma levels of Αβ isotypes across AMD progressive stages ( p values ranged from 0.052 to 0.0012) (ANCOVA). When adjusted for multiple comparisons analysis, plasma Aβ 1–42 levels, and its ratio with Aβ 1–40 were the most significantly associated with late AMD stages. Consistently with the ANCOVA results for Αβ isotypes, the ROC curve showed a moderate prediction (AUC = - ~ 0.78) of AMD vs control using the Aβ 1−42 isotype. Conclusion Plasma Aβ 1–42 may have utility as a systemic biomarker for AMD.