Evinacumab. Anti-ANGPTL3 (angiopoietin-like protein 3) monoclonal antibody, Treatment of homozygous familial hypercholesterolemia, Treatment of dyslipidemia and cardiovascular disease | Request PDFHomeHematologyAngiopoietin-like proteinsArticleEvinacumab. Anti-ANGPTL3 (angiopoietin-like protein 3) monoclonal antibody, Treatment of homozygous familial hypercholesterolemia, Treatment of dyslipidemia and cardiovascular diseaseSeptember 2020Drugs of the Future 45(9):619DOI:10.1358/dof.2020.45.9.3178109Authors: Bart DuellOregon Health and Science University Bruce A WardenOregon Health and Science University Request full-text PDFTo read the full-text of this research, you can request a copy directly from the authors.Request full-textDownload citation Copy link Link copied Request full-text Download citation Copy link Link copiedTo read the full-text of this research, you can request a copy directly from the authors.Citations (1)References (1)AbstractThe family of angiopoietin-like (ANGPTL) proteins consists of 8 members (ANGPTL1-8) that have disparate effects on physiology. Three members of the family, ANGPTL3, ANGPTL4 and ANGPTL8, modulate lipoprotein metabolism. Data from epidemiologic studies as well as investigations of the effects of reduced ANGPTL3 activity on lipoprotein metabolism and atherosclerotic cardiovascular disease (ASCVD) in humans and animal models suggest that inhibition of ANGPTL3 activity is likely associated with reduced risk of ASCVD. Data from phase I to III clinical trials demonstrate that treatment with evinacumab, a fully human monoclonal antibody directed against ANGPTL3, effectively lowers plasma triglycerides and low-density lipoprotein cholesterol (LDL-C) by roughly half with minimal side effects. Remarkably, even patients with refractory severe hypercholesterolemia caused by homozygous familial hypercholesterolemia (HoFH) have achieved a 49% reduction in LDL-C during treatment with evinacumab. The drug is under investigation for treatment of a variety of lipid disorders, the most developed of which is for reduction of LDL-C in patients with HoFH. In the meantime, patients with HoFH will be anxiously awaiting the potential clinical availability of this much-needed new LDL-C-lowering medication. Discover the world s research20+ million members135+ million publications700k+ research projectsJoin for freeNo full-text available To read the full-text of this research, you can request a copy directly from the authors.Request full-text PDFCitations (1)References (1)... Of these proteins, ANGPTL3 appears to be the most pertinent for modulating lipid and lipoprotein metabolism through its concerted interactions with ANGPTL4 and ANGPTL8. The intricate process of coordinating ANGPTL proteins and their respective effects on lipoproteins is beyond the scope of this review and has previously been summarized [42]. Briefly, ANGPTL3 exerts its effects on lipoprotein metabolism by inhibiting lipoprotein lipase (LPL), endothelial lipase (EL), and hepatic lipase (HL), thereby increasing plasma levels of LDL-C, very low-density lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides [39,40]. ...... Currently, three distinct therapeutic treatment approaches targeting ANGPLT3 inhibition are being investigated, anti-ANGPTL3 monoclonal antibody therapy, gene silencing (antisense oligonucleotide [ASO], small interfering ribonucleic acid [siRNA]) and gene editing with clustered regularly interspaced short palindromic repeats (CRISPR). Prior publications have described the mechanisms of action and developmental progress of these therapeutic approaches [41,42]. The most developed approach and the focus of this review is monoclonal antibody inhibition of ANGPTL3 with evinacumab. ...... Evinacumab is a fully human IgG4 isotype monoclonal antibody that is produced by recombinant DNA technology and targeted against ANGPTL3 [42,48]. The antibody binds the Nterminal domain of ANGPTL3 thereby abrogating inhibition of LPL and EL and producing a panlipid-lowering effect [48]. ...Evinacumab for treatment of familial hypercholesterolemiaArticleJul 2021Expet Rev Cardiovasc Ther Bruce A Warden Bart DuellIntroductionFamilial hypercholesterolemia (FH) is characterized by lifelong elevation of low-density lipoprotein cholesterol (LDL-C), early onset coronary atherosclerosis and premature death. FH is underdiagnosed and undertreated, but requires aggressive LDL-C-lowering to prevent complications. Current treatment strategies, lifestyle modification and numerous LDL-C-lowering medications, are often insufficient to achieve lipid goals in FH.Areas coveredAngiopoietin-like 3 protein (ANGPTL3) is intricately involved in lipid metabolism. Loss-of-function mutations in ANGPTL3 are associated with panhypolipidemia and reduced coronary atherosclerosis. Evinacumab, a fully human monoclonal antibody, inhibits ANGPTL3 and reduces multiple lipoprotein fractions ~50%, including LDL-C. The use of evinacumab within the FH population is described, as well as its regulatory journey to an approved therapeutic.Expert opinionEvinacumab, with its capacity to lower multiple lipoprotein fractions, particularly LDL-C, independently of LDLR function has potential to revolutionize treatment for FH patients. Current FDA-approval is only for homozygous FH (HoFH), arguably the most impactful indication, but use in other lipid disorders is under investigation. Short-term tolerability of evinacumab is very good, with infrequent, mild, and transient adverse events, however, long-term safety data are needed. The high cost and requirement for intravenous administration may limit adoption of evinacumab, but dramatic LDL-C-lowering and need for new therapeutic options for HoFH will drive interest.ViewShow abstractInhibition of Angiopoietin-Like Protein 3 With a Monoclonal Antibody Reduces Triglycerides in HypertriglyceridemiaArticleFull-text availableJun 2019CIRCULATIONZahid AhmadPoulabi Banerjee Sara C Hamon Richard L DunbarBackground: Hypertriglyceridemia is associated with increased cardiovascular risk and may be caused by impaired lipoprotein clearance. Angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein lipase activity, increasing triglycerides and other lipids. Evinacumab, an ANGPTL3 inhibitor, reduced triglycerides in healthy human volunteers and in homozygous familial hypercholesterolemic individuals. Results from 2 Phase 1 studies in hypertriglyceridemic subjects are reported here.Methods: Subjects with triglycerides 150 but ≤450 mg/dL and LDL-C ≥100 mg/dL (n=83 for single ascending dose study [SAD]; n=56 for multiple ascending dose study [MAD]) were randomized 3:1 to evinacumab:placebo. SAD subjects received evinacumab subcutaneously (SC) at 75/150/250 mg, or intravenously (IV) at 5/10/20 mg/kg, monitored up to day (d) 126. MAD subjects received evinacumab SC at 150/300/450 mg once weekly, 300/450 mg every 2 weeks, or IV at 20 mg/kg once every 4 weeks (Q4W) up to d56 with 6 months of follow-up. The primary outcomes were incidence and severity of treatment-emergent adverse events (TEAEs). Efficacy analyses included changes in triglycerides and other lipids over time.Results: In the SAD, 32 (51.6%) versus 9 (42.9%) subjects on evinacumab versus placebo reported TEAEs. In the MAD, 21 (67.7%) versus 9 (75.0%) subjects on SC evinacumab versus placebo and 6 (85.7%) versus 1 (50.0%) on IV evinacumab versus placebo reported TEAEs. No serious TEAEs or events leading to death or treatment discontinuation were reported. Elevations in alanine aminotransferase (7 [11.3%] SAD), aspartate aminotransferase (4 [6.5%] SAD), and creatinine phosphokinase (2 [3.2%) SAD, 1 [14.3%] MAD) were observed with evinacumab (none in the placebo groups), which were single elevations and were not dose-related. Dose-dependent reductions in triglycerides were observed in both studies, with maximum reduction of 76.9% at d3 with 10 mg/kg IV ( P 0.0001) in the SAD and of 83.1% at d2 with 20 mg/kg IV Q4W ( P=0.0003) in the MAD. Significant reductions in other lipids were observed with most evinacumab doses versus placebo.Conclusions: Evinacumab was well-tolerated in 2 Phase 1 studies. Lipid changes in hypertriglyceridemic subjects were similar to those observed with ANGPTL3 loss-of-function mutations. Since the latter is associated with reduced cardiovascular risk, ANGPTL3 inhibition may improve clinical outcomes.Clinical trial registration: Phase 1 single ascending dose study: URL: https://clinicaltrials.gov Unique Identifier: NCT01749878, Phase 1 multiple ascending dose study: URL: https://clinicaltrials.gov Unique Identifier: NCT02107872.ViewShow abstractRecommended publicationsDiscover more about: Angiopoietin-like proteinsArticleAngiopoietin-like proteins inhibitors: New horizons in the treatment of atherogenic dyslipidemia and...January 2021 · Cardiology JournalStanisław SurmaMonika RomańczykKrzysztof J. FilipiakAngiopoietin-like proteins (ANGPTL) are involved in the regulation of numerous physiological and biochemical processes. ANGPTL3, 4 and 8, which are involved in the regulation of lipoprotein metabolism, are particularly important. ANGPTL3, 4 and 8 have been shown to regulate triglyceride availability depending on the nutritional status of the body. In addition, a deficiency of these proteins has ... [Show full abstract] been found to cause hypolipidemia (reduction of all lipid fractions). Increases in ANGPTL3, 4 and 8 appear to be associated with cardiovascular risk. Animal studies indicate that the use of ANGPTL3 (evinacumab) inhibitors significantly reduces plasma total cholesterol, triglycerides and low-density lipoprotein concentrations. The use of evinacumab in clinical trials also led to the normalization of plasma lipid concentrations in patients with atherogenic dyslipidemia and homozygous familial hypercholesterolemia. The results of these studies indicate that evinacumab may in the future be used in the treatment of lipid disorders, especially those with hypertriglyceridemia.Read moreLooking for the full-text?You can request the full-text of this article directly from the authors on ResearchGate.Request full-textAlready a member? Log in ResearchGate iOS AppGet it from the App Store now.InstallKeep up with your stats and moreAccess scientific knowledge from anywhere orDiscover by subject areaRecruit researchersJoin for freeLoginEmail Tip: Most researchers use their institutional email address as their ResearchGate loginPasswordForgot password? Keep me logged inLog inorContinue with GoogleWelcome back! Please log in.Email · HintTip: Most researchers use their institutional email address as their ResearchGate loginPasswordForgot password? Keep me logged inLog inorContinue with GoogleNo account? 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