RESUMEN
BACKGROUND: Vupanorsen is a GalNAc3-conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia. OBJECTIVES: The aim of this study was to satisfy Chinese regulatory requirements and support ethnic sensitivity assessment by evaluating pharmacokinetics (PK), pharmacodynamics (PD), and safety of vupanorsen in healthy Chinese adults with elevated triglycerides (TG). METHODS: In this phase I, parallel-cohort, open-label study, 18 Chinese adults with elevated fasting TG (≥ 90 mg/dL) were randomized 1:1 to receive a single subcutaneous dose of vupanorsen 80 mg or 160 mg. PK parameters, PD markers (including ANGPTL3, TG, non-high-density lipoprotein cholesterol [non-HDL-C]), and safety were assessed. RESULTS: Absorption of vupanorsen was rapid (median time to maximum concentration [Tmax]: 2.0 h for both doses), followed by a multiphasic decline (mean terminal half-life 475.9 [80 mg] and 465.2 h [160 mg]). Exposure (area under curve [AUC] and maximum plasma concentration [Cmax]) generally increased in a greater than dose-proportional manner from 80 mg to 160 mg. Time-dependent reductions in ANGPTL3 and lipid parameters were observed. Mean percentage change from baseline for the 80-mg and 160-mg doses, respectively, were - 59.7% and - 69.5% for ANGPTL3, - 41.9% and - 52.5% for TG, and - 23.2% and - 25.4% for non-HDL-C. No serious or severe adverse events (AEs), deaths, or discontinuations due to AEs were reported. Three participants experienced treatment-related AEs; all were mild and resolved by end of study. CONCLUSIONS: This study provided the first clinical vupanorsen data in China. In Chinese participants with elevated TG, PK and PD parameters were consistent with those reported previously in non-Chinese participants, including in Japanese individuals. No safety concerns were noted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04916795.
Asunto(s)
Proteína 3 Similar a la Angiopoyetina , Pueblo Asiatico , Oligonucleótidos Antisentido , Triglicéridos , Humanos , Masculino , Femenino , Adulto , Oligonucleótidos Antisentido/farmacocinética , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/efectos adversos , Oligonucleótidos Antisentido/farmacología , Triglicéridos/sangre , Persona de Mediana Edad , Relación Dosis-Respuesta a Droga , Adulto Joven , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/sangre , Oligonucleótidos/farmacocinética , Oligonucleótidos/efectos adversos , Oligonucleótidos/administración & dosificación , Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , ChinaRESUMEN
INTRODUCTION: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive condition. Effective treatment is important as patients are at risk for severe and potentially fatal acute pancreatitis. We review recent developments in pharmacologic treatment for FCS, namely biological inhibitors of apolipoprotein (apo) C-III and angiopoietin-like protein 3 (ANGPTL3). AREAS COVERED: FCS follows a biallelic inheritance pattern in which an individual inherits two pathogenic loss-of-function alleles of one of the five causal genes - LPL (in 60-80% of patients), GPIHBP1, APOA5, APOC2, and LMF1 - leading to the absence of lipolytic activity. Patients present from childhood with severely elevated triglyceride (TG) levels >10 mmol/L. Most patients with severe hypertriglyceridemia do not have FCS. A strict low-fat diet is the current first-line treatment, and existing lipid-lowering therapies are minimally effective in FCS. Apo C-III inhibitors are emerging TG-lowering therapies shown to be efficacious and safe in clinical trials. ANGPTL3 inhibitors, another class of emerging TG-lowering therapies, have been found to require at least partial lipoprotein lipase activity to lower plasma TG in clinical trials. ANGPTL3 inhibitors reduce plasma TG in patients with multifactorial chylomicronemia but not in patients with FCS who completely lack lipoprotein lipase activity. EXPERT OPINION: Apo C-III inhibitors currently in development are promising treatments for FCS.
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Proteína 3 Similar a la Angiopoyetina , Hiperlipoproteinemia Tipo I , Humanos , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo I/tratamiento farmacológico , Hiperlipoproteinemia Tipo I/terapia , Apolipoproteína C-III/genética , Apolipoproteína C-III/antagonistas & inhibidores , Hipolipemiantes/uso terapéutico , Lipoproteína Lipasa/genética , Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Proteínas Similares a la Angiopoyetina/genética , Dieta con Restricción de Grasas , Receptores de LipoproteínaRESUMEN
AIMS: Remnant cholesterol and very low-density lipoprotein cholesterol (VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target. METHODS AND RESULTS: TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100â mg/dL and triglycerides 150-500â mg/dL. The primary endpoint of this analysis was percentage change in remnant cholesterol (total cholesterol minus directly measured LDL-C minus HDL-C) and VLDL-C (directly measured) over 24 weeks. Two hundred eighty-six patients were enrolled, with a median age of 64 years and 44% female. Median baseline remnant cholesterol and VLDL-C were 42 and 31â mg/dL, respectively (reference: <30â mg/dL). Vupanorsen lowered remnant cholesterol by 42-59% at 24 weeks over placebo (P < 0.001), achieving a median level of 18â mg/dL at the highest dose. Over the same period, VLDL-C was reduced by 52-67% over placebo (P < 0.001), with a median achieved level of 2.5â mg/dL at the highest dose. The effect of vupanorsen on remnant cholesterol and VLDL-C reduction was dose-dependent and directly associated with the degree of ANGPTL3 inhibition: at 90% ANGPTL3 reduction, there was a 61% and 81% decrease in remnant cholesterol and VLDL-C, respectively. CONCLUSION: Inhibition of ANGPTL3 protein synthesis significantly lowered remnant cholesterol and VLDL-C in patients with hypertriglyceridaemia. The magnitude of reduction was associated with the degree of ANGPTL3 inhibition. These findings support ANGPTL3 inhibition as a promising target for lowering cholesterol on triglyceride-rich lipoproteins.
In this randomized controlled trial of 286 participants with elevated triglycerides, treatment with vupanorsen, an ANGPTL3 inhibitor, lowered remnant cholesterol by up to 59% and VLDL cholesterol by up to 67% over placebo. The effect of the treatment was sustained throughout 24 weeks and consistent across key patient subgroups. ANGPTL3 inhibition may be a promising approach to treat patients with elevated triglycerides.
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Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , VLDL-Colesterol , Colesterol , Triglicéridos , Humanos , Femenino , Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Masculino , Método Doble Ciego , Persona de Mediana Edad , VLDL-Colesterol/sangre , Colesterol/sangre , Colesterol/biosíntesis , Triglicéridos/sangre , Anciano , Resultado del Tratamiento , Biomarcadores/sangre , Oligonucleótidos Antisentido/uso terapéutico , Angiopoyetinas , Factores de Tiempo , Regulación hacia Abajo , LipoproteínasRESUMEN
PURPOSE OF REVIEW: Hypertriglyceridemia (HTG) is an independent and casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with HTG. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are key regulators of triglyceride-rich lipoprotein (TRL) metabolism. We review recent clinical trials targeting ANGPTL3 and apoC-III with monoclonal antibody and nucleic acid therapies, including antisense oligonucleotides and small interfering RNA. RECENT FINDINGS: ANGPTL3 and apoC-III inhibitors are effective in lowering plasma triglycerides and TRLs, with possibly greater efficacy with the inhibition of apoC-III. By contrast to ANGPTL3 inhibition that has the advantage of greater lowering of plasma low-density lipoprotein (LDL)-cholesterol and apoB levels, apoC-III inhibition only has a modest or no effect in lowering plasma LDL-cholesterol and apoB concentrations. Therapeutic inhibition of ANGPTL3 and apoC-III can correct HTG possibly by reducing production and increasing catabolism of TRL particles, but this remains to be formally investigated in patients with HTG. SUMMARY: Novel agents targeting ANGPTL3 and apoC-III can correct HTG and potentially lower risk of ASCVD in patients with HTG. The long-term safety and cost-effectiveness of these agents await confirmation in ongoing and future studies.
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Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Angiopoyetinas , Apolipoproteína C-III , Hipertrigliceridemia , Apolipoproteína C-III/antagonistas & inhibidores , Apolipoproteína C-III/sangre , Apolipoproteína C-III/metabolismo , Humanos , Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Proteínas Similares a la Angiopoyetina/metabolismo , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/sangre , Hipertrigliceridemia/metabolismo , Angiopoyetinas/metabolismo , Angiopoyetinas/antagonistas & inhibidores , Animales , Triglicéridos/sangre , Triglicéridos/metabolismo , Ensayos Clínicos como AsuntoRESUMEN
PURPOSE OF REVIEW: Familial hypercholesterolemia (FH) is a monogenic disorder characterized by high plasma levels of low-density lipoprotein cholesterol (LDL-C) since birth and a high risk of premature cardiovascular disease. The genetic defect is carried in only one allele in heterozygous FH (HeFH) or in both in the most severe homozygous FH (HoFH). Current guidelines recommend to reduce substantially LDL-C levels in these high-risk patients, with the need to use association therapy combining agents with different mechanisms of action. As most cases of FH are attributable to mutations in the gene encoding the low-density lipoprotein receptor (LDLR), statins, even in combination with ezetimibe, are less effective in reducing LDL-C plasma levels in FH patients, who require a more intensive approach with additional lipid-lowering agents. Additional targets playing key roles in regulating LDL-C levels are represented by PCSK9 and ANGPTL3. RECENT FINDINGS: Two monoclonal antibodies (mAbs) targeting PCSK9, evolocumab and alirocumab, significantly reduce LDL-C levels in HeFH patients. In patients with HoFH, the efficacy of mAbs to PCSK9 is strictly related to the presence of a residual LDLR activity; thus, patients carrying null mutations do not respond to the therapy with these mAbs, whereas some effects can be appreciated in HoFH bearing defective mutations. Conversely, evinacumab, the mAb targeting ANGPTL3, is highly effective in reducing LDL-C levels even in HoFH patients carrying null LDLR mutations, thanks to its LDLR-independent mechanism of action. Monoclonal antibodies inhibiting PCSK9 have shown a robust effect in FH patients presenting a residual LDLR activity, while ANGPTL3 inhibitors appear to be promising even in patients carrying null LDLR mutations.
Asunto(s)
Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Anticuerpos Monoclonales , Hiperlipoproteinemia Tipo II , Inhibidores de PCSK9 , Proteína 3 Similar a la Angiopoyetina , Anticuerpos Monoclonales/uso terapéutico , LDL-Colesterol , Humanos , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genéticaRESUMEN
The excessive accumulation of TG-rich lipoproteins (TGRLs) in plasma is associated with dyslipidemia and atherosclerotic cardiovascular diseases (ASCVDs). Tangeretin is a bioactive pentamethoxyflavone mainly found in citrus peels, and it has been reported to protect against hyperlipidemia, diabetes, and obesity. The aim of this study was to investigate the lipid-modulating effects and the underlying mechanisms of tangeretin action in hepatic cells. Transcriptome and bioinformatics analyses with the Gene Ontology (GO) database showed that tangeretin significantly regulated a set of 13 differentially expressed genes (DEGs) associated with the regulation of lipoprotein lipase (LPL) activity. Among these DEGs, angiopoietin-like 3 (ANGPTL3), an essential inhibitor of LPL catalytic activity that regulates TGRL metabolism in plasma, was markedly downregulated by tangeretin. We demonstrated that tangeretin significantly inhibited the mRNA expression of ANGPTL3 in HepG2 and Huh-7 cells. Tangeretin treatment of hepatic cells also reduced the levels of both intracellular and secreted ANGPTL3 proteins. Moreover, we found that inhibition of ANGPTL3 production by tangeretin augmented LPL activity. We further demonstrated that the transcriptional activity of the ANGPTL3 promoter was significantly attenuated by tangeretin, and we identified a DNA element located between the -250 and -121 positions that responded to tangeretin. Furthermore, we found that tangeretin did not alter the levels of the nuclear liver X receptor α (LXRα) protein, an essential transcription factor that binds to the tangeretin-responsive element, but it can counteract LXRα-mediated ANGPTL3 transcription. On the basis of molecular docking analysis, tangeretin was predicted to bind to the ligand-binding domain of LXRα, which would result in suppression of LXRα activation. Our findings support the hypothesis that tangeretin exerts a lipid-lowering effect by modulating the LXRα-ANGPTL3-LPL pathway, and thus, it can be used as a potential phytochemical for the prevention or treatment of dyslipidemia.
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Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Flavonas/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Receptores X del Hígado/metabolismo , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/metabolismo , Evaluación Preclínica de Medicamentos , Dislipidemias/tratamiento farmacológico , Flavonas/uso terapéutico , Células Hep G2 , Humanos , Lipasa/metabolismoRESUMEN
The recombinant human monoclonal antibody evinacumab (evinacumab-dgnb, EVKEEZA™) is an angiopoietin-like protein three (ANGPTL3) inhibitor that has been developed by Regeneron Pharmaceuticals for the treatment of homozygous familial hypercholesterolaemia (HoFH), refractory hypercholesterolemia (both familial and non-familial) and severe hypertriglyceridaemia. Based on the results of the phase III ELIPSE HoFH trial, evinacumab was recently approved in the USA as an adjunct to other LDL-C lowering therapies for the treatment of adult and paediatric patients aged 12 years and older with HoFH, and has received a positive opinion in the EU. This article summarizes the milestones in the development of evinacumab leading to this first approval for HoFH.
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Anticuerpos Monoclonales/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Hipertrigliceridemia/tratamiento farmacológico , Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/farmacología , Método Doble Ciego , Aprobación de Drogas , Humanos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Estados UnidosAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , LDL-Colesterol/efectos de los fármacos , Humanos , Infusiones Intravenosas , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
PURPOSE FOR REVIEW: Despite the therapeutic advances for patients with severe hypercholesterolemia, particularly those with homozygous familial hypercholesterolemia (HoFH), most patients are unable to achieve target low-density lipoprotein cholesterol (LDL-C) levels with the current available standard lipid-lowering therapy (LLT). We review the role of angiopoietin-like 3 (ANGPTL3) inhibition as an additional therapeutic option for severe hypercholesterolemia, particularly HoFH. RECENT FINDINGS: Evinacumab is a monoclonal antibody against ANGPTL3, and reduces LDL-C independent of LDL-receptor activity. ANGPTL3 inhibitors are effective in lowering LDL-C in patients with FH, with a 50% reduction in LDL-C in those with HoFH. Longer-term efficacy and safety have been demonstrated with reductions in LDL-C maintained following 48âweeks of therapy. Gene silencing strategies directed against ANGPTL3 include antisense oligonucleotide and small-interfering ribonucleic acid (siRNA). ARO-ANG3 is a siRNA directed against ANGPTL3 messenger ribonucleic acid and is associated with up to a 42% reduction in LDL-C. SUMMARY: With the promise of these emerging novel therapeutics directed against ANGPTL3 on the horizon, achieving acceptable target LDL-C levels in HoFH without the need for lipoprotein apheresis may finally be a realistic goal and we can anticipate a decrease in cardiovascular morbidity and mortality in these difficult to treat patients.
Asunto(s)
Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Hipercolesterolemia Familiar Homocigótica , Hipercolesterolemia , Proteína 3 Similar a la Angiopoyetina/antagonistas & inhibidores , Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Hipercolesterolemia Familiar Homocigótica/terapia , Humanos , Hipercolesterolemia/terapia , ARN Interferente Pequeño/uso terapéuticoRESUMEN
[Figure: see text].
Asunto(s)
Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Anticuerpos Monoclonales/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Apolipoproteína B-100/sangre , LDL-Colesterol/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Lipoproteínas IDL/sangre , Lipoproteínas LDL/sangre , Hígado/efectos de los fármacos , Adulto , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/metabolismo , Anticuerpos Monoclonales/efectos adversos , Anticolesterolemiantes/efectos adversos , Biomarcadores/sangre , Femenino , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hígado/metabolismo , Masculino , Mutación , Países Bajos , Pennsylvania , Fenotipo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known. METHODS: In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo. RESULTS: In total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P<0.001) and -24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups. CONCLUSIONS: In patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).
Asunto(s)
Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Adulto , Proteína 3 Similar a la Angiopoyetina , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , LDL-Colesterol/sangre , Método Doble Ciego , Esquema de Medicación , Resistencia a Medicamentos , Femenino , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE OF REVIEW: Familial chylomicronemia syndrome (FCS) is a rare recessive genetic disorder often underdiagnosed with potentially severe clinical consequences. In this review, we describe the clinical and biological characteristics of the disease together with its main complication, i.e., acute pancreatitis. We focused the paper on new diagnostic tools, progress in understanding the role of two key proteins (apolipoprotein CIII (apo CIII) and angiopoietin-like3 (ANGPTL-3)), and new therapeutic options. RECENT FINDINGS: Recently, a new diagnostic tool has been proposed by European experts to help identify these patients. This tool with two recently identified parameters (low LDL and low body mass index) can help identify patients who should be genetically tested or who may have the disease when genetic testing is not available. FCS is caused by homozygous or compound heterozygous mutations of lipoprotein lipase, apolipoprotein C-II, apolipoprotein A-V, glycosylphosphatidylinositol anchored high-density lipoprotein-binding protein 1, and lipase maturation factor. Two proteins have been identified as important player in the metabolism of triglyceride-rich lipoprotein and its regulation. These two proteins are therapeutic target. Antisense oligonucleotide targeting apo CIII has been shown to significantly decrease triglyceride levels even in FCS and is the first available treatment for these patients. Further development might identify new compounds with reduced risk to develop severe thrombocytopenia. ANGPTL-3 inhibitors have not yet been tested in FCS patients but exert significant hypotriglyceridemic effect in the more frequent and less severe polygenic forms. Beyond these two new targets, microsomal triglyceride transfer protein (MTTP) inhibitors could also be part of the armamentarium, if on-going trials confirm their efficacy. New clinical tools and simple criteria can help select patients with possible FCS and identify patients who should have a genetic testing. Identifying patients with FCS is a major issue since these patients have a high risk to suffer severe episodes of acute pancreatitis and may now benefit from new therapeutic options including antisense oligonucleotide targeting apo CIII.
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Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Índice de Masa Corporal , Proteínas Portadoras/antagonistas & inhibidores , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/tratamiento farmacológico , Lipoproteínas LDL/sangre , Oligonucleótidos Antisentido/uso terapéutico , Proteína 3 Similar a la Angiopoyetina , Animales , Apolipoproteína A-V/genética , Apolipoproteína C-III/genética , Pruebas Genéticas/métodos , Humanos , Hiperlipoproteinemia Tipo I/complicaciones , Hiperlipoproteinemia Tipo I/genética , Lipoproteína Lipasa/genética , Mutación , Pancreatitis/tratamiento farmacológico , Pancreatitis/etiología , Receptores de Lipoproteína/genética , Resultado del TratamientoRESUMEN
BACKGROUND: Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. RESULTS: The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups. CONCLUSIONS: In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.).
Asunto(s)
Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Anticuerpos Monoclonales/uso terapéutico , Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Adolescente , Adulto , Anciano , Proteína 3 Similar a la Angiopoyetina , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/sangre , Anticolesterolemiantes/efectos adversos , Anticolesterolemiantes/sangre , Niño , Método Doble Ciego , Femenino , Homocigoto , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/genética , Infusiones Intravenosas , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Mutación , Receptores de LDL/metabolismo , Adulto JovenRESUMEN
Angiopoietin like protein 3 (ANGPTL3) is best known for its function as an inhibitor of lipoprotein and endothelial lipases. Due to the capacity of genetic or pharmacologic ANGPTL3 suppression to markedly reduce circulating lipoproteins, and the documented cardioprotection upon such suppression, ANGPTL3 has become an emerging therapy target for which both antibody and antisense oligonucleotide (ASO) therapeutics are being clinically tested. While the antibody is relatively selective for circulating ANGPTL3, the ASO also depletes the intra-hepatocellular protein, and there is emerging evidence for cell-autonomous functions of ANGPTL3 in the liver. These include regulation of hepatocyte glucose and fatty acid uptake, insulin sensitivity, LDL/VLDL remnant uptake, VLDL assembly/secretion, polyunsaturated fatty acid (PUFA) and PUFA-derived lipid mediator content, and gene expression. In this review we elaborate on (i) why ANGPTL3 is considered one of the most promising new cardiometabolic therapy targets, and (ii) the present evidences for its intra-hepatocellular or cell-autonomous functions.
Asunto(s)
Proteínas Similares a la Angiopoyetina/metabolismo , Enfermedades Cardiovasculares/metabolismo , Hepatopatías/metabolismo , Metaboloma , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Proteínas Similares a la Angiopoyetina/sangre , Animales , Anticuerpos/uso terapéutico , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/tratamiento farmacológico , Humanos , Resistencia a la Insulina , Metabolismo de los Lípidos/efectos de los fármacos , Lipoproteínas/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hepatopatías/sangre , Hepatopatías/tratamiento farmacológico , Metaboloma/efectos de los fármacos , Modelos Moleculares , Terapia Molecular Dirigida , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Oligonucleótidos Antisentido/uso terapéuticoRESUMEN
INTRODUCTION: The prevalence of hypertriglyceridemia (HTG) is increasing. Elevated triglyceride (TG) levels are associated with an increased cardiovascular disease (CVD) risk. Moreover, severe HTG results in an elevated risk of pancreatitis, especially in severe HTG with an up to 350-fold increased risk. Both problems emphasize the clinical need for effective TG lowering. AREAS COVERED: The purpose of this review is to discuss the currently available therapies and to elaborate the most promising novel therapeutics for TG lowering. EXPERT OPINION: Conventional lipid lowering strategies do not efficiently lower plasma TG levels, leaving a residual CVD and pancreatitis risk. Both apolipoprotein C-III (apoC-III) and angiopoietin-like 3 (ANGPTL3) are important regulators in TG-rich lipoprotein (TRL) metabolism. Several novel agents targeting these linchpins have ended phase II/III trials. Volanesorsen targeting apoC-III has shown reductions in plasma TG levels up to 90%. Multiple ANGPLT3 inhibitors (evinacumab, IONIS-ANGPTL3-LRx, ARO-ANG3) effectuate TG reductions up to 70% with concomitant potent reduction in all other apoB containing lipoprotein fractions. We expect these therapeutics to become players in the treatment for (especially) severe HTG in the near future.
Asunto(s)
Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Apolipoproteína C-III/efectos de los fármacos , Hipertrigliceridemia/tratamiento farmacológico , Proteína 3 Similar a la Angiopoyetina , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Ensayos Clínicos como Asunto , Humanos , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/metabolismo , Lipoproteínas/metabolismo , Oligonucleótidos/farmacología , Oligonucleótidos/uso terapéutico , Pancreatitis/etiología , Pancreatitis/prevención & controlRESUMEN
PURPOSE OF REVIEW: Apolipoprotein C-III (ApoC-III) and angiopoietin like protein 3 (angptl3) have emerged as key regulators of triglyceride metabolism. Based on Mendelian randomisation studies, novel therapeutic strategies inhibiting these proteins using monoclonal antibodies or gene silencing techniques might reduce residual cardiovascular disease (CVD) risk in dyslipidemic patients. This article aims to review the role of apoC-III and angptl3 in triglyceride metabolism and combine early clinical evidence of CVD reducing potential of these new therapeutic targets. RECENT FINDINGS: Angptl3 inhibition by mAb or antisense therapy has recently completed phase I and II studies, respectively and demonstrate robust apolipoprotein B (apoB) lowering up to 46%. Volanesorsen is an antisense therapy approved for patients with extremely elevated plasma triglyceride levels in which it showed no consistent apoB reduction. However, the GalNAc-conjugated oligonucleotide showed moderate (up to â¼30%) apoB reduction in a phase 1/2a dose-finding study. SUMMARY: Angptl3 and apoC-III are novel targets in lipoprotein metabolism that reduce triglycerides when inhibited. The expected CVD risk reduction may be mediated through reduced triglyceride-rich lipoprotein particle number, reflected by apoB, rather than triglyceride reduction per se. Limited human evidence shows that apoC-III and angptl3 inhibition both potently lower triglycerides, but since angptl3 inhibition reduces apoB more robustly it may be expected to confer more favorable CVD risk reduction.
Asunto(s)
Proteínas Similares a la Angiopoyetina/genética , Apolipoproteína C-III/genética , Enfermedades Cardiovasculares/tratamiento farmacológico , Triglicéridos/genética , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Apolipoproteína C-III/antagonistas & inhibidores , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Humanos , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Oligonucleótidos Antisentido/uso terapéutico , Triglicéridos/antagonistas & inhibidores , Triglicéridos/metabolismoRESUMEN
PURPOSE OF REVIEW: Homozygous familial hypercholesterolemia (HoFH) is a rare disorder associated with early atherosclerotic disease due to impairment of the LDL receptor (LDLR) pathway. Because of their molecular defect, current treatment options have limited success in bringing HoFH patient to LDL-C target and morbidity and mortality remain high. We review current and upcoming therapies directed at HoFH, including gene therapy. RECENT FINDINGS: Recent real-world studies have confirmed the strength in lomitapide as a treatment adjunct to statins and other lipid-lowering therapies in HoFH patients. The approval of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibodies has also been a welcome addition to the treatment armamentarium offering an additional average reduction in LDL-C levels of 24% when added to background lipid-lowering therapies in this population. Although achieving adequate LDL-C levels in this population is difficult, there are several therapies on the horizon that may help more patients reach goal. Evinacumab, a monoclonal antibody against ANGPTL3, has been shown to substantially reduce LDL-C of an average of 49%, independently of residual LDLR activity. RNA interference targeting PCSK9 and ANGPTL3 shows promise in clinical trials. Adeno-associated virus-mediated gene transfer and gene editing techniques are in early clinical and preclinical development. SUMMARY: LDL-C lowering in HoFH patients remains very challenging. However, novel treatment options are emerging. Upcoming therapies directed at PCSK9 and ANPTL3 may offer additional LDL-C reduction, to help patients achieve adequate LDL-C levels. Gene therapy and gene editing techniques, if proven effective, may offer a unique opportunity to treat patients with a one-time treatment.
Asunto(s)
Proteínas Similares a la Angiopoyetina/genética , LDL-Colesterol/genética , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Proproteína Convertasa 9/genética , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Anticuerpos Monoclonales/uso terapéutico , Bencimidazoles/uso terapéutico , LDL-Colesterol/análisis , Homocigoto , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/patología , Hipolipemiantes/uso terapéutico , Terapia Molecular Dirigida , Inhibidores de PCSK9 , Receptores de LDL/genéticaRESUMEN
PURPOSE OF REVIEW: Atherosclerosis is characterized by accumulation of lipids and chronic inflammation in medium size to large arteries. Recently, RNA-based antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are being developed, along with small molecule-based drugs and monoclonal antibodies, for the treatment of risk factors associated with atherosclerosis.. The purpose of this review is to describe nucleic acid-based therapeutics and introduce novel RNAs that might become future tools for treatment of atherosclerosis. RECENT FINDINGS: RNA-based inhibitors for PCSK9, Lp(a), ApoCIII, and ANGPTL3 have been successfully tested in phase II-III clinical trials. Moreover, multiple microRNA and long non-coding RNAs have been found to reduce atherogenesis in preclinical animal models. Clinical trials especially with ASOs and siRNAs directed to liver, targeting cholesterol and lipoprotein metabolism, have shown promising results. Additional research in larger patient cohorts is needed to fully evaluate the therapeutic potential of these new drugs.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Aterosclerosis/tratamiento farmacológico , MicroARNs/uso terapéutico , Oligonucleótidos Antisentido/uso terapéutico , ARN Largo no Codificante/uso terapéutico , ARN Interferente Pequeño/uso terapéutico , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Animales , Apolipoproteína C-III/antagonistas & inhibidores , Aterosclerosis/metabolismo , Humanos , Lipoproteína(a)/antagonistas & inhibidores , Lipoproteína(a)/metabolismo , Hígado/metabolismo , Oligonucleótidos Antisentido/farmacología , Inhibidores de PCSK9 , ARN Interferente Pequeño/farmacologíaRESUMEN
Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased â¼30% to 40% after 1 and 3 months of a high-fructose diet (both P < 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR)], hypertriglyceridemia, adiposity (assessed as leptin), and systemic inflammation [C-reactive peptide (CRP)] and negatively correlated with plasma levels of the insulin-sensitizing hormone adropin. Multiple regression analyses identified a strong association between circulating APOC3 and ANGPTL3 concentrations. Higher baseline plasma levels of both ANGPTL3 and APOC3 were associated with an increased risk for fructose-induced insulin resistance. Fish oil previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). ANGPTL3 RNAi lowered plasma concentrations of ANGPTL3, triglycerides (TGs), VLDL-C, APOC3, and APOE. These decreases were consistent with a reduced risk of atherosclerosis. In summary, dietary sugar-induced increases of circulating ANGPTL3 concentrations after metabolic dysregulation correlated positively with leptin levels, HOMA-IR, and dyslipidemia. Targeting ANGPTL3 expression with RNAi inhibited dyslipidemia by lowering plasma TGs, VLDL-C, APOC3, and APOE levels in rhesus macaques.