Triglyceride Transfer Protein Inhibitor Lomitapide Research Articles

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.

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.

Homozygous autosomal dominant hypercholesterolaemia: prevalence, diagnosis, and current and future treatment perspectives.

Homozygous autosomal dominant hypercholesterolemia (hoADH) is a rare genetic disorder caused by mutations in LDL receptor, apolipoprotein B, and/or proprotein convertase subtilisin-kexin type 9. Both the genetic mutations and the clinical phenotype vary largely among individual patients, but patients with hoADH are typically characterized by extremely elevated LDL-cholesterol (LDL-C) levels, and a very high-risk for premature cardiovascular disease. Current lipid-lowering therapies include bile acid sequestrants, statins, and ezetimibe. To further decrease LDL-C levels in hoADH, lipoprotein apheresis is recommended, but this therapy is not available in all countries. Recently, the microsomal triglyceride transfer protein inhibitor lomitapide and the RNA antisense inhibitor of apolipoprotein B mipomersen were approved by the Food and Drug Administration/European Medicine Agency and the Food and Drug Administration, respectively. Several other LDL-C-lowering strategies and therapeutics targeting the HDL-C pathway are currently in the clinical stage of development. Novel therapies have been introduced for LDL-C-lowering and innovative drug candidates for HDL-C modulation for the treatment of hoADH. Here, we review the current available literature on the prevalence, diagnosis, and therapeutic strategies for hoADH.

Statin intolerance: diagnosis and remedies.

Despite the efficacy of statins in reducing cardiovascular events in both primary and secondary prevention, the adherence to statin therapy is not optimal, mainly due to the occurrence of muscular adverse effects. Several risk factors may concur to the development of statin-induced myotoxicity, including patient-related factors (age, sex, and race), statin properties (dose, lipophilicity, and type of metabolism), and the concomitant administration of other drugs. Thus, the management of patients intolerant to statins, particularly those at high or very high cardiovascular risk, involves alternative therapies, including the switch to another statin or the use of intermittent dosage statin regimens, as well as nonstatin lipid lowering drugs (ezetimibe and fibrates) or new hypolipidemic drugs such as PCSK9 monoclonal antibodies, the antisense oligonucleotide against the coding region of human apolipoprotein B mRNA (mipomersen), and microsomal triglyceride transfer protein inhibitor lomitapide. Ongoing clinical trials will reveal whether the lipid-lowering effects of alternative therapies to statins can also translate into a cardiovascular benefit.

What are we able to achieve today for our patients with homozygous familial hypercholesterolaemia, and what are the unmet needs?

Homozygous familial hypercholesterolaemia (HoFH) is a rare, life-threatening disease characterised by highly elevated low-density lipoprotein cholesterol levels (LDL-C), cutaneous and tendinous xanthomata, severe and precocious atherosclerosis, and aortic and supra aortic valve disease. Although treatment with apheresis and lipid-lowering drugs has improved event-free survival of HoFH patients, the condition is still associated with early onset cardiovascular disease and death due to residual high cholesterol levels. Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins are powerful cholesterol-lowering agents, but HoFH patients are often inadequately controlled on statins alone; therefore, a variety of other medications, including the cholesterol absorption inhibitor ezetimibe, bile acid sequestrants and niacin, have been used to try to achieve recommended LDL-C goals. However, even in patients with access to the best available treatments, HoFH has continued to be associated with extreme rates of morbidity and premature mortality. The microsomal triglyceride transfer protein inhibitor lomitapide has recently received regulatory approval in the European Union and the United States of America for use in patients with HoFH and a number of other agents are currently in development, including apolipoprotein B antisense oligonucleotides (approved in the US), and proprotein convertase subtilisin kexin type 9 (PCSK-9) inhibitors. These new approaches may result in improved clinical outcomes for HoFH patients. In the future it will be important to begin treatment early and to treat as aggressively as possible.

Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study

Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease. We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI -62 to -39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI -57 to -31; p<0·0001) at week 56 and 38% (-52 to -24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.

Abstract: 62 THE VULNERABLE PLAQUE

Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease.We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model.29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI −57 to −31; p<0·0001) at week 56 and 38% (–52 to −24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities.Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia.FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.

Abstract: 28 CONSISTENCY BETWEEN LIPID LOWERING AND REDUCTION OF ISCHEMIC CARDIOVASCULAR EVENTS (ICE) IN THE SIMVASTATIN AND EZETIMIBE IN AORTIC STENOSIS (SEAS) TRIAL

Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in adults with this disease.We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model.29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L [SD 2·9]) to week 26 (4·3 mmol/L [2·5]; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI −57 to −31; p<0·0001) at week 56 and 38% (–52 to −24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities.Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia.FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.