Clinical experience of lomitapide therapy in patients with homozygous familial hypercholesterolaemia

Cuchel, Marina; Blom, Dirk; Averna, Maurizio

doi:10.1016/j.atherosclerosissup.2014.07.005

Cited by 29 publications

(22 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In both cases, defects in hepatic Apo B secretion result in very low levels of ApoB lipoproteins which are often accompanied by hepatic steatosis in addition to intestinal lipid and fat soluble vitamin malabsorption. Liver-directed inhibition of ApoB and/or MTP are being pursued as treatments for severe cases of familial hypercholesterolemia (FH)4142. Our studies support the rationale for hepatic Apo B inhibition to lower plasma cholesterol, but also demonstrate severe and potentially dangerous hepatic fat accumulation.…”

Section: Discussionsupporting

confidence: 63%

Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease

Jarrett

Lee

Yeh

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Germline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to avoid developmental phenotypes. We sought to address these experimental limitations by generating somatic mutations in the adult liver using CRISPR/Cas9, as a new strategy to model metabolic disorders. As proof-of-principle, we targeted the low-density lipoprotein receptor (Ldlr), which when deleted, leads to severe hypercholesterolemia and atherosclerosis. Here we show that hepatic disruption of Ldlr with AAV-CRISPR results in severe hypercholesterolemia and atherosclerosis. We further demonstrate that co-disruption of Apob, whose germline loss is embryonically lethal, completely prevented disease through compensatory inhibition of hepatic LDL production. This new concept of metabolic disease modeling by somatic genome editing could be applied to many other systemic as well as liver-restricted disorders which are difficult to study by germline manipulation.

show abstract

Section: Discussionsupporting

confidence: 63%

Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease

Jarrett

Lee

Yeh

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The lipid lowering effects of lomitapide are not affected by Lp apheresis [91]. In phase 3 studies with extended follow up, against a background of Lp apheresis and standard drug treatment, up to 74% achieved LDL-C <2.5 mmol/L and 58% < 1.8 mmol/L [92]. This demonstrates the feasibility of achieving EAS targets in HoFH.…”

Section: Lomitapide Treatment For Hofhmentioning

confidence: 87%

HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom

et al. 2016

View full text Add to dashboard Cite

This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK.

show abstract

“…Inhibiting MTP leads to reduced levels of these lipoproteins in the circulation. The efficacy and safety of oral lomitapide has been evaluated in three small clinical studies [65, 66]. The drug was approved in 2012 by the US FDA and in 2013 by the European Medicines Agency for patients with homozygous FH.…”

Section: Novel Therapiesmentioning

confidence: 99%

“…The drug was approved in 2012 by the US FDA and in 2013 by the European Medicines Agency for patients with homozygous FH. The possible relevant liver toxicity seen represents the main limitation of the drug; also other gastrointestinal side effects have been described (diarrhoea, nausea and vomiting) [65, 66]. …”

Section: Novel Therapiesmentioning

confidence: 99%

Management of Hypercholesterolemia, Appropriateness of Therapeutic Approaches and New Drugs in Patients with High Cardiovascular Risk

Rosei

Salvetti

2016

High Blood Press Cardiovasc Prev

View full text Add to dashboard Cite

Control of lipid levels is one of the most effective strategies for cardiovascular (CV) event prevention. In fact, many clinical trials have clearly demonstrated that low-density lipoprotein cholesterol (LDL-C) lowering, primarily with statins, reduces major CV events and mortality. The evidence from these trials has been useful in designing the cholesterol treatment guidelines, which are mainly aimed at preventing and managing cardiovascular disease (CVD). However, available data indicate that a large proportion of patients fail to achieve lipid goals, and this is particularly frequent in patients at high or very high CV risk. Furthermore, owing to side effects, a significant percentage of patients cannot tolerate statin treatment. Hence, researchers have focused their attention on novel LDL-C-lowering agents that act via mechanisms distinct from that of statins. Among the new compounds under investigation, the monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) seem particularly promising, having recently been shown to be well tolerated and highly effective at lowering LDL-C, with a possible effect on the occurrence of CV events. Currently, alirocumab is approved by the US Food and Drug Administration (FDA) as an adjunct to diet and maximally tolerated statin therapy for use in adults with heterozygous familial hypercholesterolemia (FH) or those with atherosclerotic CV disease who require additional LDL-C lowering; it has also been recently approved by the European Medicines Agency (EMA) for use in patients with heterozygous FH, non–familial hypercholesterolemia or mixed dyslipidemia in whom statins are ineffective or not tolerated. Evolocumab is approved by the FDA as an adjunct to diet and maximally tolerated statins for adults with hetero- and homozygous FH and those with atherosclerotic CV disease who require additional lowering of LDL-C, and by the EMA in adults with primary hypercholesterolemia or mixed dyslipidemia, as an adjunct to diet, in combination with a statin or a statin with other lipid lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin; alone or in combination with other lipid lowering therapies in patients who are statin-intolerant, or those for whom a statin is contraindicated. Evolocumab is also indicated in adults and adolescents aged 12 years and over with homozygous familial hypercholesterolemia in combination with other lipid-lowering therapies.

show abstract

Clinical experience of lomitapide therapy in patients with homozygous familial hypercholesterolaemia

Cited by 29 publications

References 14 publications

Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease

Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease

HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom

Management of Hypercholesterolemia, Appropriateness of Therapeutic Approaches and New Drugs in Patients with High Cardiovascular Risk

Contact Info

Product

Resources

About