Abstract 11893: Efficacy and Safety of Ongericimab in Chinese Patients With Primary Hypercholesterolemia and Mixed Dyslipidemia
Xiaozeng WangMiaohan QiuZhifeng ChengXianyou JiJiyan ChenHong ZhuYi‐Da TangZhouqing HuangGuohai SuGaopin WangZhijun HuangZhuhua YaoJinxiu LinYihong SunShunhui LiCong ShaoHui YanYi ZhaoXuelian BaiShi WangYaling Han
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Background: Ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) levels in the phase 2 trial. A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia on background lipid-lowering therapy (LLT). Methods: This was a randomized, double-blind, placebo-controlled, 52-week trial conducted in China (NCT02662569). Eligible patients receiving stable statin (±ezetimibe) therapy but not achieving LDL-C goals were enrolled. Patients were randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or placebo subcutaneously every 2 weeks (Q2W), or ongericimab 300 mg or placebo subcutaneously every 4 weeks (Q4W) for 52 weeks. The primary endpoint was percent change in LDL-C from baseline to week 24. Results: A total of 806 patients were randomized, 802 patients received at least one dose of ongericimab or placebo. The least-squares (LS) mean difference between ongericimab and placebo in LDL-C from baseline to week 24 was -67.7% (95% CI: -72.49%, -62.99%; p < 0.0001) in Q2W group and -61.2% (95% CI: -67.09%, -55.21%; p < 0.0001) in Q4W group. LDL-C reductions were maintained to Week 52. Ongericimab also favorably altered other lipid parameters (Table 1). The overall incidence of adverse events was similar between ongericimab and placebo. Conclusion: Ongericimab on stable background LLT significantly reduced LDL-C and was well tolerated in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia.Keywords:
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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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In 2003, clinical observations led to the discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism. Functional studies demonstrated that PCSK9 binds to the low-density lipoprotein (LDL) receptor directing it to its lysosomal degradation. Therefore, carriers of gain-of-function mutations in
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SAŽETAK: LDL kolesterol (LDL-K) snažan je nezavisni čimbenik kardiovaskularnog (KV) rizika na koji je moguće utjecati.Statini su danas terapija izbora u postizanju ciljnih vrijednosti LDL-K-a.Iako su u kontroliranim kliničkim ispitivanjima dokazano učinkoviti i sigurni, u praksi se često susrećemo s nepodnošenjem statina, a u značajnog dijela bolesnika i nepostizanjem ciljnih vrijednosti LDL-K-a unatoč maksimalnim dozama.U bolesnika s visokim i vrlo visokim KV rizikom i preostala eulipemijska farmakoterapija često nije dostatna.Inhibitori PCSK9 (PCSK9-I) novi su, revolucionarni lijekovi s potentnim učinkom na LDL-K.Brzi razvoj PCSK9-I-a započeo je 2003.godine otkrićem mutacije gena PCSK9 u bolesnika s porodičnom hiperkolesterolemijom.Produkt tog gena, enzim proprotein konvertaza subtilizin/keksin tip 9 (PCSK9) ima važnu ulogu u regulaciji ekspresije LDL receptora i u metabolizmu kolesterola.Istraživanjima na životinjama dokazano je da inaktivacija PCSK9 gena snizuje LDL-K s regresijom aterosklerotskih promjena aorte.Heterozigoti i homozigoti s inaktivirajućom mutacijom gena PCSK9 imaju niske vrijednosti LDL-K-a i manju pojavnost ateroskleroze.Među različitim skupinama PCSK9-I-a, snažan razvoj doživjela su monoklonska protutijela (alirokumab, evolokumab i bokocizumab).Klinička ispitivanja treće faze porodične i primarne hiperkolesterolemije sa statinskom intolerancijom ili rezistencijom pokazala su snažan povoljan učinak alirokumaba i evolokumaba na LDL-K (sniženje od 60 %), uz visoku sigurnost i dobru podnošljivost.OSLER studija s evolokumabom dokazala je i povoljne učinke na KV ishode.U tijeku je više kliničkih pokusa različitih PCSK9-I-a, u kojima se prati njihov učinak na KV pobol i smrtnost.Pozitivni rezultati tih studija potvrdili bi veliki potencijal PCSK9-I-a
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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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After the approval of alirocumab and evolocumab, the first two monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin kexin type 9 (PCSK9), this review provides an update on recent PCSK9 inhibitors data and describes recommendations for the use before the results of the ongoing cardiovascular endpoint trials.New studies and complementary analysis of phase III trials have consistently shown that alirocumab and evolocumab are highly effective in reducing LDL-cholesterol and to some extent lipoprotein (a). Some preliminary findings coming from exploratory and post-hoc analyses of the longer-term safety phase III trials and meta-analyses suggest that these mAbs can decrease the incidence of cardiovascular events. Whether or not mAbs targeting PCSK9 definitively reduce the incidence of cardiovascular events without safety concerns shall be demonstrated with the ongoing cardiovascular outcome trials. Waiting these outcome trials and given the high cost of these mAbs, groups of experts have proposed as priorities groups of patients with familial hypercholesterolemia and with atherosclerotic cardiovascular disease who have substantially elevated LDL-cholesterol on maximally tolerated statin/ezetimibe therapy.Before the results of large cardiovascular outcome trials, PCSK9 inhibitors should be only used in some categories of patients with familial hypercholesterolemia and/or with atherosclerotic cardiovascular disease.
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Abstract: Heterozygous familial hypercholesterolemia (FH) is a genetic disorder characterized by high low-density lipoprotein cholesterol levels from birth, which exposes the arteries to high levels of atherogenic lipoproteins lifelong and results in a significantly increased risk of premature cardiovascular events. The diagnosis of FH, followed by an appropriate and early treatment is critical to reduce the cardiovascular burden in this population. Phase I–III clinical trials showed the benefit of proprotein convertase subtilisin kexin 9 inhibitors, both alirocumab and evolocumab, in these patients with an average low-density lipoprotein cholesterol reduction ranging from −40% to −60%. The aim of this review is to address the unmet needs in cholesterol management, elucidate the biology and the clinical benefit of proprotein convertase subtilisin kexin 9 inhibition and finally discuss the open gaps and future directions in the treatment of patients with heterozygous FH. Keywords: HeFH, dyslipidemia, cholesterol, alirocumab, evolocumab
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Proprotein convertase subtilisin/kexin type 9 (PCSK9), first described in 2003, binds to the low-density lipoprotein receptor (LDLR) resulting in its degradation. Inhibition of PCSK9 results in increased LDLR recycling and a reduction in LDL-cholesterol (LDL-C). The clinical development of monoclonal antibodies (mAbs) that bind to circulating PCSK9 has been rapid with large phase II and III trials demonstrating substantial reductions in LDL-C when given to a very broad group of patients including those with familial and non-familial hypercholesterolemia, diabetes, heart disease, and in those intolerant to statins. Despite sub-cutaneous administration these mAbs are well tolerated and have demonstrated good safety. Two agents, alirocumab and evolocumab, received regulatory approval in 2015 in the US and Europe and evolocumab in 2016 in Japan.
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