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In a phase 1 trial, healthy volunteers were assigned to an RNAi therapeutic inhibitor of PCSK9 or placebo. Single doses of 300 mg or more reduced LDL cholesterol by up to 50%; multiple-dose regimens reduced LDL cholesterol by up to 59%. No serious adverse events were reported. An elevated level of low-density lipoprotein (LDL) cholesterol is a major risk factor for cardiovascular disease. 1 Despite the use of statin therapy, alone or in combination with other lipid-lowering medications, many at-risk patients continue to have elevated levels of LDL cholesterol. 2 – 4 Hence, there is a need for additional treatment options for lowering of the LDL cholesterol level to reduce cardiovascular risk. Proprotein convertase subtilisin–kexin type 9 (PCSK9) is a recently identified but well-validated target for LDL cholesterol–lowering therapy. 5 This serine protease, which is expressed and secreted into the bloodstream predominantly by the liver, binds LDL receptors both intracellularly and . . .

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation. Genetics studies have shown that loss-of-function mutations in PCSK9 result in reduced plasma LDL cholesterol and decreased risk of coronary heart disease. We aimed to investigate the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits PCSK9 synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment. We did a randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3·00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0·015 to 0·400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol and we used ANCOVA to analyse pharmacodynamic endpoint data. This trial is registered with ClinicalTrials.gov, number NCT01437059. Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0·015 mg/kg [n=3], 0·045 mg/kg [n=3], 0·090 mg/kg [n=3], 0·150 mg/kg [n=3], 0·250 mg/kg [n=6], or 0·400 mg/kg [n=6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0·400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p<0·0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0·0001). Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol. These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins. This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings. Alnylam Pharmaceuticals.

In six trials comparing the anti–PCSK9 antibody bococizumab with placebo, the reduction in LDL cholesterol at 12 weeks was 55.2 percentage points lower with bococizumab. However, antidrug antibodies that developed in many patients reduced the magnitude of the reduction. Reducing levels of low-density lipoprotein (LDL) cholesterol with statin therapy is a highly effective method for reducing cardiovascular risk. 1 Trial data, observational studies, and genetic analyses indicate that further reductions in LDL cholesterol levels are likely to confer greater cardiovascular benefits. 2 – 4 Yet, recent studies have shown wide variability in the individual response of patients to statin therapy in terms of the percent reduction in LDL cholesterol levels. 5 , 6 Inhibitors of proprotein convertase subtilisin–kexin type 9 (PCSK9) reduce plasma LDL cholesterol levels by slowing PCSK9-mediated degradation of the LDL receptor. 7 Fully human monoclonal antibodies such as alirocumab and evolocumab that . . .

A monoclonal antibody to PCSK9 was studied in two single-dose trials in healthy volunteers and one multiple-dose trial in patients with familial or nonfamilial hypercholesterolemia. In all three groups, the antibody reduced levels of LDL cholesterol. In 2003, Abifadel and colleagues 1 described two families with autosomal dominant hypercholesterolemia that was associated with gain-of-function mutations in proprotein convertase subtilisin/kexin 9 (PCSK9), one of the serine proteases. These patients had high plasma levels of low-density lipoprotein (LDL) cholesterol, which was associated with an increased incidence of coronary heart disease. Shortly thereafter, studies of animal models identified a role for PCSK9 in the post-translational regulation of LDL-receptor activity. 2 , 3 PCSK9, which is synthesized primarily in the liver, enters the circulation, where it binds to hepatic LDL receptors and targets them for degradation. This process reduces the capacity of the . . .

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 . . .

Inclisiran, a small interfering RNA that targets PCSK9 mRNA, was given as a single injection at baseline or in two doses at baseline and 90 days. At 180 days, LDL cholesterol was significantly lowered among persons at high cardiovascular risk who had elevated levels at baseline. Low-density lipoprotein (LDL) cholesterol is a causal factor in atherosclerotic cardiovascular disease. Statins have been shown to reduce LDL cholesterol levels and cardiovascular events in large outcome trials, findings that have made them the therapeutic cornerstone of clinical practice. 1 Despite the proven efficacy of statins, there is considerable variability in individual responses to these drugs. 2 Furthermore, some observational data suggest that as many as half of persons who begin statin therapy discontinue it within a year. 3 Moreover, among patients receiving statin therapy who are at high risk for cardiovascular disease and who have persistent elevation of LDL cholesterol levels, the . . .

In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the lower-risk group but did have a significant benefit in the higher-risk group. Monoclonal antibodies that inhibit proprotein convertase subtilisin–kexin type 9 (PCSK9) lower levels of plasma low-density lipoprotein (LDL) cholesterol and are promising agents for vascular risk reduction. 1 Patients who have received the fully human monoclonal antibodies evolocumab and alirocumab, for example, have had reductions in cardiovascular events in preliminary analyses; these drugs are under evaluation in large-scale trials involving patients with known cardiovascular disease. 2 , 3 Bococizumab is a third inhibitor of PCSK9 that, unlike evolocumab and alirocumab, is a humanized monoclonal antibody in which approximately 3% of the murine sequence remains in the antigen-binding complementarity-determining region. As part of the Studies . . .

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases serum LDL-cholesterol (LDL-C) concentrations. We assessed the effects of AMG 145, a human monoclonal antibody against PCSK9, in patients with hypercholesterolaemia in the absence of concurrent lipid-lowering treatment. In a phase 2 trial done at 52 centres in Europe, the USA, Canada, and Australia, patients (aged 18–75 years) with serum LDL-C concentrations of 2·6 mmol/L or greater but less than 4·9 mmol/L were randomly assigned equally through an interactive voice response system to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or placebo every 2 weeks; subcutaneous AMG 145 280 mg, 350 mg, or 420 mg or placebo every 4 weeks; or oral ezetimibe 10 mg/day. The primary endpoint was percentage change from baseline in LDL-C concentration at week 12. Analysis was by modified intention to treat. Study personnel and patients were masked to treatment assignment of AMG 145 or placebo. Ezetimibe assignment was open label. This trial is registered with ClinicalTrials.gov, number NCT01375777. 406 patients were assigned to AMG 145 70 mg (n=45), 105 mg (n=46), or 140 mg (n=45) every 2 weeks; AMG 145 280 mg (n=45), 350 mg (n=45), or 420 mg (n=45) every 4 weeks; placebo every 2 weeks (n=45) or every 4 weeks (n=45); or ezetimibe (n=45). AMG 145 significantly reduced LDL-C concentrations in all dose groups (mean baseline LDL-C concentration 3·7 mmol/L [SD 0·6]; changes from baseline with every 2 weeks AMG 145 70 mg −41·0% [95% CI −46·2 to −35·8]; 105 mg −43·9% [–49·0 to −38·7]; 140 mg −50·9% [–56·2 to −45·7]; every 4 weeks AMG 145 280 mg −39·0% [–44·1 to −34·0]; 350 mg −43·2% [–48·3 to −38·1]; 420 mg −48·0% [–53·1 to −42·9]; placebo every 2 weeks −3·7% [–9·0 to 1·6]; placebo every 4 weeks 4·5% [–0·7 to 9·8]; and ezetimibe −14·7% [–18·6 to −10·8]; p<0·0001 for all doses vs placebo or ezetimibe). Treatment-emergent adverse events occurred in 136 (50%) of 271 patients in the AMG 145 groups, 41 (46%) of 90 patients in the placebo groups, and 26 (58%) of 45 patients in the ezetimibe group; no deaths or serious treatment-related adverse events were reported. The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse populations including patients with documented statin intolerance. Amgen.

Proprotein convertases (PCs), including furin and PC1/3 among nine mammalian homologues, mediate the maturation of numerous secreted substrates by proteolytic cleavage. Disbalance of PC activity is associated with diseases like cancer, fibrosis, neurodegeneration and infections. Therefore, PCs are promising drug targets for the treatment of many diseases. However, the highly conserved active site of PCs complicates the development of specific inhibitors. Here we investigate the activation mechanism of PCs using X-ray crystallography and biochemical methods. The structure-based optimization of the multibasic secondary cleavage site loop not only prevents the prodomain’s proteolytic cleavage but also increases its inhibition of furin. Combination of cleavage-resistant PC1/3-prodomain variants and a furin-specific nanobody in fusion proteins reveal very potent inhibitors (K i  = 1.2 pM) with a more than 25,000-fold higher specificity for furin compared to the closely related PC-member PCSK5. Such fusion proteins effectively suppress the replication of a furin-dependent H7N7-influenza virus in cell-based assays. In this work, the authors investigate the activation mechanism of proprotein convertases (PC) based on the PC1/3-prodomain and the PC furin. They engineer a prodomain-nanobody fusion protein that effectively blocks propagation of a H7N7 bird flu virus.

LDL cholesterol (LDL-C) is a well established risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDL receptors, targeting them for degradation. We therefore assessed the efficacy, safety, and tolerability of AMG 145, a human monoclonal IgG2 antibody against PCSK9, in stable patients with hypercholesterolemia on a statin. In a phase 2, dose-ranging study done in 78 centres in the USA, Canada, Denmark, Hungary, and Czech Republic, patients (aged 18–80 years) with LDL-C greater than 2·2 mmol/L on a stable dose of statin (with or without ezetimibe), were randomly assigned equally, through an interactive voice response system, to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or matching placebo every 2 weeks; or subcutaneous injections of AMG 145 280 mg, 350 mg, or 420 mg, or matching placebo every 4 weeks. Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules. The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01380730. 631 patients with hypercholesterolaemia were randomly assigned to AMG 145 70 mg (n=79), 105 mg (n=79), or 140 mg (n=78), or matching placebo (n=78) every 2 weeks; or AMG 145 280 mg (n=79), 350 mg (n=79), and 420 mg (n=80), and matching placebo (n=79) every 4 weeks. At the end of the dosing interval at week 12, the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks (ranging from 41·8% to 66·1%; p<0·0001 for each dose vs placebo) and AMG 145 every 4 weeks (ranging from 41·8% to 50·3%; p<0·0001). No treatment-related serious adverse events occurred. The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or life-threatening. The results suggest that PCSK9 inhibition could be a new model in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials. Amgen.