Sunday, May 3, 2015

Lomitapide | Treatment of Familial Hypercholesterolemia | Microsomal Triglyceride Transfer Protein Inhibitor | MTP Inhibitor | Cholesterol Lowering Drug

Lomitapide [N-(2,2,2-Trifluoroethyl)-9-[4-[4-[[[4'-(trifluoromethyl)[1,1'-biphenyl]2-yl]carbonyl]amino]-1-piperidinyl]butyl]9H-fluoren-9-carboxamide] is an orally available small molecule microsomal triglyceride transfer protein (MTP) inhibitor, for the treatment of hypercholesterolemia, both familial and primary. Microsomal triglyceride transfer protein inhibitors have a dual mechanism to reduce both low-density lipoprotein (LDL) and triglyceride levels. Lomitapide is beneficial to patients resistant to HMG-CoA reductase inhibitors (statins) either due to abnormalities in liver function or to discontinuation because of muscle pain.

Lomitapide, an orally administered inhibitor of the microsomal triglyceride transfer protein (MTP or MTTP), inhibits the synthesis of chylomicrons and very low-density lipoprotein, thereby reducing plasma levels of low-density lipoprotein cholesterol (LDL-C). Lomitapide is used to lower lipid levels in adults with homozygous familial hypercholesterolemia, a rare, potentially life-threatening genetic disease that is commonly caused by mutations in the LDL receptor gene or other genes that affect the function of the LDL receptor.

Lomitapide: 2D and 3D Structure

Bristol-Myers Squibb donated the compound (BMS-201038) to the University Pennsylvania School Of Medicine. After a successful study in familial hypercholesterolemia, the University licensed the drug candidate to Aegerion. Aegerion Pharmaceuticals has a cross-license agreement with Pfizer and the University of Pennsylvania to develop microsomal triglyceride transfer protein (MTP) inhibitors to reduce levels of LDL cholesterol in men and women.

What is Familial Hypercholesterolemia?

Homozygous familial hypercholesterolemia (FH) is a serious life-threatening genetic disease. Total plasma cholesterol levels are generally over 500 mg/dl and markedly premature cardiovascular disease is the major consequence. Untreated, most patients develop atherosclerosis before age 20 and generally do not survive past age 30. The primary goal of therapy involves reducing cholesterol (specifically, LDL cholesterol) and preventing coronary artery disease. Unfortunately, patients with homozygous FH are minimally responsive or unresponsive to available drug therapy and thus there are limited treatment options. The current standard of care is LDL apheresis, a physical method of removing the plasma of LDL cholesterol which can transiently reduce cholesterol by more than 50%. However, there is rapid re-accumulation of LDL cholesterol in plasma, and therefore apheresis has to be repeated frequently (every 1-2 weeks) and requires 2 separate sites for IV access. Although anecdotally this procedure may delay the onset of atherosclerosis, it is laborious, expensive, and not readily available. Furthermore, although it is a procedure that is generally well tolerated, the fact that it needs frequent repetition and IV access can be challenging for many of these young patients. Therefore, there is a tremendous unmet medical need for new medical therapies for this orphan disease.
In a multinational single-arm, open-label, 78-week, Phase III trial, Lomitapide reduced mean plasma LDL-C levels by 50 % from baseline in 23 evaluable adults with homozygous familial hypercholesterolemia over a 26 week treatment period. Reductions from baseline in LDL-C levels were sustained for up to 78 weeks with continued Lomitapide treatment. In this study, the initial dosage of Lomitapide was 5 mg once daily for two weeks, with upward titration thereafter to 10, 20, 40, and 60 mg at weeks 2, 6, 10, and 14, respectively, or until an individually assessed maximum dosage was achieved. Prior to the start of treatment with lomitapide, other lipid-lowering therapy (including LDL apheresis) was stabilized over a 6-week period, and then continued throughout the lomitapide treatment phase. Lomitapide was generally well tolerated; the most common adverse events in the phase III trial were gastrointestinal events [1,2].

Lomitapide inhibit’s MTP
In vitro, Lomitapide inhibited MTP with an IC50 value of 8 nM in the MTP triglyceride transfer assay and inhibited apoB secretion in HepG2 cells with an IC50 value of 0.8 nM. In hamsters and monkeys, oral administration of Lomitapide lowered plasma total cholesterol with ED50 values of 2.3 mg/kg and 2.0 mg/kg, respectively.

Approval and Dosages

Lomitapide (Trademark: Juxtapid in the US and Lojuxta in the EU) is once a daily approved drug for the treatment of familial hypercholesterolemia. Lomitapide was approved by the US Food and Drug Administration (FDA) on 21 December 2012, as an orphan drug to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and non-high-density lipoprotein (non-HDL) cholesterol in patients with homozygous familial hypercholesterolemia (HoFH). On 31 July 2013 the European Commission approved Lomitapide as an adjunct to a low-fat diet and other lipid-lowering medicinal products with or without low density lipoprotein (LDL) apheresis in adult patients with HoFH.

The recommended initial dosage of lomitapide is 5 mg once daily, with subsequent upward dose (upto 60 mg) adjustment at specified intervals according to tolerability. Specifically, the dosage may be increased to 10 mg after at least two weeks and up to 20 mg, 40 mg, and the maximum dose of 60 mg with a minimum of four weeks between dosage adjustments.
Common name: Lomitapide; AEGR 733; AEGR-733; BMS 201038; BMS-201038; Juxtapid; Lojuxta; Lomitapide Mesylate
Trademarks: Juxtapid; Lojuxta
Molecular Formula: C39H37F6N3O2
CAS Registry Number: 182431-12-5; 202914-84-9 (Mesylate)
CAS Name: N-(2,2,2-trifluoroethyl)-9-[4-(4-{2-[4-(trifluoromethyl)phenyl]benzamido}piperidin-1-yl)butyl]-9H-fluorene-9-carboxamide
Molecular Weight: 693.720
InChI: InChI=1S/C39H37F6N3O2/c40-38(41,42)25-46-36(50)37(33-13-5-3-10-30(33)31-11-4-6-14-34(31)37)21-7-8-22-48-23-19-28(20-24-48)47-35(49)32-12-2-1-9-29(32)26-15-17-27(18-16-26)39(43,44)45/h1-6,9-18,28H,7-8,19-25H2,(H,46,50)(H,47,49)
Activity: Treatment of Familial Hypercholesterolemia; Microsomal Triglyceride Transfer Protein Inhibitor; MTP Inhibitor; Cholesterol Lowering Drug; Hypolipidemic Agents
Status: Launched 2012 (US); 2013 (EU)
Originator: Aegerion Pharmaceuticals Inc

The activity of Lomitapide is as follows:

IC50 (MTP triglyceride transfer assay) = 8 nM
IC50 (Inhibibiton of apoB secretion in HepG2 cells) = 0.8 nM

Lomitapide as Chemical Compound: 
Lomitapide chemically belongs to the class of organic compounds known as fluorenes. These are compounds containing a fluorene moiety, which consists of two benzene rings connected through either a cyclopentane, cyclopentene, or cyclopenta-1,3-diene. Other important chemical classifications are: 
1. Piperidine derivatives
2. Organofluorine compounds
3. Benzamides
4. Fluorenes derivatives
5. Alkyl fluoride
6. Alkyl halide
7. Amide Linkage
8. Trifluoro derivatives

Lomitapide Synthesis

US5739135A: It is reported as the industrial route. For easy viewing the synthesis is broken into steps.
Step 1: Intermediate synthesis

Step 2: Final synthesis


1H NMR (Estimated) for Lomitapide

Sideffects: The most commonly reported adverse events (over 90%) were gastrointestinal (GI) (reflux, indigestion, abdominal pain, constipation, and diarrhea), and appeared to improve with dose titration. Diarrhea, nausea, dyspepsia and vomiting were reported in over 30% of the patients, while pain, discomfort and bloating of the abdomen, constipation and flatulence were observed less frequently (± 20%). Elevated liver aminotransferase levels are a serious side effect reported in 10 out of 29 patients in a phase 3 trial.
Increased GI adverse effects are seen when lomitapide is administered with high-fat meals, the medication should be swallowed whole and taken with water, without food, and at least two hours after the evening meal. Due to reductions in absorption of fat-soluble vitamins and fatty acids caused by lomitapide, it is recommended that patients take daily vitamin E, linoleic acid, α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid supplements.
The frequency and severity of these adverse reactions are reduced when patients are on a low fat diet. The inhibition of VLDL-mediated triglyceride secretion can lead to hepatic accumulation of triglycerides [4].
1. Perry, C. M. Lomitapide: a review of its use in adults with homozygous familial hypercholesterolemia. Am J Cardiovasc Drugs 2013, 13(4), 285-296.
2. Goulooze, S. C.; et. al. Lomitapide. Br J Clin Pharmacol 2015 doi: 10.1111/bcp.12612
3. Biller, S. A.; et. al. Inhibitors of microsomal triglyceride transfer protein and method. US5739135A
4. Rader, D. J.; et. al. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation 2014, 129(9), 1022-1032.