Alirocumab approved to help lower LDL cholesterol
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FDA on July 24 approved the marketing of alirocumab injection, or Praluent, as an add-on cholesterol-lowering treatment for certain adults whose plasma low-density lipoprotein cholesterol (LDL-C) concentration should be even lower. The monoclonal antibody, the agency said, is the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor approved in this country for use in lowering LDL-C. Alirocumab lowers the plasma LDL-C concentration by interfering with PCSK9’s interference in the liver’s normal work. According to the labeling for alirocumab, PCSK9 binds to hepatocytes’ low-density lipoprotein receptors, which normally would bind LDL-C and serve as the primary cell-surface receptor for removing that type of cholesterol from the bloodstream. By decreasing the amount of PCSK9 that binds to low-density lipoprotein receptors, alirocumab keeps those receptors available to bind LDL-C. The PCSK9 inhibitor, its labeling states, is for use in adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (ASCVD) who are already adhering to dietary measures and taking as high a statin dosage as can be tolerated.Keywords:
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The role of proprotein convertase subtilisin/kexin type 9 inhibitors in managing cardiovascular risk
Hypercholesterolaemia and dyslipidaemia, marked by decreased levels of high-density lipoprotein and elevated levels of lowdensity lipoprotein (LDL), increase the risk of cardiovascular disease. Familial hypercholesterolaemia (FH), diagnosed based on the clinical features seen in patients with a positive family history, constitutes a heritable disorder involving a single gene. FH can exist in either the heterozygous or homozygous form, and may be differentiated based on clinical features and genetic studies. A novel drug target, proprotein convertase subtilisin/kexin type 9 (PCSK9), has resulted in the development and subsequent approval of new, targeted monoclonal antibodies in the treatment of FH. Targeting PCSK9 with monoclonal antibodies, i.e. evolocumab and alirocumab, inhibits the degradation of LDL receptors, and against a background of optimised statin therapy, increases the life expectancy of patients with hypercholesterolaemia by reducing the incidence and severity of coronary artery disease.
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The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to lysosomes for intracellular degradation. This results in decreased numbers of LDLR available on the hepatic cell surface to bind LDL particles and remove them from the circulation and therefore to a subsequent increase in circulating LDL-cholesterol (LDL-C) plasma levels. Since 2003, when the role of PCSK9 in LDL-C metabolism was discovered, there have been major efforts to develop efficient and safe methods to inhibit it. Amongst those, monoclonal antibodies against PCSK9 are the furthest in development, with multiple phase 3 trials already published and with cardiovascular endpoint trials currently underway. Two fully human monoclonal antibodies, evolocumab (AMG 145) and alirocumab (REGN727/SAR236553), have been extensively studied in a wide range of subjects, such as those with statin intolerance, as an add-on to statin therapy, as a monotherapy and in patients with familial hypercholesterolemia. PCSK9 antibodies result in a consistent and robust decrease in LDL-C plasma levels ranging from 40% to 70%, either on top of statins or as a monotherapy. If the safety data from the on-going phase 3 trials remain as reassuring as the data available till now, PCSK9 antibodies will offer a novel, powerful therapeutic option to decrease LDL-C plasma levels and, hopefully, cardiovascular risk.
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FDA on July 24 approved the marketing of alirocumab injection, or Praluent, as an add-on cholesterol-lowering treatment for certain adults whose plasma low-density lipoprotein cholesterol (LDL-C) concentration should be even lower. The monoclonal antibody, the agency said, is the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor approved in this country for use in lowering LDL-C. Alirocumab lowers the plasma LDL-C concentration by interfering with PCSK9’s interference in the liver’s normal work. According to the labeling for alirocumab, PCSK9 binds to hepatocytes’ low-density lipoprotein receptors, which normally would bind LDL-C and serve as the primary cell-surface receptor for removing that type of cholesterol from the bloodstream. By decreasing the amount of PCSK9 that binds to low-density lipoprotein receptors, alirocumab keeps those receptors available to bind LDL-C. The PCSK9 inhibitor, its labeling states, is for use in adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (ASCVD) who are already adhering to dietary measures and taking as high a statin dosage as can be tolerated.
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The serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein (LDL) receptor (LDLR) and directs it to lysosomal degradation. This results in decreased numbers of LDLR available on the cell surface to bind LDL particles and remove them from the circulation which in turn leads to an increase in circulating LDL-cholesterol (LDL-C) concentrations. Since the role PCSK9 plays in LDLC metabolism has been discovered in 2003 there have been major efforts in finding efficient and safe methods to inhibit it. Amongst those the fully human anti-PCSK9 antibodies alirocumab and evolocumab have been studied in a wide range of patients such as in those with statin intolerance, as add-on to statin therapy, as monotherapy and in patients with familial hypercholesterolemia and have been shown to decrease LDL-C overall by ~50-70%. Rates of achieving LDL-C goals, depending on individual risk, are up to 87 -98% of treated subjects. Multiple phase III studies with these drugs are already completed and cardiovascular endpoint trials are expected to be concluded by the end of 2016 and 2017 for evolocumab and alirocumab, respectively. In 2015 both alirocumab and evolocumab were approved for the treatment of hypercholesterolemia in the European Union and in the US. Preliminary data show an improvement in cardiovascular morbidity and mortality by ~50%. If the large ongoing endpoint trials confirm the cardiovascular efficacy and overall safety of these drugs, PCSK9 antibodies will revolutionarize lipid-lowering therapy.
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Mutations in the genes for the low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH).The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab.Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR, apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations.Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39-114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10-165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials.Clinically meaningful LDL-C-lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH.
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Abstract Taking into account the discordance between low‐density lipoprotein cholesterol (LDL‐C) and LDL particle (LDL‐P) number, cardiovascular risk more closely correlates with LDL‐P in patients. The aim of our study was to evaluate the number of lipid particles in patients with severe hypercholesterolemia treated with different lipid‐lowering regimens. Four groups of patients differing with respect to lipid‐lowering therapy were recruited from hypercholesterolemic outpatients and lipoprotein apheresis (LA) facilities, and were treated with statins alone (group A), with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9i) (group B), with statins and LA (group C), or with statins, PCSK9i, and LA (group D). Cholesterol, triglycerides, LDL‐C, high‐density lipoprotein cholesterol (HDL‐C), LDL‐P number and size, HDL‐P number and size were determined using nuclear magnetic resonance spectroscopy. The lowest LDL‐P number was achieved at the end of LA sessions in combination with statins or in combination with statins and a monoclonal PCSK9i (median; 25th and 75th percentile) (group C: 244 nmoL/L: 237, 244, P < 0.05; group D: 244 nmoL/L: 99, 307, P < 0.05). Comparing LDL‐P number at the start of LA (group C: 978 nmoL/L: 728, 1404; group D: 954 nmoL/L: 677, 1521) to the other patient groups (groups A and B), the lowest LDL‐P number was measured in patients treated with PCSK9i and a statin (group B): LDL‐P (762 nmoL/L: 604, 1043, P < 0.05), large LDL‐P (472 nmoL/L: 296, 574, P < 0.05), and small LDL‐P (342 nmoL/L: 152, 494, P < 0.05). Very low‐density lipoprotein and HDL particle sizes remained approximately the same in all groups. LA in combination with statins or in combination with statins and PCSK9i most reduced LDL‐P numbers in hypercholesterolemic patients.
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In 2003, families were described with a rare, autosomal dominant form of familial hypercholesterolemia due to gain-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) [1]. Subsequent studies demonstrated that PCSK9 is secreted from liver and accelerates degradation of LDL receptors [2,3]. Heterozygosity for PCSK9 null mutations in 2.6% of African-Americans was found to be associated with 28% reduction in LDL cholesterol (LDL-C) and an 88% reduction in CAD risk [4]. These findings stimulated intense interest in PCSK9 as a pharmaceutical target. In this issue of Trends in Cardiovascular Medicine, Desai and Sabatine [5] thoroughly review recent and ongoing trials of three monoclonal antibodies that disrupt PSCK9 binding to LDL receptors, leading to marked reductions in LDL-C. As detailed in their review, evolocumab (AMG145), alirocumab (SAR236553/REGN727), and bococizumab (RN316) given every 2–4 weeks, reduced LDL-C up to 75% in patients on statin therapy as compared to statin therapy alone, up to 51% in statin-intolerant patients and other patients not in statin therapy, and up to 55% in patients with heterozygous familial hypercholesterolemia, most of whom were on statin therapy. Evolocumab reduced LDL-C up to 31% in patients with homozygous familial hypercholesterolemia, although there was no effect in LDL receptor-negative patients. Ongoing cardiovascular outcome trials that will rigorously test the ability of these agents to reduce major adverse cardiovascular events in high-risk patients are also described. PCSK9 is secretory serine endoprotease [6]. Pro-PCSK9 is autocatalytically cleaved during its maturation in the Golgi, but the prodomain remains tightly bound after secretion, precluding further catalytic activity [6]. Effects of PCSK9 on LDL-C clearance thus do not depend on its protease activity.
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