Lomitapide

Multimodal Treatment of Homozygous Familial Hypercholesterolemia

Thomas Gossios, Ioanna Zografou, Veta Simoulidou, Athina Pirpassopoulou, Konstantinos Christou and Asterios Karagiannis
1 Barts Heart Centre, St Bartholomew’s Hospital, W Smithfield, London EC1A 7BE, UK;
2 Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece

Abstract:
Background: Familial Hypercholesterolemia (FH) is an autosomal-dominant genetic disease, associated with premature atherosclerotic Cardiovascular Disease (CVD), especially in its homozygous type (HoFH).
Objective: The aim of this review is to discuss the safety and efficacy of combination treatments (procedures and drugs) for HoFH.
Results: Historically, liver transplantation was used first; however, it is currently considered only as a last resort for some patients. In the mid 70’s, LDL aphaeresis was introduced and remains up today the treatment of choice for patients of any age, despite its significant cost. The use of Ezetimibe results in additive 15-20% reductions in LDL-C regardless of the therapeutic approach, while statins are modestly effective in patients with class 4 or 5 mutations, in which LDL Receptors (LDLR) are present. One of the novel drugs for HoFH is Lomitapide, which is a highly effective oral agent, but is also exceedingly expensive ($350, 000/year). Mipomersen is administered every week subcutaneously, is also effective but has been approved only in the US mainly due to injection site reactions up to 80%. Both Lomitapide (mainly) and Mipomersen have been found to promote fat accumulation in the liver, resulting in subsequent serum transaminases elevations. PCSK9 inhibitors are effective in those with partial LDLR presence and function by reducing frequency of LDL apheresis, improve cost effectiveness of treatment.
Conclusion: Pediatric and adult HoFH treatment needs combination of procedures and drugs. The main treatment is LDL-C apheresis aided by ezetimibe and PCSK9 inhibitors. Lomitapide needs caution, and liver transplantation is an alternative as the last resort.

1. INTRODUCTION
Familial hypercholesterolemia (FH) is the most common lipid hereditary disease [1]. It is a monogenic genetic disorder affecting lipid metabolism, mainly low-density lipoprotein cholesterol [LDL- C]) that plays a pivotal role in developing Cardiovascular Disease (CVD) [1]. Affected individuals have isolated high serum LDL-C levels [2]. The disease is primarily inherited in an autosomal domi- nant manner (AD), but it also has an Autosomal Recessive (AR) mode of inheritance [2]. Genetic mutations in one or more genes could be the cause of FH. The mutations related to FH are mainly in genes encoding LDL receptors (LDLR) (60-80%) [2], to a lesser degree of apolipoprotein B-100 (APOB) (1-5%) [3], or to a small degree of proprotein convertase subtilisin/kexin type 9 (PCSK9) (1- 3%); in some patients, there is no genetic tracing (20-40%) [4]. Mutations in the LDL-receptor adaptor protein 1 (LDLRAP1) gene are also responsible for the AR form of FH (Fig. 1) [5]. Mutations in one allele of either of these genes may lead to the heterozygous FH (HeFH) phenotype and mutations in both alleles (in some cases in two different genes, one from the mother and one different from the father) lead to the more severe homozygous FH (HoFH) pheno- type(or compound heterozygous familial hypercholesterolemia- cHeFH) [1]. The AR form of FH has clinical similarity to both HeFH and HoFH with intermediate LDL-C levels, if both alleles are affected [5]. However, a normal or near normal lipid profile has been reported in carriers of AR mutations in the LDLRAP1 gene, and a greater response to lipid-lowering treatment (statins) was achieved in these patients [6].
Recent data from the International Atherosclerosis Society Se- vere Familial Hypercholesterolemia Panel [7] suggests that about 1/200-250 people may have HeFH, and up to 1/300, 000 people may have HoFH [7]. Patients with HoFH usually have total choles- terol levels above 500 mg/dL (13 mmol/L) and LDL-C levels above 450 mg/dL (11.7 mmol/L) [8]. The deposition of cholesterol leads to characteristic tendon xanthomas of the hands, feet, and Achilles tendons, xanthelasmata on the eyelids and corneal arcus in the eyes [9, 10]. Myocardial infarction (MI) and sudden cardiac events may appear early in adolescence due to coronary atherosclerosis or aor- tic valve stenosis [9]. Patients with null mutations of the LDLR gene (class 1), resulting in no LDL receptor protein product, have a higher susceptibility to CVD than those missense mutations, that alter the gene sequence and partially disrupt LDLR function (classes 2-5) [8, 10]. In contrast, in HeFH, patients have lower se- rum cholesterol (250-450 mg/dL or 6.5-11.6 mmol/L) and LDL-C (200-400 mg/dL or 5.2-10.4 mmol/L) levels than in HoFH [5]. They demonstrate the above clinical symptoms with slower pro- gression of their disease. Patients with HeFH usually develop pre- mature CVD before the age of 55 years for men and 60 years for women. HeFH men tend to suffer from CVD more frequently than HeFH women, probably due to sex-related hormonal factors [11].

2. TREATMENT ACCORDING TO THE GENOTYPE VARIABILITY OF HOFH
LDLR mutations account for the vast majority of FH cases and more than 1,200 different LDLR mutations have been described worldwide [12, 13]. There are five classes of genetic variants ac- cording to the degree of defect in the LDLR function [13]. Class 1 defect: no LDLR synthesis; class 2 defect: no LDLR transport; class 3 defect: no Low-density Lipoprotein (LDL) to LDLR bind- ing; class 4 defect: No LDLR/LDL internalization; and class 5 de- fect: No LDLR recycling [13].

2.1. Statins with or Without Ezetimibe
A large study included 254 patients from North Western Greece with the clinical diagnosis of FH [14]. A substantial genetic hetero- geneity for FH (with at least ten LDLR gene mutations) was found in the study population [14]. There was a relatively high prevalence of HoFH (among patients with HeFH phenotype) in this area sug- gesting a founder effect [15, 16]. Notably low cholesterol levels for HoFH patients possessing the exon 4 deletion mutation (c.387_410del24), have been found in only one family in this re- gion and were reported for the first time worldwide [14]. This novel deletion mutation resulted in the loss of 8 amino acids from the mature Apo B-100 binding domain (repeat IV). This is probably a class 5 mutation, in which the LDLR retains its ability to bind and internalize its ligand but fails to release it in the endosome and therefore, the receptor does not recycle back to the cell surface [14]. This leads to lower plasma LDL-C and less severe clinical out- comes than other HoFH cases [14, 17]. Moreover, patients with this mutation responded to statin or statin plus ezetimibe treatment, with reductions of LDL-C levels within the target range [18-20].
This was also the case in a 10-year-old Chinese HoFH boy with balletic LDLR mutations (compound heterozygote) with elevated serum LDL-C levels of 575 mg/dl (14.9 mmol/l) [21]. Treatment with a fixed combination of 40 mg/d of simvastatin and 10 mg/d ezetimibe led to a substantial (57%) reduction in LDL-C [21]. De- spite the substantial reduction in LDL-levels by this combination, additional treatment with PCSK9i would be required to achieve the designated targets [21]. Thus, statins plus ezetimibe, alone or in combination with PCSK9i, may be sufficient to reduce LDL-C levels within target range in some class 5 mutation carriers or dou- ble heterozygotes.
In more severe forms of HoFH like in carriers of the class 2 mutation p.W556R, response to statin therapy is insufficient, and patients have to undergo LDL-C apheresis. Nonetheless, ezetimibe monotherapy on top of LDL-C apheresis has been shown to further reduce LDL-C by 15% [22]. Thus, in class 5 mutation HoFH and in cHeFH we may use the combination of statin with ezetimibe, while PCSK9i can be added depending on the patient’s age [21]. In class 2 mutation HoFH carriers, only LDL-C apheresis with or without ezetimibe can be used [22].

2.2. Liver Transplantation and Concomitant Immunosuppres- sion
Liver transplantation replaces the missing LDLR and normal- ises LDL-C [23]. Data from the European Liver Transplant Regis- try (ELTR) indicates that 21 liver transplants for HoFH patients were performed in Europe from 1988 to 2009 [24]. However, it seems that liver transplantation is more common in countries where LDL apheresis is not available [23]. A series of 36 liver transplanta- tions in HoFH patients’ cases were reported in Iran [25], while there are several publications with successful outcomes worldwide [26]. Liver transplantation should ideally be performed before the onset of overt cardiovascular consequences [27]. However, if there is already overt CVD, combined heart and liver transplantation can be considered as a last resort [23]. Restrictions in liver transplanta- tion in HoFH patients include its priority on the basis of clinical urgency and mainly the availability of donors [23]. Whether early liver transplantation offers a better life-long alternative in compari- son to LDL apheresis, lomitapide or mipomersen, especially in young children, remains unresolved [23, 28], but split liver trans- plantation and improvements in immunosuppression might render this option more attractive [23, 29].
A recent study from the US (Columbia University, New York), where LDL apheresis is available, showed that liver transplantation in 8 children resulted in total cholesterol, LDL-C, Lp(a), and apol- ipoprotein B/apolipoprotein A1 ratio normalization in all patients (p <0.001 vs baseline) at 1 month after transplantation, with sustained results throughout the entire follow-up period (2-6 years) [30]. Few complications observed were related to liver transplantation or im- munosuppressive therapy per se, similar to patients transplanted for other indications. Progression of aortic stenosis was observed in 2 of 4 subjects despite normalisation of lipid profile. In conclusion, liver transplantation is an effective therapeutic choice for patients with HoFH with CVD and elevated serum LDL-C despite potent medical therapy [30]. Notwithstanding the fact that liver transplantation is a success- ful therapeutic strategy, either alone or combined with heart trans- plant [31], the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) underlines the caveats of liver transplantation, including the high risk of post- surgical complications and mortality (especially rejection and infec- tions), the shortage of donors, and the need for life-long immuno- suppression [31, 32]. For these reasons, EAS does not favour liver transplantation as first choice for the treatment of HoFH [31]. 2.3. LDL Apheresis LDL apheresis is a form of apheresis, resembling dialysis, aim- ing to eliminate the apolipoprotein B-containing lipoproteins from the bloodstream by affinity columns (filters) containing anti- apolipoprotein B antibodies or dextran sulphate, or their precipita- tion at low pH, after separating plasma from blood cells with a cell separator [33]. It is used in patients with high LDL-C, such as HoFH, or HeFH that do not respond to medical treatment, or intol- erant to conventional treatment due to dangerous side-effects (such as statin-induced rhabdomyolysis) [33]. The procedure takes 2-4 hours and must be repeated every week or two to prevent LDL-C accumulation and reduce risks of CVD disease [33].Acute LDL lowering ranges from 70% to 80%, while the time-averaged LDL lowering is approximately 40% to 50%; Lp(a) is also substantially lowered [34]. LDL-C levels rebound rapidly after treatment, return- ing to 50 and 90 % of pre-apheresis levels after 4 and 14 days, re- spectively [35]. Long-term use of LDL apheresis has been reported to promote regression of xanthomas, slow the progression of athe- rosclerotic plaques, and cause a substantial reduction in the in- flammation of arterial walls of FH patients [36, 37]. In terms of history, the late 60’s unselective plasmapheresis was used in patients with HoFH in an attempt to control hypercholes- terolemia, slow coronary atherosclerosis, and prolong survival with limited success [38]. In mid 70’s, treatment began to focus on re- moving LDL-C more selectively [39]. Since then LDL apheresis is the main treatment of HoFH or refractory HeFH with high CVD risk [31]. However, LDL apheresis is time consuming, not widely accessible to all HoFH patients, and very expensive (it is estimated that each session costs $6, 000). Consequently, the concomitant use of hypolipidaemic drugs is useful in two ways. Firstly, to reduce the needs for regular LDL apheresis and secondly to maintain lower LDL levels LDL-C level within or near the optimal range for as long as possible in between sessions. A rapid rebound of LDL-C has been described after each apheresis session. In this manner, concurrent pharmacotherapy is mandatory [40]. The addition of PCSK9i (evolocumab) may be useful. Some phenotypes of HoFH respond well to PCSK9i, to the degree that LDL apheresis might be performed once a month or even be abol- ished [41-43]. This approach is definitely more cost effective than usual LDL apheresis, because omission of one apheresis procedure a month saves equivalent costs for a year of PCSK9i administration (at least in Europe). Discontinuation of LDL apheresis altogether and maintenance of LDL-C targets with pharmacotherapy has been shown to save more than 95% of the usual apheresis costs; and this has been demonstrated in real world clinical practice. Another approach in HoFH treatment combination would be to start with life-style changes, potent statin, ezetimibe, and mainly evolocumab and if LDL-C targets are not reached, LDL apheresis with a frequency that is necessary to attain LDL-C targets can be utilised [41, 43]. Novel lipid lowering agents, such as lomitapide or mipomersen (in US) can also be combined with LDL apheresis or even replace it in some cases [43]. The aforementioned data suggest that there is a need for a com- bination of lifestyle, statin treatment, ezetimibe and LDL apheresis to manage HoFH. Colesevelam is not easy to use, is costly and has been withdrawn from some countries. While this therapeutic ap- proach may be sufficient to attain LDL-C goal in patients with a milder HoFH phenotype, HoFH that is refractory existing lipid- lowering therapies should be treated with LDL apheresis despite all its aforementioned caveats [36, 43]. Combination of novel lipid- lowering drugs with different mechanisms of action might improve the management of HoFH [36, 43]. In any case, early detection of HoFH and aggressive intervention with combination of treatments is generally recommended for HoFH patients [36]. However, the combination of these agents and procedures cannot always maintain LDL-C levels to the optional treatment goals [36, 43]. The clinical benefit of these new treatments on CVD events has not been estab- lished and needs evaluation [36, 43]. 2.4. Lomitapide Lomitapide inhibits the microsomal triglyceride transfer protein (MTP or MTTP), which is necessary for Very Low-Density Lipo- protein (VLDL) assembly and secretion in the liver, and is used as a lipid-lowering agent for the treatment of HoFH [44, 45]. It has been tested in clinical trials as monotherapy and in combination with atorvastatin, ezetimibe and fenofibrate [46]. Inhibition of LDL-C production by lomitapide, either alone or in combination, could be an effective therapeutic option for HoFH patients unable to reach target LDL-C levels [46]. Ezetimibe monotherapy led to a 20% decrease in LDL-C levels [46]. Lomitapide monotherapy led to a dose-dependent decrease in LDL-C levels: 19% at 5.0 mg, 26% at 7.5 mg and 30% at 10 mg [46], while combined treatment induced even larger dose-dependent decreases (35%, 38% and 46%, respec- tively) [46]. However, the use of lomitapide has two important limitations: a serious adverse effect is the elevation in liver aminotransferase (ALT) levels and accumulation of hepatic fat, ranging from 10% to more than 40%, which leads to non-alcoholic fatty liver disease (NAFLD) [44], while the second limitation is financial: the daily cost of treatment exceeds $1, 000 (https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0087956). The instructions suggest to initiate treatment with 5 mg once daily per os, and titrate the dose according to safety/tolerability: increase to 10 mg daily after at least 2 weeks; and then, at a mini- mum of 4-week intervals, to 20 mg, 40 mg, and up to the maximum recommended dose of 60 mg daily. Due to reduced absorption of fat-soluble vitamins/fatty acids, it is suggested to take daily vitamin E, linoleic acid, Alpha-Linolenic Acid (ALA), Eicosapentaenoic Acid (EPA), and Docosahexaenoic Acid (DHA) supplements. Pa- tients with end-stage renal disease on dialysis or with baseline mild hepatic impairment should not exceed 40 mg daily (https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/20385 8s000lbl.pdf). Overall, it is a difficult to use and expensive drug. It can be administered with ezetimibe [44], or potent statins [44]. It has to be taken into consideration that atorvastatin or rosuvastatin may ameliorate NAFLD [47, 48]. Thus, they could be administered as adjunctive treatment for this purpose, even if they are not effec- tive in reducing LDL-C for the specific genotype of HoFH. 2.5. Mipomersen Mipomersen is a drug that binds to the messenger RNA coding for apolipoprotein B-100 (ApoB-100), a protein that is the main component of LDL and VLDL particles. As a consequence, the RNA is degraded by the enzyme ribonuclease H, and ApoB-100 is not translated [49]. Mipomersen, a second generation antisense oligonucleotide (ASO), is used to treat HoFH and it is administered by subcutaneous (SC) injection once every week at an increasing dose in the range of 30-400 mg [49]. There is a serious risk of liver damage from this drug and it can only be prescribed in the context of a risk management plan [49]. The percentage change from base- line in LDL-C in patients treated with mipomersen 200 mg SC weekly ranged from -25 to -37%, while those treated with placebo ranged from −5 to +13 % [50]. Mipomersen has a relatively high discontinuation rate attributed to Injection Site Reactions (ISRs), up to 80% of patients, and Flu- Like Symptoms (FLS); however, the most common adverse effect was elevated liver enzymes and increased liver fat (NAFLD) [50]. In a post hoc analysis of prospectively collected data of three randomized trials and an open-label one, it was shown that long- term mipomersen administration not only lowers the levels of atherogenic lipoproteins but may also lead to a reduction in CVD events in FH patients [51]. CVD events were reported in 61.5% of patients during 24 months before mipomersen treatment, and in 9.6% of patients during 24 months after initiation of mipomersen (OR= 0.053; 95% CI: 0.016-0.168; p <0.0001). The reduction in CVD events was related with a mean absolute reduction in LDL-C by 70 mg/dL (-28%) and of non-HDL cholesterol by 74 mg/dL (- 26%) as well as a reduction in Lp(a) by 11 mg/dL (-17%) [51]. The drug has been approved for HoFH treatment by the US Food and Drug Administration (FDA) but not from the European Medicines Agency (EMA) yet. In December 2012, EMA rejected the applica- tion of mipomersen as a commercial product for Europe, because of concerns about its efficacy and safety. In March 2013, EMA con- cerns remained unresolved and were not fully addressed by meas- ures proposed by the company. Therefore, the EMA refusal was confirmed after re-examination (https://www.ema.europa.eu/ medi- cines/human/EPAR/kynamro). The above suggest that mipomersen could be cautiously consid- ered for the current management of HoFH, at least in US, on top of lifestyle interventions and potent statin therapy, in combination with ezetimibe [31]. 2.6. PCSK9i Evolocumab, a PCSK9 inhibitor (neutralizing antibody), lowers LDL-C in HoFH in patients with reduced LDLR function and is an effective additional option to treat patients with HoFH, with or without apheresis [52-54]. It has no effect in patients with muta- tions that result in absence of LDLR [53, 55]. In the Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities (TESLA, part B) 50 eligible patients were randomly assigned to the two treatment groups; 49 received the study drug and completed the study (16 in the placebo group and 33 in the evolocumab group) [53]. In patients with HoFH receiving stable background lipid-lowering treatment, but not on apheresis, evolocumab 420 mg/every 4 weeks, was well tolerated and signifi- cantly reduced LDL-C by 31% at 12 weeks (95% CI: -44% to - 18%; p<0.0001 compared with placebo) [53]. In the Trial Assessing Long Term USe of PCSK9 Inhibition in Subjects With Genetic LDL Disorders (TAUSSIG) patients from 35 sites in 17 countries were included in this analysis [54]. A 23% drop in LDL-C levels was observed, with no deaths, myocardial infractions, or hospitali- zations for unstable angina over 48 weeks with open-label treatment with evolocumab, with one third (n=106) of the patients receiving apheresis at study entry (https://www.medscape.com/ viewarti- cle/864207) [56]. According to the HEART UK statement on the management of HoFH in UK, evolocumab is licensed from the age of 12, while alirocumab has no license for treatment of HoFH at any age yet [57]. LDL-C lowering is influenced by genotype. Mean reductions were -24% for LDLR defective patients, -6% for LDLR nega- tive/negative, -51% for PCSK9 gain of function/LDLR negative and -43% for Autosomal Recessive Hypercholesterolaemia (ARH) [57]. Treatment with evolocumab should be considered in all HoFH patients on apheresis and standard drug treatment with LDL-C above target, who are receptor defective [57]. HoFH or compound HeFH with gain of function PCSK9 mutation or double HeFH with, for example, an LDLR defective allele and a gain of function PCSK9 mutation are likely to respond well to PCSK9 inhibition [57]. HoFH patients who show a 10-15% reduction in LDL-C (or increase in interval of LDL-C apheresis) with evolocumab should continue treatment on top of apheresis and ezetimibe [57]. The subcutaneous injection of evolocumab should be performed straight after apheresis [57]. Evolocumab has a cost of $5, 000or less (in Europe), LDL- apheresis $200, 000, and lomitapide $350, 000 a year [57]. Lomi- tapide should be considered for HoFH patients who have failed to achieve LDL-C treatment targets with apheresis and standard drug treatment (statin and ezetimibe) and had at least one trial of evolo- cumab treatment [57]. The frequency of LDL-C apheresis may be reduced if combined with lomitapide or (most importantly) with evolocumab [57]. These new agents are expected to make the treatment more affordable for health care systems. If the above are not accessible, usually in poor countries, liver transplantation might be the last resort [57]. CONCLUSION The above suggests that HoFH cannot be treated with mono- therapy and combination of procedures with drugs is required (Fig. 2) [58]. Usual lipid-lowering drugs like potent statins, ezetimibe, or resins are usually insufficient to achieve LDL-C treatment targets in this population [58]. Lipoprotein apheresis has been a more effec- tive therapy and is the basis of treatment in many patients from a very young age [23]. Novel drug therapies like mipomersen or lomitapide have reduced LDL-C dramatically in some patients but are often ineffective in others [58]. PCSK9i can reduce LDL substantially but are ineffective in those with null genes for the LDLR [58]. Finally, liver transplantation remains in the arsenal for treating HoFH as a last resort [59, 60]. Wider availability of these combina- tions of drugs has markedly improved the potential to control LDL-C values and prolong the life of familial hypercholesterolemia patients [61-72].