ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia-Brief Report.
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SUBMITTER: Reeskamp LF
PROVIDER: S-EPMC8057526 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHomozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels due to profoundly defective LDL receptor (LDLR) function. Given that severely elevated LDL-C starts in utero, atherosclerosis often presents during childhood or adolescence, creating a largely unmet need for aggressive LDLR-independent lipid-lowering therapies in young patients with HoFH. Here we present the first evaluation of the efficacy and safety of evinacumab, a novel LDLR-independent lipid-lowering therapy, in pediatric patients with HoFH from parts A and B of a 3-part study.MethodsThe phase 3, part B, open-label study treated 14 patients 5 to 11 years of age with genetically proven HoFH (true homozygotes and compound heterozygotes) with LDL-C >130 mg/dL, despite optimized lipid-lowering therapy (including LDLR-independent apheresis and lomitapide), with intravenous evinacumab 15 mg/kg every 4 weeks.ResultsEvinacumab treatment rapidly and durably (through week 24) decreased LDL-C with profound reduction in the first week, with a mean (SE) LDL-C reduction of -48.3% (10.4%) from baseline to week 24. ApoB (mean [SE], -41.3% [9.0%]), non-high-density lipoprotein cholesterol (-48.9% [9.8%]), and total cholesterol (-49.1% [8.1%]) were similarly decreased. Treatment-emergent adverse events were reported in 10 (71.4%) patients; however, only 2 (14.3%) reported events that were considered to be treatment-related (nausea and abdominal pain). One serious treatment-emergent adverse event of tonsillitis occurred (n=1), but this was not considered treatment-related.ConclusionsEvinacumab constitutes a new treatment for pediatric patients with HoFH and inadequately controlled LDL-C despite optimized lipid-lowering therapy, lowering LDL-C levels by nearly half in these extremely high-risk and difficult-to-treat individuals.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT04233918.
| S-EPMC10814999 | biostudies-literature
Project description:Evinacumab, an angiopoietin-like protein 3 (ANGPTL3) inhibitor, has been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) in patients with homozygous familial hypercholesterolemia (HoFH). This work characterized the population pharmacokinetics (PK)/pharmacodynamics (PD) of evinacumab using pooled phase III clinical data. Total evinacumab PK were described by a two-compartment model with combined linear and saturable (Michaelis-Menten) elimination, and first-order absorption. At clinically relevant concentrations, plasma drug concentrations were mainly influenced by the linear clearance pathway. Although the maximum target-mediated rate of elimination (Vmax ) parameter for the saturable pathway was found to be positively related to baseline ANGPLTL3, variability in body weight contributed more to the variability in evinacumab exposure than variability in ANGPTL3. An effect of HoFH versus healthy volunteers on Vmax was also identified. Weight-based dosing regimens resulted in consistent evinacumab exposure across weight ranges. An indirect exposure-response model adequately described the relationship between evinacumab and LDL-C, where drug concentration is assumed to inhibit LDL-C production. The final population PK/PD model included two nonclinically significant covariates (race and baseline body weight) on the maximum drug-induced inhibitory effect (Imax ) and one (baseline LDL-C) on the evinacumab concentration inducing 50% of Imax (IC50 ). A smaller IC50 was observed in patients with higher baseline LDL-C, suggesting greater sensitivity to treatment. Population exposure-response analysis permitted estimation of derived PD parameters and individual LDL-C levels over time for patients with HoFH. The model accurately predicted the proportion of patients with HoFH achieving prespecified LDL-C goals with evinacumab during the ELIPSE HoFH study, further supporting a dosing strategy.
| S-EPMC8592514 | biostudies-literature
Project description:Background and aimsHomozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH.MethodsIn this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15 mg/kg every 4 weeks with stable lipid-lowering therapy.ResultsA total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively.ConclusionsIn this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.
| S-EPMC11242450 | biostudies-literature
Project description:Familial homozygous hypercholesterolemia is one of the high risk factors that can result in premature coronary arterial disease leading to severe morbidity and premature death in children and young adults. We describe a rare example of extensive xanthoma tuberosum in a case of familial homozygous hypercholesterolemia.
| S-EPMC4070200 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is characterized by the accumulation of excess cholesterol in tissues including the artery wall and tendons. We describe a patient with homozygous FH who presented with asymptomatic cholesterol granuloma of the brain. The patient's plasma low-density lipoprotein cholesterol level was remarkably responsive to combination hypolipidemic therapy with statin plus ezetimibe. This case illustrates another potential complication of whole-body cholesterol excess and underscores the differences in phenotype and in response to therapy among patients with FH.
| S-EPMC548411 | biostudies-literature
Project description:Purpose of reviewWe reviewed current and future therapeutic options for patients with homozygous familial hypercholesterolemia (HoFH) and place this evidence in context of an adaptable treatment algorithm.Recent findingsLowering LDL-C levels to normal in patients with HoFH is challenging, but a combination of multiple lipid-lowering therapies (LLT) is key. Patients with (near) absence of LDL receptor expression are most severely affected and frequently require regular lipoprotein apheresis on top of combined pharmacologic LLT. Therapies acting independently of the LDL receptor pathway, such as lomitapide and evinacumab, are considered game changers for many patients with HoFH, and may reduce the need for lipoprotein apheresis in future. Liver transplantation is to be considered a treatment option of last resort. Headway is being made in gene therapy strategies, either aiming to permanently replace or knock out key lipid-related genes, with first translational steps into humans being made. Cardiovascular disease risk management beyond LDL-C, such as residual Lp(a) or inflammatory risk, should be evaluated and addressed accordingly in HoFH.SummaryHypercholesterolemia is notoriously difficult to control in most patients with HoFH, but multi-LLT, including newer drugs, allows reduction of LDL-C to levels unimaginable until a few years ago. Cost and availability of these new therapies are important future challenges to be addressed.
| S-EPMC9640271 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is a common inherited disorder that results in premature atherosclerosis. Diagnosis of FH is suspected on the basis of clinical criteria, but confirmation requires genetic testing. In the era of statins, early diagnosis and initiation of treatment can modify disease progression and outcomes. Therefore, cascade screening with a combination of lipid concentration measurements and DNA testing should be used to identify relatives of index cases with a clinical diagnosis of FH. Autosomal dominant FH is related to mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Genetic screening of the LDLR gene is challenging to achieve at a feasible cost, especially in people who do not have a founder effect. Nucleotide sequencing of all exons and flanking splicing regions in combination with multiplex ligation probe amplification to detect large insertions or deletions is considered the gold-standard approach to screen for LDLR mutations. Alternatively, the cDNA can be sequenced; however, this procedure is not suitable for use in large populations, because of the need of RNA extraction. Multiplex analysis can be appropriate for population with founder effects or a low number of different mutations. Finally, there are many techniques for a mutation scanning approach, which have some benefits over sequencing, and also with the potential for detecting known and novel mutations. Familial defective Apo B is amenable to genetic diagnosis by screening for a few mutations. Recently, gain-of-function mutations in PCSK9 gene have been demonstrated to cause FH phenotype. Strategies for population screening, cost-effectiveness of genetic screening, ethical aspects, and insurance policies are discussed and need implementation worldwide.
| S-EPMC3681171 | biostudies-literature
Project description:This case report describes a 67-year-old African-American woman with homozygous familial hypercholesterolemia caused by 2 pathogenic variants in the LDLR gene. Initial surgical, pharmacological, and low-density lipoprotein apheresis interventions were insufficient; the addition of proprotein convertase subtilisin-kexin type 9 and angiopoietin-like 3 inhibitors lowered her low-density lipoprotein cholesterol to <70 mg/dL. (Level of Difficulty: Advanced.).
| S-EPMC9730161 | biostudies-literature
Project description:Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder with extreme elevations of low-density lipoprotein cholesterol (LDL-C) leading to premature atherosclerotic cardiovascular disease (ASCVD) as early as in childhood. Management of HoFH centers around aggressive and adequate reduction of LDL-C levels to slow the trajectory of ASCVD development. Historically, lowering LDL-C levels in HoFH has been challenging because of both the markedly elevated LDL-C levels (often ＞400 mg/dL) and reduced response to treatment options, such as statins, for which the mechanism of action requires a functional LDL receptor. However, the treatment landscape for HoFH has rapidly progressed over the last decade. While statins and ezetimibe remain first-line treatment, patients often require addition of multiple therapies to achieve goal LDL-C levels. The PCSK9 inhibitors are an important recent addition to the available treatment options, along with lomitapide, bile acid sequestrants, and, possibly, bempedoic acid. Additionally, ANGPTL3 has emerged as an important therapeutic target, with evinacumab being the first available ANGPTL3 inhibitor on the market for the treatment of patients with HoFH. For patients who cannot achieve adequate LDL-C reduction, lipoprotein apheresis may be necessary, with the added benefit of reducing lipoprotein(a) levels that carries an added risk if also elevated in patients with HoFH. Finally, gene therapy and genome editing using CRISPR/Cas-9 are moving through clinical development and may dramatically alter the future landscape of treatment for HoFH.
| S-EPMC9371762 | biostudies-literature
Project description:Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib.We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR).Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR.These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance.ClinicalTrials.gov NCT00990808.Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).
| S-EPMC4497759 | biostudies-literature