UNIVERSITA DI PISA CHIMICA E TECNOLOGIE FARMACEUTICHE FAMILIAL HYPERCHOLESTEROLEMIA DIPARTIMENTO DI FARMACIA GENETIC CAUSES AND THERAPY

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1 UNIVERSITA DI PISA DIPARTIMENTO DI FARMACIA CHIMICA E TECNOLOGIE FARMACEUTICHE CORSO DI BASI BIOCHIMICHE DELL AZIONE DEI FARMACI FAMILIAL HYPERCHOLESTEROLEMIA GENETIC CAUSES AND THERAPY ERIKA ROSARIA PACCIOLLA Pisa, 18/11/2014

Familial hypercholesterolemia (FH) is characterized by raised serum LDL cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and

2 Familial hypercholesterolemia (FH) is characterized by raised serum LDL cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease. Figura 1 Procedure for identifying and treating patients with familial hypercholesterolemia in clinical practice Dtsch Arztebl Int. Aug 2014;111(31 32): Published online Aug 4, 2014

3 FH IS PRIMARILY AN AUTOSOMAL DOMINANT DISORDER. Depending on the genetic mutation, patients can be identified as having either heterozygous(hefh) or homozygous FH(HoFH). The frequency of heterozygous FH in most populations is about 1/500, so homozygous FH is rare (1/10 6 ) in European populations. Figure 2 Dominant pattern of inheritance of familial hypercholesterolemia due to mutations in the LDL-receptor gene (LDLR ). Soutar AK and Naoumova RP (2007) Mechanisms of Disease: genetic causes of familial hypercholesterolemia Nat Clin Pract Cardiovasc Med 4:

4 GENETIC CAUSES OF THE FH PHENOTYPE 1. Mutations in LDLR; 2. Familial ligand-defective apolipoprotein B; 3. Mutations in PCSK9. 1. The LDL receptor is a cell-surface glycoprotein that is synthesized as an immature protein in ER and processed in the Golgi apparatus, producing the mature form that is transported to the cell surface. Its pathway maintains intracellular cholesterol homeostasis. Soutar AK and Naoumova RP (2007) Mechanisms of Disease: genetic causes of familial hypercholesterolemia Nat Clin Pract Cardiovasc Med 4:

5 Figure 3 The LDL-receptor pathway for uptake and degradation of LDL Soutar AK and Naoumova RP (2007) Mechanisms of Disease: genetic causes of familial hypercholesterolemia Nat Clin Pract Cardiovasc Med 4:

6 LDL-RECEPTOR Brown and Goldstein purified the LDL-receptor protein and raised specific anti-ldl-receptor antibodies that allowed them to confirm that multiple mutations cause FH. They classified the cellular defects of LDL-receptor function into five groups: 1) ligand-binding defective; 2) transport defective; 3) internalization defective; 4) recycling defective; 5) 'null', which resulted in no detectable protein. Ann. Ist. Super. Sanità. Vol.35 n.2 (1999). pp Fig 4 LDL receptor

2. Familial ligand-defective apolipoprotein B The most common mutation in FDB is an adenine for guanine substitution in complementary DNA of exon 26 of apo B gene.

7 2. Familial ligand-defective apolipoprotein B The most common mutation in FDB is an adenine for guanine substitution in complementary DNA of exon 26 of apo B gene. Often it results in an Arginine for Glutamine change in the 3500 amino acid position of the protein, but also other two mutations (Arg3500Trp and Arg3531Cys) are responsible for the disease by reducing the binding of LDL particles to the LDLR. Figure 5 Lipoprotein(a) and coronary disease moving closer to causality. Danesh J. and Erqou S. (2009) Nat Rev Cardiol Influence of LDL receptor gene mutations and the R3500Q mutation of the apob gene on lipoprotein phenotype of familial hypercholesterolemic patients. 24 September 2003 European Journal of Human Genetics (2003) 11,

3. PCSK9 (rare cause of FH) is a sterol-regulated gene (indicating involvement in cholesterol metabolism) that encodes a putative protease named proprotein convertase subtilisin/kexin type 9.

8 3. PCSK9 (rare cause of FH) is a sterol-regulated gene (indicating involvement in cholesterol metabolism) that encodes a putative protease named proprotein convertase subtilisin/kexin type 9. Under normal circumstances, the pro-protein convertase, PCSK9, normally reduces hepatic LDL receptor activity. Figure 6 LDL-cholesterol metabolism in the presence of PCSK9 Nature Reviews Cardiology 11, (2014) Published online 24 June 2014 Mechanisms of Disease: genetic causes of familial hypercholesterolemia Anne K Soutar* and Rossi P Naoumova 20 December 2006 Nature Clinical Practice Cardiovascular Medicine (2007) 4,

9 STANDARD THERAPIES Statins competitively inhibit the enzyme HMG-CoA reductase; Figura 7 The mevalonate cycle and statin interaction But also regulate post-translational modification (prenylation) of a large variety of proteins, including the GTP-binding proteins Ras, Rho and Rac that have specific roles in cell motility, shape, proliferation, differentiation and survival. Drug Insight: immunomodulatory effects of statins potential benefits for renal patients? Nature Clinical Practice Nephrology (2006) 2, March 2006

Figura 8 Pleiotropic Effects of statins Inhibiting the RhoA signal transduction pathway using statins activates receptors PPARs, that are involved in the control of vascular inflammation related to

10 Figura 8 Pleiotropic Effects of statins Inhibiting the RhoA signal transduction pathway using statins activates receptors PPARs, that are involved in the control of vascular inflammation related to atherosclerosis and exert anti-inflammatory effects by preventing the binding of transcription factor NFkB (in vsmcs and monocytes) to its DNA target sequence. It has a central role in inflammation, regulating genes encoding pro-inflammatory cytokines, adhesion molecules and chemokines. Drug Insight: immunomodulatory effects of statins potential benefits for renal patients? Nature Clinical Practice Nephrology (2006) 2, March 2006

11 Drug Insight: immunomodulatory effects of statins potential benefits for renal patients? Nature Clinical Practice Nephrology (2006) 2, March 2006 PLEIOTROPIC EFFECTS indicate that the therapeutic potential of statins might extend beyond cholesterol lowering and cardiovascular disease to other inflammatory conditions such as transplantation, multiple sclerosis and rheumatoid arthritis. enos NO 1. IMPROVMENT OF ENDOTHELIAL FUNCTION endothelin-1 AT2 vsmcs proliferation 2. ANTI-INFLAMMATORY ACTIVITY IFNγ C-reactive protein chemokines (IL-8) IL-6 and IL-1 TNF MMPs 3. IMMUNOMODULATORY ACTIVITY TGFβ T helper 1, T helper 2 4. APOPTOSYS Involvment of RhoA (caspase 3-9)

12 Adverse Effects of Statins - Myths and Reality The most common adverse effects of statins are: 1. Muscular symptoms; 2. Rhabdomyolysis; 3. Increased liver enzyme activities; 4. Higher incidence of diabetes mellitus; 5. Side effects due to interaction with other drugs. Several studies have indicated a possible benefit of statins in patients with different types of cancer or a protective effect of these drugs on renal dysfunction. Early concerns about cognitive dysfunction and memory loss associated with statins use could not be proven and most recent data even suggest a possible beneficial effect of statins in the prevention of dementia. Adverse Effects of Statins - Myths and Reality. Curr Pharm Des Oct 13

13 o Ezetimibe o Fibrates o Ac. Nicotinic o Bile-acid sequestrants selectively inhibits absorption of cholesterol at the brush border membrane in the intestinal lumen. Interruption of cholesterol absorption stimulates LDL-receptor expression in the liver and thereby increases LDL clearance from the circulation; activation of the nuclear transcription factor PPARα, controlling lipid and glucose metabolism; to inhibit the secretion of apo B-containing lipoproteins by the liver; sequester bile acids in the intestine and interrupt their enterohepatic circulation. This enhances conversion of cholesterol into bile acids, reduces hepatic cholesterol content, and thereby enhances synthesis of LDL receptor; o Omega-3 fatty acid decrease LDL cholesterol when the saturated fatty acid content decrease or when they are used at high doses. Kidney International, Vol. 37 (1990), pp

14 Several novel therapies are in development.. Mipomersen (Approved by FDA, not by EMA) Antisense drugs Orphan drug an antisense oligonucleotide inhibitor of apo B100 synthesis, as an orphan drug for the management of HoFH strands of nucleic acid, such as DNA, designed to bind and inactivate the RNA produced by a given gene granted for therapies that are used to manage rare diseases, such as HoFH, which affects fewer than 200,000 people in the U.S. Mipomersen is indicated as an adjunct therapy to lipid-lowering agents.the suggested (only) SC dose is 200 mg once weekly. Mipomersen (Kynamro) A Novel Antisense Oligonucleotide Inhibitor for the Management of Homozygous Familial Hypercholesterolemia

15 MECHANISM OF ACTION Figura 9 Mechanism of action of Mipomersen Mipomersen, an Apolipoprotein B Synthesis Inhibitor, Reduces Atherogenic Lipoproteins in Patients With Severe Hypercholesterolemia at High Cardiovascular Risk. December 2013

Lomitapide (Approved by FDA and EMA) inhibitor of microsomal triglyceride transfer protein (MTP) that is indicated as an adjunct to a low-fat diet and other lipidlowering treatments.

16 Lomitapide (Approved by FDA and EMA) inhibitor of microsomal triglyceride transfer protein (MTP) that is indicated as an adjunct to a low-fat diet and other lipidlowering treatments. MTP antagonists dramatically lower LDL-cholesterol (LDL-C) in animals. The suggested dose of Lomitapide is at first 5 mg by mouth daily and increase based on safety and tolerability to a maximum of 60 mg daily. Lomitapide for the management of homozygous familial hypercholesterolemia. degoma EM Rev Cardiovasc Med. 2014;15(2):

MECHANISM OF ACTION MTP is involved in the accumulation of fats in lipoproteins, in particular it plays a critical role in the assembly and secretion of very-low-density lipoproteins (VLDL), and its

17 MECHANISM OF ACTION MTP is involved in the accumulation of fats in lipoproteins, in particular it plays a critical role in the assembly and secretion of very-low-density lipoproteins (VLDL), and its absence leads to apo B deficiency. Figura 10 Mechanism of action of Lomitapide Nature Reviews Cardiology 8, (May 2011) Microsomal transfer protein (MTP) inhibition-a novel approach to the treatment of homozygous hypercholesterolemia 2014 Nov; 46(7): pub 2014/06/02

18 Differences Mipomersen VS Lomitapide Apo B-100 is specific to the hepatocytes, so side effects associated with blocking Apo B in enterocytes (seen with lomitapide) are not seen with mipomersen use; Side effects associated with the route of administration. Analogies The risks of transaminase elevations, hepatic steatosis, and the potential for drug interactions; High costs. New Therapies: Homozygous Familial Hypercholesterolemia Jenna M. Siskey, PharmD, BCPS, and Zachariah M. Deyo, PharmD, BCPS, CPP. Pharmacy Times. Tuesday, January 14, 2014

19 PCSK9 inhibitors (Not yet approved by FDA) human monoclonal antibodies against PCSK9, now in late-stage clinical development. The inhibition of PCSK9 favors LDL catabolism and reduces plasma LDLC levels. Figura 11 LDL-cholesterol metabolism in the presence or absence of PCSK9 Nature Reviews Cardiology 11, (2014) Published online 24 June 2014 [PCSK9 inhibitors and dyslipidemias: an update on clinical evidence] G Ital Cardiol (Rome).2014 May;15(5):301-5.

Juxtapid. Juxtapid (lomitapide) Description

Juxtapid. Juxtapid (lomitapide) Description Federal Employee Program 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 Subject: Juxtapid Page: 1 of 6 Last Review Date: September 20, 2018 Juxtapid Description Juxtapid (lomitapide)