Familial hypercholesterolaemia (FH) is an inherited disorder of lipid metabolism that is linked with significant morbidity and mortality. FH (also known as hyperlipoproteinaemia type IIa) is characterised by the presence of defective or insufficient receptors for low-density lipoprotein cholesterol (LDL-C) on the cell surface of hepatocytes, which leads to elevated levels of plasma LDL-C from birth onwards. Inheritance is autosomal dominant, with homozygotes affected more severely than heterozygotes. Heterozygous familial hypercholesterolaemia (HeFH) is relatively common, occurring in approximately 1 in 500 Caucasians. Homozygous familial hypercholesterolaemia (HoFH) is a rare condition, found in approximately 1 in 1,000,000 individuals.
Patients with FH have a significantly increased risk of atherosclerosis, as their hypercholesterolaemia begins in infancy. In patients with HeFH who are left untreated, myocardial infarction is reported in 50 per cent of males before the age of 50 and in 30 per cent of females before the age of 60. Symptoms are still more severe in patients with HoFH; coronary artery bypass grafts may be needed in teenagers with this condition. Also, in addition to the development of coronary disease, deterioration of the aortic valve (leading to aortic stenosis) often occurs in HoFH.
The presence of FH may not be obvious; the condition often goes undetected. A plasma cholesterol level of more than 7.5 mmol/L is an indication that the possibility of FH should be investigated.
Treatment of HeFH should begin in childhood to prevent the early development of atherosclerotic cardiovascular disease. According to the American Heart Association, initial treatment should begin in males at the age of not less than 10 years and in females after the onset of menses. Statins (also known as HMG CoA reductase inhibitors) are regarded as standard therapy. These drugs reduce the formation of LDL-C by upregulation of liver LDL receptors. However, statins are much less effective in patients with HoFH as most of their LDL receptors are not functioning. Liver transplantation has been used in patients with HoFH to introduce functioning LDL receptors. However, the preferred option for the management of HoFH is lipid apheresis, which is also used in patients with HeFH who do not respond to pharmacologic therapy.
The National Institute for Health and Clinical Excellence (NICE) in the UK recommends that LDL-C should be reduced by more than 50 per cent from baseline in patients with FH. However, this goal is not met in a significant proportion (perhaps 50 per cent or more) of patients with HeFH who are treated with statins. In addition, statins are not always well tolerated (they are associated with an increased risk of muscular disorders) and their use is contraindicated in pregnancy. Consequently, other therapies are often used in addition to statins in patients not reaching treatment goals or as replacement therapy in those not tolerating statins. Additional or alternative therapies to statins that are currently approved are ezetimibe, bile acid sequestrants, fibric acid derivatives and niacin.
The use of ezetimibe, an inhibitor of cholesterol absorption, in combination with high-dose statin therapy has become standard practice in the treatment of HeFH. This combination is also used as an adjunctive therapy to other lipid-lowering agents in the treatment of HoFH. However, the European and Dutch guidelines for treatment of FH, which recommend reduction of LDL-C to plasma levels of less than 2.5 mmol/L, are achieved in only a minority of patients receiving statins plus ezetimibe.
Bile acid levels
Bile acid sequestrants bind to bile acids in the intestinal tract and thus remove them from the entero-hepatic circulation. This stimulates the liver to remove cholesterol from the circulation to restore bile acid levels. The older drugs in this class, such as cholestyramine and colestipol, are associated with gastrointestinal toxicity. However, the second-generation drug colesevelam has better gastric tolerability and has been approved in the US for the treatment of HeFH in children and adolescents.
Fibric acid derivatives such as fenofibrate decrease the synthesis of very low density lipoprotein cholesterol and increase triglyceride clearance through agonistic interaction with peroxisome proliferator-activated receptor-α. In practice, however, fibric acid derivatives are used in patients with FH only when elevated triglyceride levels are present, as combining these drugs with statins increases the risk of muscular disorders such as rhabdomyolysis.
Targeting cholesterol ester transfer protein (CETP) is a relatively new approach to increasing plasma levels of HDL-C
Niacin is a B vitamin that acts via G-protein coupled receptors to increase levels of beneficial high density lipoprotein cholesterol (HDL-C) and decrease levels of LDL-C and triglycerides. Combining this agent with the prostaglandin D2 receptor antagonist laropiprant greatly decreases the risk of niacin-induced flushing. The HSP2-THRIVE study in the UK is evaluating fixed combination laropiprant/niacin to determine whether this agent can further reduce cardiovascular risk in patients already undergoing LDL-lowering treatment with simvastatin or ezetimibe. The outcome of this study, which is due for completion in 2012, could trigger changes in international guidelines for the management of dyslipidaemia, including FH.
Recently, attention has focused on two quite different drugs that are likely to be approved in the near future for the treatment of FH. Mipomersen sodium (developed by Genzyme Corporation and Isis Pharmaceuticals) is a subcutaneously administered oligonucleotide antisense inhibitor of apolipoprotein B-100 (apoB-100). Lomitapide (developed by Aegerion Pharmaceuticals) is an orally administered, small-molecule inhibitor of microsomal triglyceride transfer protein (MTP). Both apoB-100 and MTP have significant roles in the production of LDL.
Mipomersen sodium has shown promising efficacy in placebo-controlled phase III trials in patients with high LDL levels who were already taking maximally tolerated lipid-lowering medication. Over six months, LDL was reduced by at least 36 per cent, compared with no more than 13 per cent for placebo. The drug showed an acceptable benefit-to-risk ratio in patients with FH, but a considerably less acceptable profile in patients with refractory, high LDL that was not a result of FH. This was because of high dropout rates and persistent liver enzyme elevations.
In the FH indication, mipomersen sodium looks extremely promising overall and the developers may well opt for a 'pure orphan' drug development programme. The drug was submitted for regulatory approval in the EU in July 2011 for the treatment of HoFH and severe HeFH. In the US, a filing for the treatment of HoFH is expected during 2012; orphan drug status has been granted for this indication.
Lomitapide has shown a clinically relevant therapeutic effect on levels of LDL and triglycerides in patients with HoFH already receiving existing lipid-lowering therapy (a reduction in LDL and triglycerides of 44 per cent and 33 per cent, respectively, over 13 months), but a small phase III sample size (n = 29) has indicated that individual patient net benefit will be crucial for the approval and clinical success of the agent. The open-label format (probably necessitated by the fact that HoFH is a rare and severe condition) is also an issue. Lomitapide is intended to be used as an adjunct to a low fat diet and other lipid-lowering agents. The drug was submitted for regulatory approval in the EU and the US in March 2012 for the treatment of HoFH and has orphan drug status for this indication in the US. Regulatory approval of lomitapide is anticipated during 2012.
Clinical trials of other potential therapies for FH are in progress. Several companies are investigating inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of LDL-C metabolism, for the treatment of HeFH.
The role of PCSK9 as a therapeutic target has been supported by the observation that loss-of-function PCSK9 mutations result in a cardiovascular risk reduction of approximately 80 per cent. REGN 727, a fully human monoclonal antibody targeting PCSK9, is being developed by Regeneron Pharmaceuticals and Sanofi. Results of a phase III trial of the drug, reported in November 2011, showed that the trial had met its primary endpoint of reduction in LDL-C levels over 12 weeks (a reduction of 30-65 per cent, depending on dose/regimen, compared with 10 per cent for placebo). In addition, Amgen is developing AMG 145 (a monoclonal antibody to PCSK9) in phase II trials and Santaris Pharma is developing SPC 5001 (an oligonucleotide antisense inhibitor of PCSK9) in phase I trials.
In February 2012, Merck & Co initiated the phase III REALIZE clinical trial of its small-molecule oxazolidinone drug anacetrapib, in addition to ongoing statin therapy, in patients with HeFH. Anacetrapib is a selective inhibitor of cholesterol ester transfer protein (CETP), which has a major role in promoting the transfer of cholesterol esters from beneficial HDL to proatherogenic apoB-containing lipoproteins such as LDL. Targeting CETP is a relatively new approach to increasing plasma levels of HDL-C. The trial is scheduled for completion in mid-2014.
Cerenis Therapeutics is developing CER 001, a potential therapy for HoFH that is designed to mimic HDL through a process known as reverse lipid transport. It is a synthetic mimetic peptide consisting of a complex of human apolipoprotein A-I and phospholipids. The Modifying Orphan Disease Evaluation (MODE) phase II trial of CER 001 in 30 patients with HoFH was initiated in November 2011 and is scheduled for completion in early 2013.
The prospects for patients with FH are looking brighter with the arrival of new, potent therapies that lower LDL-C or increase HDL-C. With the addition of these therapies to the existing statin-based regimens, the proportion of patients with FH who meet treatment goals should increase. Of particular interest will be the new therapies mipomersen and lomitapide, both of which are likely to become available over 2012/2013 and offer the realistic possibility of greatly improved control of LDL-C in patients with HoFH.
Pipeline was written by Philip Hair of Adis International (Springer Healthcare), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought. For further information on Adis services, please contact Daniela Ranzani on +39 02 423 4562 or Email: Daniela.Ranzani@wolterskluwer.