Microsomal Triglyceride Transfer Protein Inhibitor Research Articles

Efficacy and safety of lomitapide in familial chylomicronaemia syndrome

Background and aimsFamilial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder, resulting in elevated triglycerides (TGs), abdominal pain and pancreatitis. Treatment options are limited. Lomitapide, a microsomal triglyceride transfer protein inhibitor, is approved for the treatment of homozygous familial hypercholesterolaemia. Whether its therapeutic use may be extended to FCS remains unknown. The aim of this study was to evaluate the efficacy and safety of lomitapide in adult patients with FCS. MethodsThe open-label, single-arm ‘LOCHNES’ study of lomitapide in FCS enrolled patients >18 years with genetically confirmed FCS, elevated fasting TG ≥ 750 mg/dL and history of pancreatitis. Patients were administered lomitapide to the maximum tolerated dose for 26 weeks. The primary endpoint was the percent change in TGs from baseline to Week 26. ResultsEighteen patients were enrolled with median baseline TG levels 1803.5 mg/dL (97.5% CI, 1452–2391 mg/dL). At Week 26, median fasting TGs were reduced to 305 mg/dL (97.5% CI 219–801 mg/dL; 70.5% reduction); median lomitapide dose was 35 mg/day; 13 patients achieved TGs ≤750 mg/dL. Adverse events were mild to moderate and mainly related to gastrointestinal tolerability. Liver imaging at baseline and Week 26 revealed hepatic fat increases from median 12.0%–32.5%, while median hepatic stiffness remained normal. No patient experienced acute pancreatitis or severe abdominal pain during lomitapide treatment. ConclusionsLomitapide is effective and well tolerated in reducing TGs in FCS patients with a history of pancreatitis. Larger studies are warranted to determine lomitapide effectiveness in FCS.

Lomitapide effectively reduces triglyceride (TG) levels in familial chylomicronemia syndrome (FCS)

Background and Aims : FCS is a rare autosomal recessive disorder of impaired lipoprotein lipase (LPL) function, elevated TG levels, abdominal pain and pancreatitis. Current treatment (extremely low-fat diet <10% fat/day to reduce TG levels ≤750mgldL) is ineffective. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that reduces circulating levels of TGs.

The Microsomal Triglyceride Transfer Protein Inhibitor, Lomitapide, Improves Vascular Function in Obesity

ObjectivesIn this study, we investigate the effect of lomitapide, a microsomal triglyceride transfer protein inhibitor, on cardiovascular function in obesity.HypothesisWe hypothesize that lipid level downregulation by lomitapide is a fundamental mechanism that improves cardiovascular function.MethodsEight‐week‐old C57/b6 mice were fed with a high fat diet (HFD) for 12 weeks in the presence and absence of lomitapide. Lomitapide was administered by gavage (1mg/Kg/Day) for the last 2 weeks of HFD feeding. Bodyweight, blood glucose, body composition, and lipid profile were determined. Vascular function and endothelial function markers were studied in aorta and mesenteric resistance arteries (MRA).ResultsLomitapide treatment reduced the body weight in obese mice. Blood glucose, % of fat mass, total cholesterol, and LDL levels were significantly reduced and the % of lean mass was significantly increased after lomitapide treatment. Aortic and mesenteric arteries vascular response to sodium nitroprusside (SNP) was similar among groups. However, the vascular response to acetylcholine (Ach) was improved in the treated group. This was associated with a decreased level of vascular endoplasmic (ER) reticulum stress, inflammation, and oxidative stress.ConclusionsTreatment with lomitapide attenuated the increase in body weight in obese mice and restored the lipid profile and vascular function. These effects were accompanied by a decrease in inflammation and oxidative stress.

The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity.

In this study, the effect of lomitapide, a microsomal triglyceride transfer protein inhibitor, on the cardiovascular function in obesity was investigated. Eight-week-old C57BL/6 mice were fed with high-fat diet for 12 weeks in the presence and absence of lomitapide. Lomitapide was administered by gavage (1 mg/kg/d) during the last 2 weeks of high-fat feeding. Body weight, blood glucose, body composition, and lipid profile were determined. Vascular function and endothelial function markers were studied in the aorta and mesenteric resistance arteries. Lomitapide treatment reduced body weight in mice with obesity. Blood glucose, percentage of fat mass, total cholesterol, and low-density lipoprotein levels were significantly reduced, and the percentage of lean mass was significantly increased after lomitapide treatment. The vascular response to sodium nitroprusside in the aorta and mesenteric arteries was similar among groups. However, the vascular response to acetylcholine was improved in the treated group. This was associated with decreased levels of vascular endoplasmic reticulum stress, inflammation, and oxidative stress. Treatment with lomitapide attenuated the increase in body weight in mice with obesity and restored the lipid profile and vascular function. These effects were accompanied by a decrease in inflammation and oxidative stress.

A Case Series Assessing the Effects of Lomitapide on Carotid Intima-Media Thickness in Adult Patients with Homozygous Familial Hypercholesterolaemia in a Real-World Setting.

IntroductionHomozygous familial hypercholesterolaemia (HoFH) is characterised by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and results from multiple mutations in genes affecting the LDL receptor pathway. Patients are at risk of premature atherosclerotic cardiovascular disease (ASCVD) and premature death. Lomitapide is a microsomal triglyceride transfer protein inhibitor developed to treat HoFH, but cardiovascular outcome data are lacking.MethodsWe evaluated detailed data from five HoFH patients and one patient with heterozygous FH (HeFH) and a very severe phenotype. We also analysed confirmatory data from a further 8 HoFH cases. In total, we analysed data from patients in seven global centres in six countries who were all treated with lomitapide with long-term follow-up. Carotid intima-media thickness (CIMT) imaging was recorded on an ad hoc basis to monitor ASCVD in HoFH.ResultsLomitapide resulted in marked decreases in LDL-C of 56.8–93.9% [77.7–93.9% in the 6 initial cases (mean nadir 64.8 ± 30.1 mg/dL); 56.8–86.0% in the 8 confirmatory cases (mean nadir 131.4 ± 38.2 mg/dL)]. CIMT regressed in 50% of cases (mean follow-up 5.0 ± 3.1 years in initial six cases, and 4.4 ± 1.4 years in confirmatory cases). In the remaining patients, CIMT showed little further change. In patients where assessments of plaque area were available, regression or stabilisation in CIMT was accompanied by clinically significant regression of plaque area.ConclusionsLomitapide reduces LDL-C levels in patients with HoFH and severe LDL-C phenotypes, and results in stabilisation and/or regression of CIMT, which is an established marker of ASCVD risk. Additional data are needed to determine if this confers a survival benefit in these very high-risk patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-02031-y.

Attenuation of obesity-induced hyperlipidemia reduces tumor growth

Accumulating evidence suggests that hyperlipidemia is associated with obesity and cancer mortality in humans. We tested the hypotheses that inhibition of microsomal triglyceride transfer protein (MTP) would attenuate obesity-induced hyperlipidemia and reduce tumor growth by treating BCR-ABL B cell tumor-bearing hyperlipidemic obese ob/ob obese mice with a MTP inhibitor. MTP inhibition in tumor-bearing mice reduced concentrations of plasma apoB100 5-fold together with a corresponding decrease in VLDL triacylglycerol (TG) and cholesterol. Inhibition of MTP decreased tumor volume by 50%. MTP inhibitor did not alter tumor cell viability in vitro, suggesting that the in vivo tumor shrinkage effect was related to altered circulating lipids. Tumor volume reduction occurred without change in the protein expression of LDLR, FASN and HMGCR in the tumor, suggesting a lack of compensatory mechanisms in response to decreased hyperlipidemia. Expression of genes encoding GLUT4 and PEPCK was increased 6- and 10-fold, respectively, but no change in the expression of genes encoding regulatory enzymes of glycolysis was observed, suggesting that the tumors were not dependent on or switching to carbohydrates for energy requirement to support their growth. No change of proliferative signaling PI3K/AKT and ERK pathways after MTP inhibition was observed in the tumors. In conclusion, MTP inhibition decreased dyslipidemia and tumor growth in obese, insulin resistant mice. Therefore, decreasing VLDL secretion could be further explored as an adjuvant therapeutic intervention together with standard care to reduce tumor growth in obese patients.

Oxidant resistant human apolipoprotein A-I functions similarly to the unmodified human isoform in delaying atherosclerosis progression and promoting atherosclerosis regression in hyperlipidemic mice.

BackgroundTransgenic overexpression of apolipoprotein A-I (apoA1) has been shown to delay atherosclerosis lesion progression and promote lesion regression in mouse models; however, apoA1 is subject to oxidation by myeloperoxidase (MPO) and loss of function. The activity of oxidant resistant human apoA1 was compared to unmodified human apoA1 in mouse models of atherosclerosis progression and regression.Methods and resultsHuman apoA1 and the MPO oxidant resistant 4WF isoform transgenic mice were bred to LDL receptor deficient (LDLr KO) mice and fed a western-type diet. High level expression of these human apoA1 isoforms did not lead to increased HDL-cholesterol levels on the LDLr KO background. In males and females, lesion progression was studied over time, and both apoA1 and 4WF transgenic mice vs. LDLr KO mice had significant and similar delayed lesion progression and reduced non-HDL cholesterol. Using time points with equivalent lesion areas, lesion regression was initiated by feeding the mice a low-fat control diet containing a microsomal triglyceride transfer protein inhibitor for 7 weeks. Lesions regressed more in the male apoA1 and 4WF transgenics vs. the LDLr KO, but the 4WF isoform was not superior to the unmodified isoform in promoting lesion regression.ConclusionsBoth human apoA1 and the 4WF MPO oxidant resistant apoA1 isoform delayed lesion progression and promoted lesion regression in LDLr KO mice, with more pronounced effects in males than females; moreover, the 4WF isoform functioned similarly to the unmodified human apoA1 isoform.

Lomitapide Reduces LDL-C and Favourably Affects Carotid Intima Media Thickness in Adult Patients with Homozygous Familial Hypercholesterolaemia in a Real-World Setting

<h3>Lead Author's Financial Disclosures</h3> D.B. has received consulting fees from Amryt. <h3>Study Funding</h3> Amryt Pharma. <h3>Background/Synopsis</h3> Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic condition characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) secondary to bi-allelic pathogenic mutations affecting key proteins in the LDL receptor pathway. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that acts independently of the LDL receptor and is licenced for the treatment of adult patients with HoFH. To date, there are few prospective cardiovascular outcomes data for HoFH patients receiving lomitapide. <h3>Objective/Purpose</h3> To evaluate the effect of lomitapide use on carotid intima-media thickness (CIMT) in patients with HoFH. <h3>Methods</h3> Thirteen HoFH patients (mean+/-SD age 29.3+/-12.5 years) in seven global centers were treated in accordance with the lomitapide product label and local clinical practice. Patients underwent routine laboratory testing, including lipid and liver panels. CIMT imaging was recorded to monitor atherosclerotic cardiovascular disease (ASCVD) according to local protocols. <h3>Results</h3> Lomitapide resulted in marked decreases in LDL-C (mean+/-SD: 76.5+/-11.7%; range 56.8-93.9% at the lowest point). Notably, eight patients achieved LDL-C levels below the European Atherosclerosis Society target of <100mg/dL, and three patients achieved LDL-C <70mg/dL at least once. Over a mean follow-up of 3.9+/-2.3 years between measurements, CIMT regressed in 7 cases. The remaining patients demonstrated no progression (Supplementary Table). In two patients where assessments of plaque area were available, modest regression or stabilisation in CIMT (0.82mm to 0.65mm over 24 months [20.7% reduction]; 0.56mm to 0.57mm over 26 months [1.8% increase]) was accompanied by clinically significant regression of plaque area (147.1mm2 to 120.5mm2 [18.1% reduction]; 64.0 mm2to 42.1 mm2 [34.7% reduction]. Calculation of vascular age in n=9 patients indicated mean improvement of -18.8+/-32.6 years (range -60 to +30 years). Elevations in ALT/AST enzyme levels >3x upper limit of normal were evident in 6/13 patients. In all cases, these elevations either resolved without intervention or were managed with brief, transient reductions in lomitapide dose. <h3>Conclusions</h3> Lomitapide dramatically reduces LDL-C levels in patients with HoFH, and results in stabilisation and/or regression of CIMT, which is an established marker of ASCVD risk.

Lomitapide Effectively Reduces Triglyceride (TG) Levels in Familial Chylomicronemia Syndrome (FCS)

Lead Author's Financial Disclosures A.C. has received consulting fees from Amryt. Study Funding Amryt Pharma. Background/Synopsis FCS is a rare autosomal recessive disorder caused by impaired lipoprotein lipase (LPL) function, resulting in elevated TG levels, intense abdominal pain, hepatosplenomegaly, and recurrent episodes of acute pancreatitis. Treatment requires a strict, extremely low-fat diet (<10% fat/day) to control TG levels <750-1000mg/dL, which does not fully control the disease. Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor that prevents assembly of triglycerides (TGs) into chylomicrons, in addition to very low-density lipoproteins and thereby reduces circulating levels of TGs. Objective/Purpose The LOCHNES study was designed to evaluate the efficacy and safety of lomitapide in FCS. Methods This open-label, single arm LOCHNES study of lomitapide in FCS, enrolled adult patients ≥18 years with genetically confirmed FCS, elevated fasting TG≥750mg/dL and a history of pancreatitis, across 3 Italian centres. Patients were administered escalating-doses of lomitapide to maximum tolerated dose (MTD) for 26 weeks. The primary endpoint was the percent change in TGs from baseline to week 26, with lomitapide in combination with other lipid lowering therapy. Results Eighteen patients were enrolled in the study (mean+/-SD: age 46.6+/-16.7y; body mass index 23.7+/-4.1kg/m2). Median baseline TG levels were 1804mg/dL (range 810-4151mg/dL). Lomitapide increased from standard starting dose 5mg/day at baseline to mean 32.8+/-17.8mg/day at week 26. Median TGs reduced to 305mg/dL (range 70-1818mg/dL) at week 26. This equates to a 70.5% reduction in median fasting triglyceride levels. At week 26, 13 patients achieved TGs ≤750mg/dL. Treatment with lomitapide was generally well tolerated with no patient discontinuations. Adverse events were mild to moderate and were mainly related to gastrointestinal tolerability (n=9) and ALT/AST enzyme elevations ≥3x upper limit of normal (n=4). Where available (n=13), liver MRI imaging revealed increases in hepatic fat in some patients (n=5/13), and three patients with a baseline hepatic fat >20% (range 22-30%), experienced increases to 30-50% hepatic fat at 26 weeks. No patient experienced an episode of acute pancreatitis or severe abdominal pain during lomitapide treatment. One patient who temporarily interrupted lomitapide treatment due to an episode of diarrhoea, experienced acute pancreatitis during the treatment interruption period. Conclusions Lomitapide is effective in reducing triglycerides in FCS and preventing the recurrence of acute pancreatitis in this pilot study. The extent of the benefit of lomitapide to patients with FCS should be further evaluated in a larger prospective clinical trial. A.C. has received consulting fees from Amryt.

Microsomal triglyceride transfer protein inhibitor lomitapide-induced liver toxicity is ameliorated by Triiodothyronine treatment following improved bile homeostasis and β-oxidation

Dyslipidemia or its severe version like familial hypercholesterolemia causes a high risk for cardiovascular diseases. Lomitapide, a microsomal triglyceride transfer protein inhibitor, is approved to treat familial hypercholesterolemia, associated with liver fat accumulation. In this work, we investigated the effect of the combination of lomitapide and triiodothyronine (T3) in Zucker fatty rats. Lomitapide (1 mg/kg, PO), or T3 (13 μg/kg, PO), or their combination, were given to these rats once daily for fourteen days. Body weight and food intake were recorded once daily during the treatment period. Serum and hepatic lipids, glucose tolerance, serum aminotransferases, bile fluids, hepatic gene expression, and liver histology were assessed at the end of the treatment. Lomitapide treatment reduced body weight, food intake, glucose intolerance, and serum lipids, and elevated serum aminotransferases and liver lipids. When combined with T3, lomitapide showed an enhanced reduction in body weight, food intake, serum cholesterol, serum LDL, and glucose intolerance. The combination treatment increased bile flow rate and biliary cholesterol excretion rate. Combining T3 with lomitapide attenuated the elevation of serum aminotransferases and liver lipids. Hepatic ABCB11, ABCG5, ABCG8, CYP7A1, CPT1, and ACOX1 expressions were increased with combination treatment. Histological analysis indicated that T3 attenuated hepatic fat accumulation caused by lomitapide. These data suggests that combining lomitapide with T3 may reduce lomitapide-induced hepatic toxicity and provide additional benefits in obesity and glucose intolerance.

An improved assay to measure the phospholipid transfer activity of microsomal triglyceride transport protein

Microsomal triglyceride transfer protein (MTP) is essential for the assembly and secretion of apolipoprotein B-containing lipoproteins. MTP transfers diverse lipids such as triacylglycerol (TAG) and phospholipids (PLs) between vesicles in vitro. Previously, we described methods to measure these transfer activities using N-7-nitro-2-1,3-benzoxadiazol-4-yl (NBD)-labeled lipids. The NBD-TAG transfer assay is sensitive and can measure MTP activity in cell and tissue homogenates. In contrast, the NBD-PL transfer assay shows high background and is less sensitive; therefore, purified MTP is required to measure its PL transfer activity. Here, we optimized the assay to measure also the PL transfer activity of MTP in cell and tissue homogenates. We found that donor vesicles containing dioleoylphosphoethanolamine and palmitoyloleoylphosphoethanolamine result in a low background signal and are suitable to assay the PL transfer activity of MTP. This assay was capable of measuring protein-dependent and substrate-dependent saturation kinetics. Furthermore, the MTP inhibitor lomitapide blocked this transfer activity. One drawback of the PL transfer assay is that it is less sensitive at physiological temperature than at room temperature, and it requires longer incubation times than the TAG transfer assay. Nevertheless, this significantly improved sensitive assay is simple and easy to perform, involves few steps, can be conducted at room temperature, and is suitable for high-throughput screening to identify inhibitors. This assay can be adapted to measure other PL transfer proteins and to address biological and physiological importance of these activities.

Familial Chylomicronemia Syndrome (FCS): Recent Data on Diagnosis and Treatment.

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. 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.

Bempedoic Acid: A Novel LDL Cholesterol-Lowering Agent.

Hypercholesterolemia is commonly associated with diabetes. In combination with diabetes, it puts patients at an increased risk for premature coronary heart disease and atherosclerosis (1). Lipoproteins are developed in one of two ways, via the exogenous or endogenous pathways. LDL cholesterol is a product of VLDL metabolism via the endogenous pathway. Levels of LDL in the plasma are determined by the rate of LDL production and clearance. The LDL production rate from VLDL depends on LDL receptor activity. High receptor activity leads to a decrease in LDL production. Alternatively, low LDL receptor activity leads to an increase in LDL production. These levels of receptors in the liver are regulated by the cholesterol content of the hepatocytes. If the content is low, LDL receptor activity increases to allow for the increased uptake of cholesterol. If the content is higher, LDL receptor activity is decreased, and the LDL uptake is diminished (2). Many medications are available today to manage hypercholesterolemia. The most commonly used are statins, fibrates, bile acid sequestrants, niacin, and dietary cholesterol uptake inhibitors. Less commonly used therapies for cholesterol management include PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, and apolipoprotein B-100 antisense oligonucleotides. None of these therapies have the same mechanism of action as the novel therapy bempedoic acid (Esperion Therapeutics). Bempedoic acid has been shown to significantly lower LDL cholesterol levels when added to maximally tolerated statin therapies compared with ???

LONG-TERM SAFETY AND EFFICACY OF LOMITAPIDE IN PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA: FIVE-YEAR DATA FROM THE LOMITAPIDE OBSERVATIONAL WORLDWIDE EVALUATION REGISTRY (LOWER)

Lomitapide is a microsomal triglyceride transfer protein inhibitor licensed as adjunctive therapy for adults with homozygous familial hypercholesterolemia (HoFH). LOWER is an international, observational registry assessing the long-term safety and effectiveness of lomitapide. This analysis examines

P5365Microsomal triglyceride transfer protein inhibitor (lomitapide) efficacy in the treatment of patients with homozygous familial hypercholesterolemia phenotype

Abstract Introduction The majority of patients with homozygous familial hypercholesterolemia (HoFH) phenotype are treated additionally to lipid lowering (LL) drugs (statin + ezetimibe ± colesevelam) with lipoprotein apheresis (LA) sessions. The aim of this study was to evaluate the effect of microsomal triglyceride transfer protein inhibitor (lomitapide) in HoFH patients. Patients and methods In 12 HoFH patients treated with LL drugs ± biweekly LA sessions (9 patients) the 5–40 mg daily of lomitapide was added. Lipid profile [total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C)] before (LL drugs ± LA) and after lomitapide treatment were evaluated. Results The follow-up period of lomitapide treatment for 12 patients was 3–24 months (13.8±7.9). The median baseline LDL-C levels was 1000 mg/dL (339–1150). During LL drug therapy, patients showed a median LDL-C level of 383.5 mg/dL (Range: 214–866 mg/dL) and with LL drugs + Time-averaged levels (CAVG) the median was 288.1 mg/dL (Range: 183.69–716.65 mg/dL). The addition of lomitapide at the average dosage of 21.4 mg/day lowered LDL-C levels by 56.8% comparing to LL drugs alone therapy [mean reduction 262.12, 95% CI (105.53, 418.71), p=0.005] and by 54% [mean reduction −182.89, 95% CI (−342.35, −23.43), p=0.031] comparing to LL drugs + LA (CAVG). The CAVG of LDL-C in LL drugs + LA patients compared with LL drugs + lomitapide was 54% in favour of lomitapide (p=0.031). After lomitapide administration to LL drugs + LA treatment, 78% patients discontinued LA and 2 patients reduced their LA frequency by 50%. During follow-up, 2 patients (16.6%) reported side effects (transient diarrhea, 1 patient had liver transaminase &gt;5× ULN and had to decrease dose of lomitapide). Two patients stopped lomitapide due to diet and alcohol restrictions. Median and ranges of lipid and lipoprotein values before any intervention, after LL drugs, LL drugs plus LA, LL drugs plus LA (CAVG) and LL drugs plus lomitapide Total Cholesterol LDL-C HDL-C Triglycerides Before any intervention 1000 (339–1150) 900 (245–1070) 34.5 (25–50) 125 (87–314) After LL drugs 434 (278–915) 383.5 (214–866) 36 (27–51) 113 (62–198) LL drugs + LA (CAVG) 336.13 (248.57–784.16) 288.07 (183.69–716.65) 42.81 (25.84–46.68) 105.09 (55.79–166.68) LL drugs + Lomitapide 228.5 (118–554) 173.5 (74–515) 37.5 (29–50) 83.5 (23–316) LDL graph Conclusions Treatment with lomitapide in HoFH patients has beneficial effect with constant decrease of LDL-C by 57% compared with classical LL therapy and by 54% compared with classical LL therapy and CAVG and seems to be with good safety profile. Although, in some cases the hybrid (all availably drug treatment and LA) therapy may be needed.

Microsomal triglyceride transfer protein inhibitor (lomitapide) efficacy in the treatment of patients with homozygous familial hypercholesterolaemia.

The aim of this study was to evaluate the effect of microsomal triglyceride transfer protein inhibitor (lomitapide) in patients with homozygous familial hypercholesterolaemia. In 12 homozygous familial hypercholesterolaemia patients treated with lipid-lowering drugs ± biweekly lipoprotein apheresis sessions (nine patients), daily lomitapide was added. The lipid profile (total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol) before and after lomitapide treatment was evaluated. The follow-up period with lomitapide treatment was 3-24 months (13.8 ± 7.9). The median baseline low-density lipoprotein cholesterol level was 900 mg/dl (348-1070), after lipid-lowering drugs therapy was 383.5 mg/dl (214-866) and after lipid-lowering drugs + time-averaged level was 288 mg/dl (183.7-716.6). The addition of lomitapide lowered low-density lipoprotein cholesterol levels further by 56.8% compared to lipid-lowering drugs alone (mean reduction 262, 95% confidence interval (105.5-418.7), p = 0.005) and by 54% (mean reduction 182.9, 95% confidence interval (-342 - -23), p = 0.031) comparing to lipid-lowering drugs + lipoprotein apheresis (time-averaged level). The time-averaged level of low-density lipoprotein cholesterol in lipid-lowering drugs + lipoprotein apheresis patients compared with lipid-lowering drugs + lomitapide was 54% in favour of lomitapide (p = 0.031). Treatment with lomitapide in homozygous familial hypercholesterolaemia patients has a beneficial effect with a constant decrease of low-density lipoprotein cholesterol by 57% compared with classical lipid-lowering therapy and by 54% compared with classical lipid-lowering therapy and time-averaged level of low-density lipoprotein cholesterol.

Real-World Outcomes with Lomitapide Use in Paediatric Patients with Homozygous Familial Hypercholesterolaemia.

IntroductionHomozygous familial hypercholesterolaemia (HoFH) is a rare, autosomal disease affecting the clearance of low-density lipoprotein cholesterol (LDL-C) from circulation, and leading to early-onset atherosclerotic cardiovascular disease (ASCVD). Treatment consists mainly of statins, lipoprotein apheresis (LA) and, more recently, the microsomal triglyceride transfer protein inhibitor lomitapide. Lomitapide is not licensed for use in children, but has been made available through an expanded access programme or on a named patient basis.MethodsThis case series includes 11 HoFH patients in 10 different centres in eight countries, less than 18 years of age (mean 11.6 ± 1.1 years, 64% male), with signs of ASCVD, and who have received treatment with lomitapide (mean dose 24.5 ± 4.3 mg/day; mean exposure 20.0 ± 2.9 months). Background lipid-lowering therapy was given according to local protocols. Lomitapide was commenced with a stepwise dose escalation from 2.5 mg or 5 mg/day; dietary advice and vitamin supplements were provided as per the product label for adults. Laboratory analysis was conducted as part of regular clinical care.ResultsIn the 11 cases, mean baseline LDL-C was 419 ± 74.6 mg/dL and was markedly reduced by lomitapide to a nadir of 176.7 ± 46.3 mg/dL (58.4 ± 6.8% decrease). Six patients achieved recommended target levels for children below 135 mg/dL, five of whom had LA frequency reduced. In one case, LDL-C levels were close to target when lomitapide was started but remained stable despite 75% reduction in LA frequency (from twice weekly to biweekly). Adverse events were mainly gastrointestinal in nature, occurred early in the treatment course and were well managed. Three patients with excursions in liver function tests were managed chiefly without intervention; two patients had decreases in lomitapide dose.ConclusionsLomitapide demonstrated promising effectiveness in paediatric HoFH patients. Adverse events were manageable, and the clinical profile of the drug is apparently similar to that in adult patients.FundingAmryt Pharma.

Caracterización clínica y molecular en hipercolesterolemia familiar homocigota

Introducción. La hipercolesterolemia familiar homocigota es un desorden genético raro que se caracteriza por niveles muy elevados de colesterol y por una pobre respuesta al tratamiento farmacológico convencional (estatinas, ezetimibe). El estudio molecular es un recurso importante que puede impactar de forma positiva en el tratamiento y pronóstico de estos pacientes; sin embargo, este tipo de estudio no siempre está disponible en todos los centros de atención. El resultado de estas pruebas genéticas permite identificar pacientes que se pueden beneficiar de nuevas opciones terapéuticas asociadas a mayor disminución de colesterol total y LDL.Presentación de casos. Se presentan los casos de dos hermanas con hipercolesterolemia severa y pobre respuesta al tratamiento farmacológico convencional, en quienes el diagnóstico molecular confirmó una mutación en homocigosis del gen del receptor de la lipoproteína de baja densidad. Con base en estos resultados, en ambos casos se adicionó un inhibidor selectivo de proteína microsomal de transferencia de triglicéridos al manejo hipolipemiante convencional, con lo que se logró una reducción de más del 49% en los niveles séricos de colesterol total y LDL.Conclusión. Las pruebas moleculares son una herramienta importante para definir el diagnóstico, pronóstico y tratamiento de los pacientes con hipercolesterolemia familiar homocigota.

A wild-type mouse-based model for the regression of inflammation in atherosclerosis.

Atherosclerosis can be induced by the injection of a gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 (PCSK9)–encoding adeno-associated viral vector (AAVmPCSK9), avoiding the need for knockout mice models, such as low-density lipoprotein receptor deficient mice. As regression of atherosclerosis is a crucial therapeutic goal, we aimed to establish a regression model based on AAVmPCSK9, which will eliminate the need for germ-line genetic modifications. C57BL6/J mice were injected with AAVmPCSK9 and were fed with Western diet for 16 weeks, followed by reversal of hyperlipidemia by a diet switch to chow and treatment with a microsomal triglyceride transfer protein inhibitor (MTPi). Sixteen weeks following AAVmPCSK9 injection, mice had advanced atherosclerotic lesions in the aortic root. Surprisingly, diet switch to chow alone reversed hyperlipidemia to near normal levels, and the addition of MTPi completely normalized hyperlipidemia. A six week reversal of hyperlipidemia, either by diet switch alone or by diet switch and MTPi treatment, was accompanied by regression of atherosclerosis as defined by a significant decrease of macrophages in the atherosclerotic plaques, compared to baseline. Thus, we have established an atherosclerosis regression model that is independent of the genetic background.

Abstract 12117: Global Real-World Data on the Use of Lomitapide in Treating Homozygous Familial Hypercholesterolemia: The Lomitapide Observational Worldwide Evaluation Registry (LOWER), Two-Year Data

Introduction: Lomitapide is a microsomal triglyceride transfer protein inhibitor indicated as adjunctive therapy for adults with homozygous familial hypercholesterolemia (HoFH). LOWER is a global observational registry to prospectively assess long-term, safety and effectiveness of lomitapide in clinical practice. Adult HoFH patients treated with lomitapide in clinical practice are eligible. Results: As of March 1, 2016, 143 patients had been enrolled in the USA, Canada, EU and Taiwan (Table); 139 patients had lomitapide exposure data (median 17.7 months, range 0.3-35.9 months). Globally, median lomitapide dose was 10 mg QD (range 5 mg QOD-40 mg QD, 6-33 months). A ≥ 50% reduction in LDL-C at any time post-baseline was measured in 58% of patients; 62% of patients achieved LDL-C &lt; 100 mg/dL and 37% achieved LDL-C &lt; 70 mg/dL. AEs were experienced by 73% of patients; GI disorders were the most common (45%). Serious AEs occurred in 21 (15%) patients. Thirty-three (24%) patients discontinued lomitapide because of an AE. Events of special interest comprised: major adverse cardiovascular events (11 patients, resulting in 2 deaths); hepatic events (19 patients, 6 discontinuations); GI events (20 patients, 16 discontinuations); oncologic events (2 patients: 1 pancreatic mass [diagnosis unconfirmed], 1 mediastinal B-cell lymphoma); 1 pregnancy; no coagulopathy events. Liver function tests were always performed per the label in 48% of patients. Peak ALT and AST was normal in 35% of patients and ≥ 3x ULN in 21% (among which 5% had ≥ 5x - &lt;10x ULN). No cases of Hy’s Law were recorded. Conclusions: The LOWER registry demonstrated safety and efficacy consistent with product labeling in patients treated with lomitapide for up to 3 years, but efforts are needed to improve prescriber adherence to recommended hepatic safety monitoring. There were no new safety signals and LDL-C reduction was consistent and robust, with 62% of patients achieving LDL-C &lt; 100 mg/dL.