NOVEL THERAPEUTIC OPTIONS FOR FAMILIAL HYPERCHOLESTEROLEMIA

Received on 10 February, 2014; received in revised form, 26 March, 2014; accepted, 13 June, 2014; published 01 August, 2014

NOVEL THERAPEUTIC OPTIONS FOR FAMILIAL HYPERCHOLESTEROLEMIA

Muthukumar Rajaram, Melvin George and Elangovan Shanmugam

Department of Cardiology, SRM Medical College Hospital & Research Centre, Chennai – 603203, Tamil Nadu, India

ABSTRACT:

Background: Familial Hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutation in the LDL receptor gene and characterized by raised LDL-C, tendon xanthomata and premature atherosclerosis. Existing therapies for FH such as statins and LDL apheresis do not offer adequate lipid control in most patients, which has led to the search for more definite alternatives. Two new drugs have been approved by the US FDA in the recent past for FH, namely mipomersen, an anti-sense oligo-nucleotide and lomitapide, a microsomal triglyceride transfer protein.

Methods: We did a literature search across PubMed to retrieve articles related to efficacy and safety of mipomersen and lomitapide.

Results:Mipomersen has been found to have reasonable efficacy in clinical trials over and above that seen with concomitant statin therapy in FH. Lomitapide has also shown evidence of adequate LDL-C reduction in clinical trials though the number of studies performed with lomitapide is relatively fewer. The subcutaneous route of administration for mipomersen may affect compliance especially with long term treatment.  The most common adverse reactions seen with mipomersen include injection site reactions and flu-like symptoms. Lomitapide has a boxed warning for hepatic steatosis, though there is no evidence so far to indicate that it could progress to hepatic cirrhosis.

Conclusion: Although mipomersen and lomitapide show promise as novel therapeutic options for FH, the long term safety data is definitely warranted before it becomes a front line therapy in FH.

Mipomersen, Microsomal triglyceride transfer protein inhibitor, Lomitapide, Antisense oligonucleotide

INTRODUCTION: Familial hypercholesterolemia (FH) is an autosomal-dominant condition that is characterized by elevated levels of plasma LDL cholesterol and apo-lipoprotein B resulting in an increased risk for atherosclerosis¹. If untreated, patients may develop premature coronary artery disease (CAD).

FH is considered to be the first genetic disease of lipid metabolism to be characterized at the molecular level ².

Studies have consistently shown a positive correlation between plasma levels of LDL-C and the prevalence of CAD ³. It is not surprising that, several cases of FH go undiagnosed or only diagnosed after their first coronary event.

The major underlying defect in FH is mutations of the low-density lipoprotein (LDL) receptor gene i.e., mutations in the pro-protein convert as subtilisin/ kexin type 9 gene and mutations in the apolipoprotein B100 gene ⁴.

The molecular mechanisms by which these sequence variations in PCSK9 reduce the LDL-C level are not known. PCSK9 is a glycoprotein that is expressed at its highest levels in the liver, intestine, and kidney ⁵. Over expression of PCSK9 or the mouse orthologue in the livers of mice results in a marked reduction in LDL receptors in this organ ^6-9, which is the main pathway for the removal of LDL from the plasma, and a corresponding increase in circulating LDL-C levels.

Thus, high levels of PCSK9 lead to high plasma levels of LDL-C, whereas low levels of PCSK9 lead to low LDL-C levels. It was the seminal work of Goldstein and Brown et al that led to the elucidation of LDL-receptor pathway ¹⁰. The concept that defects in the LDL-receptor lead to FH came to light through their work, for which they were awarded the Nobel Prize in Physiology or Medicine in 1985 ^{11, 12}.

The treatment of FH continues to be a challenging prospect since many patients do not achieve adequate lipid control even with maximal statin therapy. This is because patients with homozygous familial hypercholesterolemia (HoFH) lack functional LDL receptor activity and most of the current drugs work mainly through upregulation of LDL receptor in the liver. Over the last decade intensive research has been undertaken to discover novel drug targets that could be modulated favorably for the treatment of FH. This article is an overview on two molecules that have been recently approved for HoFH, namely mipomersen and lomitapide by the US FDA ¹³.

Mipomersen:Mipomersen, an antisense oligonucleotide, is a novel approach in the management of familial hypercholesterolemia (FH) ¹⁴. Mipomersen consists of a 20-mer 2′-O-methoxyethyl modified nucleotide complementary and specific to human ApoB-100 mRNA ¹⁵. It specifically targets ApoB-100 mRNA, blocking the translation of the gene product ^16-18. Following the binding of the oligonucleotide to the mRNA, degradation by endogenous RNase H is induced. As a result, the synthesis of apolipoprotein B is reduced, resulting in decreased production and secretion of apolipoprotein B-containing lipoproteins.

Pharmacokinetics of Mipomersen: The pharmacokinetic studies have shown that mipomersen has complete systemic absorption and is rapidly and extensively distributed to tissues (volume of distribution in humans 48.3 L/kg). Greater than 85% of mipomersen in plasma is bound to plasma proteins. Animal studies have also showed that the highest levels of the oligonucleotide are found in liver and kidney. Mipomersen is catabolized by endonucleases and exonucleases, which are abundantly expressed in all cells and tissues. The metabolites are largely excreted in the urine ^{18, 19}. The drug does not have any dependency on Cytochrome P450 metabolism. The half-life of mipomersen in humans has been calculated to be approximately 30 days ¹⁵. Urinary excretion of mipomersen was found to be minimal in the first 24 hours. Oligonucleotide metabolites can also be detected in urine along with mipomersen. Mipomersen does not have any pharmacokinetic interactions when, co-administered with either simvastatin or ezetimibe ¹⁹. The proposed mipomersen dose is 200 mg once weekly as a subcutaneous injection.

Efficacy of Mipomersen: A Phase I trial by Kastelein et al demonstrated that, in healthy individuals with mild dyslipidemia, once weekly dose of mipomersen (50-400 mg/week) therapy for 4 weeks brought a dose-dependent reduction of LDL-C, total cholesterol, lipoprotein(a), apolipoprotein B100, and triglycerides ¹⁷. The observed reduction in LDL-C, lipoprotein(a), and apolipoprotein B was found to be independent of the underlying cause and independent of concomitant drug therapy. There was a sustained decrease in plasma apolipoprotein B and LDL-C for 3 months.

Phase II and III trials have demonstrated that mipomersen is an effective lipid-lowering therapy in FH. In a Phase II randomized double blind dose escalation study, 44 patients with heterozygous FH were administered 8 doses of mipomersen or placebo at weekly intervals. The dose of mipomersen varied between 50 to 300 mg/week ²⁰. The results showed significant reductions in apolipoproteinB (23% and 33%) and LDL-C (21% and 34%) in the 200 mg and 300 mg dose groups respectively.

But there was a trend towards reductions in lipoprotein (a) [Lp(a)], an important risk factor for coronary artery disease in FH ^21-23, though the  changes were not significant. Mipomersen did not have any effect on triglycerides and HDL-C. In a randomized double blind placebo controlled phase 3 clinical trial by Raal et al, 51 patients with    HoFH  were randomized to receive mipomersen (200mg/week) or placebo for 26 weeks in addition to standard therapy. The study showed that the mean percentage change in LDL-C concentration was significantly greater with mipomersen (-24.7%, 95% CI -31.6 to -17.7) than with placebo (-3.3%, -12.1 to 5.5; p=0.0003). Yet a high degree of variability was observed in changes to LDL-C, which ranged between 2% to −82% which could not be explained by baseline LDL-C, age, race, or sex.

Mipomersen also caused a significant reductions in Lp(a) (−31%) and triglyceride levels (−17%), and an increase in HDL-C (15%) ²⁴. Visser et al showed the effect of mipomersen in 33 statin-intolerant patients at high risk for cardiovascular disease ²⁵. More than half the patients in this study were found to be FH heterozygotes. The result showed that the patients who are on treatment with 200 mg/week mipomersen for 26 weeks had a 47% decrease in LDL-C, ranging from −19% to −77%. This was predominantly the result of a reduction in small LDL particles (−56%; P = 0.001 vs placebo) rather than large LDL particles (−4%; P, 0.017 vs placebo). While triglycerides and Lp(a) levels were significantly reduced by mipomersen treatment, HDL-C and ApoA-I concentrations did not change. A summary of studies done with mipomersen is depicted in Table 1.

TABLE 1.CLINICAL STUDIES PERFORMED WITH MIPOMERSEN AS ON DATE

Safety of Mipomersen: Initially the potential of mipomersen in causing tumors was assessed in carcinogenicity studies in mice and rats. There was a statistically significant increase in the incidence (over control) of benign hepatocellular adenoma in female mice treated with 60 mg/kg/week mipomersen. There was also an increased incidence of malignant fibrous histiocytoma in both males and females species at 10 and 20 mg/kg/ wkmipomersen respectively and an increase in malignantfibrosarcoma in females alone at the same dose as mentioned.But no malignant neoplasms have been reported at the injection site in mipomersen-treated individuals ²⁶.

Mipomersen demonstrated a fair degree of safety in Phase II and Phase III studies. The most common adverse events experienced were injection site reactions (75%–100%). These reactions were dose-dependent and characterized by transient, mild to moderate erythema, occurring within 24 hours of drug injection. The two types of delayed responses observed were reappearance of erythema and hyperpigmentation. Whereas hyperpigmentation may be a common response to skin injury ²⁷, the pathophysiological mechanism for reappearance of the erythema is unknown. Injection site reactions are considered an antisense class-related phenomenon as they are common with other antisense drugs. Though injection site reactions may not be classified as serious safety concerns, it could interefere with patient compliance.

Flu-like symptoms were also more often reported in the mipomersen group than in the placebo group in most studies. The flu-like symptoms usually appear shortly after mipomersen administration, but resolve within 1–2 days, and are generally limited to the first few weeks of treatment. Elevated transaminases (alanine aminotransferase level more than three times the upper limit of normal) was observed in 6%–15% of mipomersen-treated patients (0% in the placebo groups). After discontinuation of treatment, transaminases returned to normal in all patients. The exact reason for elevation of transaminase during mipomersen treatment is unclear, and it was not seen in preclinical studies. Hepatic steatosis was also been detected in some mipomersen-treated patients ²⁸. But hepatic steatosis and alanine aminotransferase resolved soon after discontinuation of treatment. Although the drug has been approved by the FDA, the high discontinuation rate among patients in clinical trials, hepatic steatosis and unproven cardiovascular benefit have made the regulators of EMA to with-hold approval of the drug ²⁹. The use of mipomersen in conjunction with LDL apheresis is currently being investigated in a phase 3 clinical trial in Germany to determine whether mipomersen will result in reduced apheresis time or frequency³⁰.Future trials with larger patient numbers will help establish the utility of mipomersen as a potential therapeutic option for the treatment of patients with severe hypercholesterolemia.

Lomitapide: Lomitapide (AEGR-733, previously known as BMS-201038) is a microsomal triglyceride transfer protein (MTTP) inhibitor and is the only drug that has been approved by both FDA and EMA ³¹ for homozygous familial hypercholesterolemia. MTTP is mainly responsible for transferring the triglycerides onto apolipoprotein B within the liver in the assembly of very-low-density lipoprotein (VLDL), the precursor to LDL ³². Inhibition of MTP by lomitapide leads to a reduction in the circulating levels of apoB-containing lipoproteins, including LDL-C ³³.The development of MTP inhibitors was facilitated by the identification of patients with abetalipoproteinemia, a rare genetic disorder resulting from inhibition of the assembly of apolipoproteinB containing lipoproteins due to the absence of functional MTP ^{33, 34}. The action of MTP inhibitor provide potentially a powerful therapeutic method to reduce the production of apolipoproteinB-containing lipoproteins, especially VLDL, the precursors of LDL.

Pharmacokinetics of lomitapide: The proposed dose range of MTP inhibitor that is administered orally is based upon a well characterized dose–response relationship ^35-37. The results of phase I study indicated a mean absolute bioavailability of approximately 7% and a terminal half-life of ~29 h. Lomitapide is a CYP3A4 substrate Co-administration with strong CYP3A4 inhibitors or inducers may alter the exposure to lomitapide. But when it is administered with other lipid-lowering agents such as statins or fibrates there is no significant interaction. The recommended dose of lomitapide is 5- 60 mg orally once daily ³⁸.

Efficacy of lomitapide: In animal studies lomitapide had shown to have dose-dependent decreases in LDL-C and triglyceride levels by 29% and 87% respectively with subsequent decrease in HDL levels ³⁹. It was initially tested ina dose-escalation study of 6 patients with HoFH  byCuchel et al in 2007 [Table 2]. The patients had been instructed to follow a low fat diet and after cessation of all other lipid-lowering therapies they received lomitapide orally for 4 weeks. The results showed that lomitapide caused an approximately 50% reduction of plasma LDL-C levels in the highest dosage (0.1 mg/kg/day) ⁴⁰. A subsequent trial was conducted in 10 homozygous patients, at a maximum dose of 60 mg/day and this resulted in a 44% reduction in LDL-C levels, over and above the effect achieved already by concomitant lipid lowering therapy ⁴¹.

TABLE 2: CLINICAL STUDIES PERFORMED WITH LOMITAPIDE AS ON DATE

A multi-centric randomized double blind study by Samaha et al used a low dose regimen of lomitapide in 84 patients with hyper-cholesterolemia for 12 weeks. Patients were randomized to ezetimibe, 10 mg, daily (n=29); or lomitapide in increasing dosages (5.0, 7.5, and 10 mg daily, each dose for 4 consecutive weeks [n=28]); or ezetimibe, 10 mg daily, and lomitapide administered with the similar dosetitration described as in the second group (n=28). Ezetimibe therapy resulted in an expected LDL-C reduction of 20%.

Lomitapide was shown to induce a lowering of LDL-C levels in a dose dependent manner: 19%, 26%, and 30% in the 5, 7.5, and 10mg dosing regimens, respectively.Combined therapy produced similarbut larger dose-dependent decreases in LDL-C (35%, 38% and 46%, respectively).Out of 56 patients, nine had increase in hepatic transaminases, and other side effects included such as nausea, diarrhea, gassiness, and gastrointestinal cramping. But the mainreason for discontinuation from study was elevated transaminases ⁴². In a phase III study lomitapide demonstrated the LDL reduction in a single arm, open label trial in patients with HoFH. The study was performed in 29 patients who had HoFH and it was observed that lomitapide reduced LDL between 24% and 62% (mean 38%) after 78 weeks of treatment. Patients were also on maximally tolerated background therapy, including other lipid-lowering medications and LDL-apheresis. Due to a significant number of patients discontinuing treatment early (21%) and lack of a control group, the precision of these results is uncertain. However, there is no evidence currently that it improves clinically meaningful outcomes, such as cardiovascular morbidity and mortality. A summary of the evidence for lomitapide is mentioned in Table 2.

Safety of Lomitapide: The most common adverse reactions reported with an incidence of at least 20% include: diarrhea, nausea, vomiting, dyspepsia, and elevations in liver transaminases ³⁸. Lomitapide has a boxed warning for risk of elevated transaminases and hepatic steatosis. Hepatic steatosis estimated by magnetic resonance imaging ranged from less than 10% to 40% (normal b1%) and was consistent with changes seen in animal studies ⁴³. Another adverse effect that hinders the beneficial effects of MTP inhibitors was increased stool frequency ³⁸. Because of potential serious side effects, the FDA has initiation a Risk Evaluation and Mitigation (REMS) program to ensure lomitapide is only used in HoFH ⁴⁴.

Limitations: Lomitapide received approval from FDA for use only in patients with HoFH, with the requirement of use by a restricted program called the JUXTAPID Risk Evaluation and Mitigation Strategy by the manufacturer ⁴⁵. In addition to that the dose of lomitapide is not fixed and must be titrated in individual patients according tothe gastrointestinal side-effects, liver enzyme elevation, and the amount of hepatic fat accumulation. So the drug usage will probably be restricted to patients at specialized lipid clinics. Since HoFH is a rare disease; all studies performed so far with lomitapide are limited by a small sample size ⁴⁶. So it is important to continue evaluating the drug in post marketing studies to study the safety of the drug especially with respect to its long term consequences and to detect rare adverse effects that could be gauged in a larger population.

CONCLUSION: Familial hypercholesterolemia is a disorder of LDL-C metabolism. FH patients are at a sharply increased lifetime risk for cardiovascular disease (CVD) and, if left untreated, clinical symptoms of CVD typically manifest in men, in the fourth decade and in women, in the fifth decade of life. Mipomersen, an anti-sense oligonucleotide and lomitapide, an MTP inhibitor are two new drugs approved by US FDA for FH, which may offer benefit in these patients beyond that seen with existing drug therapy. Clinical trials have shown mipomersen and lomitapide to be highly effective and safe as lipid-lowering agents when used as monotherapy or in conjunction with statin therapy.

Nevertheless, the long-term safety of these drugs needs to be explored before they become front-line therapy in the management of FH.

Conflict of Interest: The authors declare that they do not have any conflict of interest.

ACKNOWLEDGMENTS: We wish to than Ms. Amrita Jena for helping us edit the manuscript.

REFERENCES:

1. Hopkins PN, Toth PP, Ballantyne CM, Rader DJ: National Lipid Association Expert     Panel on Familial Hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Journal Clinical Lipidology 2011;5:S9–17.
2. Bell DA, Hooper AJ, Watts GF, Burnett JR. Mipomersen and other therapies for the treatment of severe familial hypercholesterolemia. Vascular Health Risk Management  2015 ;8:651–659.
3. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.Circulation 2002; 106:3143–3421.
4. Soutar AK, Naoumova RP: Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nature Clinical Practice Cardiovascular  Medicine 2007;4:214–225.
5. Seidah NG, Benjannet S, Wickham L: The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proceedings of the National Academy of Sciences of the U S A 2003; 100:928–933.
6. Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proceedings of the National Academy of Sciences of the U S A  2004 ;101:7100–7105.
7. Park SW, Moon Y-A, Horton JD: Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver.Journal of Biological Chemistry 2004; 279:50630–50638.
8. Lalanne F, Lambert G, Amar MJA: Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells. Journal of Lipid Research 2005 ;46:1312–1319.
9. Benjannet S, Rhainds D, Essalmani R: NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. Journal of Biological Chemistry 2004 ,279:48865–48875.
10. Brown MS, Kovanen PT, Goldstein JL: Regulation of plasma cholesterol by lipoprotein receptors.Science1981 ,212:628–635.
11. Goldstein JL, Brown MS: The LDL receptor.Arteriosclerosis, Thrombosis, and Vascular Biology   2009, 29:431–438.
12. Brown MS, Goldstein JL: A receptor-mediated pathway for cholesterol homeostasis.Science1986, 232:34–47.
13. Genzyme and Isis Announce FDA Approval of KYNAMRO^TM (mipomersen sodium) Injection for the Treatment of Homozygous Familial Hypercholesterolemia | Genzyme Corporation Online Newsroom [Internet]. [updated 2013 Jan 29; cited 2013 Nov 8]. Available from:http://news.genzyme.com/press-release/genzyme-and-isis-announce-fda-approval-kynamro-mipomersen-sodium-injection-treatment-h
14. Goldberg AC: Novel therapies and new targets of treatment for familial hypercholesterolemia. Journal of  Clinical Lipidology 2010 ;4:350–356.
15. Yu RZ, Lemonidis KM, Graham MJ: Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100. Biochemical Pharmacology  2009 ;77:910–919.
16. Toth PP: Antisense therapy and emerging applications for the management of dyslipidemia. Journal of Clinical Lipidology 2011; 5:441–449.
17. Kastelein JJP, Wedel MK, Baker BF: Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation 2006; 114:1729–1735.
18. Yu RZ, Kim T-W, Hong A, Watanabe TA, Gaus HJ, Geary RS.:Cross-species pharmacokinetic comparison from mouse to man of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100. Drug Metabolism and Disposition 2007; 35:460–468.
19. Yu RZ, Geary RS, Flaim JD: Lack of pharmacokinetic interaction of mipomersen sodium (ISIS 301012), a 2’-O-methoxyethyl modified antisense oligonucleotide targeting apolipoprotein B-100 messenger RNA, with simvastatin and ezetimibe. Clinical Pharmacokinetics 2009; 48:39–50.
20. Akdim F, Visser ME, Tribble DL: Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. American Journal of Cardiology 2010; 105:1413–1419.
21. Clarke R, Peden JF, Hopewell JC:Genetic variants associated with Lp(a) lipoprotein level and coronary disease. The New England Journal of Medicine 2009; 361:2518–2528.
22. Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A: Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA The Journal of the American Medical Association 2009; 302:412–423.
23. Nenseter MS, Lindvig HW, UelandT: Lipoprotein(a) levels in coronary heart disease-susceptible and -resistant patients with familial hypercholesterolemia. Atherosclerosis 2011; 216:426–432.
24. Raal FJ, Santos RD, Blom DJ: Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomized, double-blind, placebo-controlled trial. Lancet 2010; 375:998–1006.
25. Visser ME, Wagener G, Baker BF: Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. European Heart Journal 2012; 33:1142–1149.
26. ucm323927.pdf [Internet]. [updated 2012 Oct 18; cited 2013 Nov 9]. Available  from : http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm323927.pdf
27. Taylor S, Grimes P, Lim J, Im S, Lui H. Postinflammatory hyperpigmentation: Journal of Cutaneous Medicine and Surgeryg2009 ;13:183–191.
28. Visser ME, Akdim F, Tribble DL: Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia. J Lipid Res  2010 ; 51:1057–1062.
29. European Medicines Agency - Human medicines - Kynamro [Internet]. [updated 2013 March 21; cited 2013 Nov 8]. Available from:http://www.ema.europa.eu/ ema/index.jsp?curl=pages/medicines/human/medicines/002429/smops/Negative/human_smop_000460.jsp&mid=WC0b01ac058001d127
30. Effect of Mipomersen on LDL-Cholesterol Levels in Patients Treated by Regular Apheresis - View - clinicalTrials.gov [Internet]. [updated 2013 December 2; cited 2013 Nov 10]. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01598948?term=mipomersen&rank=7
31. European approval for lomitapide to treat homozygous Familial Hypercholesterolemia (HoFH) [Internet]. [updated 2013 August 15; cited 2013 Nov 8]. Available from: http://www.pace-cme.org/d/771/european-approval-for-lomitapide-to-treat-homozygous-familial-hypercholesterolemia-hofh
32. Wetterau JR, Lin MC, Jamil H: Microsomal triglyceride transfer protein. Biochimica et Biophysica Act  1997 ;1345:136–150.
33. Raval SK, Raval PS, Jain MR:Emerging therapies for dyslipidemia: known knowns and known unknowns of MTP inhibitors. Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2012 ;6:24–29.
34. Cuchel M, Meagher EA, duToitTheronH: Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381:40–46.
35. Rizzo M: Lomitapide, a microsomal triglyceride transfer protein inhibitor for the treatment of hypercholesterolemia.Investigational Drug   2010; 13:103–111.
36. Rizzo M, Wierzbicki AS: New lipid modulating drugs: the role of microsomal transport protein inhibitors. Current Pharmaceutical Design 2011; 17:943–949.
37. Raal FJ: Lomitapide for homozygous familial hypercholesterolaemia.Lancet  2013 ; 381:7–8.
38. Juxtapid^TM, lomitapide - dru302.pdf [Internet]. [updated 2013 May 16 ;cited 2013 Nov 8]. Available from: http://blue.regence.com/trgmedpol/drugs/dru302.pdf
39. Wetterau JR, Gregg RE, Harrity TW: An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits. Science 1998; 282:751–754.
40. Cuchel M, Bloedon LT, Szapary PO: Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. New England Journal of Medicine 2007; 356:148–156.
41. Sjouke B, Kusters DM, Kastelein JJP, Hovingh GK: Familial hypercholesterolemia: present and future management. Current Cardiology Reports  2011; 13:527–536.
42. Samaha FF, McKenney J, Bloedon LT, Sasiela WJ, Rader DJ:Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nature Clinical Practice Cardiovascular Medicine 2008; 5:497–505.
43. Chandler CE, Wilder DE, Pettini JL: CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans. Journal of Lipid Research 2003; 44:1887–9901.
44. Juxtapid REMS - UCM333438.pdf [Internet]. [cited 2013 Nov 8]. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM333438.pdf
45. FDA Approves Aegerion Pharmaceuticals’ JUXTAPID(TM) (lomitapide) Capsules for Homozygous Familial Hypercholesterolemia (HoFH) –MarketWatch [Internet]. [update 2012 December 24; cited 2013 Nov 8]. Available from: http://www.marketwatch.com/story/fda-approves-aegerion-pharmaceuticals-juxtapidtm-lomitapide-capsules-for-homozygous-familial-hypercholesterolemia-hofh-2012-12-24
46. Joy TR, Hegele RA: Microsomal triglyceride transfer protein inhibition-friend or foe? Nature Clinical Practice Cardiovascular Medicine 2008; 5:506–508.
47. Abstract 1077: A Phase III Study of Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide (AEGR-733) in Patients with Homozygous Familial Hypercholesterolemia: Interim Results at 6 Months -- Cuchel et al. 120 (10018): S441 -- Circulation [Internet]. [cited 2013 Nov 10]. Available from: http://circ.ahajournals.org/cgi/content/meeting_abstract/120/18_MeetingAbstracts/S441-a
48. McGowan MP, Tardif J-C, Ceska R: Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PloSOne 2012; 7:e49006.
49. Abstract/Presentation [Internet]. [updated 2013 October 11; cited 2013 Nov 10]. Available from: http://www.ichg2011.org/cgi-bin/showdetail.pl?absno=21549
50. Akdim F, TribbleDL,Flaim JD: Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. European Heart Journal 2011 ;32:2650–2659.
51. Cromwell WC, Thomas GS, BoltjeI , Chin W, Davidson M : Journal of the American College of Cardiology 2011;57:E504
52. Stein EA, Dufour R, Gagne C: Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation 2012; 126:2283–2292.
53. Akdim F, Stroes ESG, Sijbrands EJG: Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. Journal of the American College of Cardiology 2010; 55:1611-1618.
    

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    How to cite this article:

    Rajaram M, George M and Shanmugam E: Novel therapeutic options for Familial Hypercholesterolemia. Int J Pharm Sci Res2014; 5(8): 3304-11.doi: 10.13040/IJPSR.0975-8232.5(8).3304-11

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