Recent therapeutic approaches for dyslipidaemia

Marwa oraby

April 2014

Dyslipidemia

• is a range of disorders that include both abnormally high and low lipoprotein levels, as well as disorders in the composition of these particles.

• the term is applied to lipid levels for which treatment has proven beneficial

ATP III Treatment Priorities

Reduce LDL-C to goal

Correct other lipid/lipoprotein abnormalities ( TG & HDL- C ) by non HDL-C goals (30 mg/dl higher than LDL-C goals)

Apo B 100 ? For residual CVR

ATP III Update(2004)LDL-C goals (Recommendations)

Modalities of dyslipidaemia management

Non pharmacological ( Therapeutic life style changes )

Pharmacological

Surgical

Therapeutic lifestyle changes

LIFESTYLE INTERVENTIONS

Smoking Cessation

Weight Loss

Improved Diet

Habits

Increased Physical Activity

Smoking Cessation

Advice all patients not to smoke (A)

Initiate cessation counseling (B)

Offer combined pharmacological and behavioral

interventions(B)

Weight Loss

Moderate weight loss (7%body weight) (A)

Reduce caloric intake(1200-1800 Kcal/day) (A)

As a part of weight loss program ;diet and physical activity (A)

Improved dietary habits

Dietary modifications( fat< 30 %, protein < 20% CHO 50-60 % of total calories)

Saturated fat intake should be < 7 % of total calories (A)

Polyunsaturated fat up to 10% total calories

Monounsaturated fat up to 20% total calories

Low cholesterol diet (< 200mg/day)

Minimize intake of trans fat (B)

Increase plant sterol and stanol intake modestly lower LDL-C and serum cholesterol

Dietary Management of Dyslipidemia(ATP III Recommendations)

•

Increased physical activity

Regular physical activity ( 150 min / week ) (A)

“moderate-intensity aerobic exercise“

Resistance training ( 3 times / week ) unless

containdicated (A)

Start gradually and slowly build intensity

Benefits of Exercise

Increased insulin sensitivity

Improved lipid levels (↑HDL-c)

Lower blood pressure

Weight control

Improved blood glucose control

Reduced risk of CVD

Prevent/delay onset of type 2 diabetes

PHARMACOLOGICAL MANAGEMENT

• SURGICAL MODALITIESPartial ileal bypass that eliminates the

reabsorption of bile acids at the distal portion of the ileum has been shown to be a viable treatment in some cases of severe dyslipidemia

Portacaval shunt altering cholesterol hepatic and lipoprotein metabolism

liver transplantation shown to be effective in treating severe hypercholesterolemia in homozygosfamilial hypercholestrolemia.

Novel Therapies for Lipid Management

Therapies for lowering levels of atherogenic

lipoproteins

Blocking Lipoprotein OutputApoB Blockade(anti sense oligonucleotide) (Mipomersen)

MTP Inhibition (Lomitapide)

Increasing Lipoprotein ClearancePCSK9 Inhibitors

LDL apheresis

Therapies for raising levels of anti atherogenic

lipoproteins

Therapies promoting Apo A I productionAutologus Apo A I (IV infusion)

Apo A I mimetic peptidase inhibitors (IV)

Apo A I mimetic peptidase inhibitors oral

Therapies promoting cholesterol efflux and RCT PPAR alpha agonists

PPAR gamma agonists

DUAL PPAR agonists

Therapies slowing removal of HDL from blood CETP Inhibitors

CETP vaccine

Gene therapy for LPL deficeincyGlybera))Alipogene tiparvovec

Therapies for lowering levels of

atherogenic lipoproteins

Blocking Lipoprotein OutputApoB Blockade(anti sense oligonucleotide) (Mipomersen)

MTP Inhibition (Lomitapide)

Increasing Lipoprotein ClearancePCSK9 Inhibitors

LDL apheresis

Blocking Lipoprotein Output

ApoB Blockade (Mipomersen)

(Anti sense oligonucleotides)

Mipomersen sodium (Kynamro) Approved January 30, 2013

Antisense oligonucleotide that decreases secretion of apo B containing lipoproteins from the liver by decreasing the number of specific mRNA available for translation of the encoded protein in the hepatic synthesis of apoB 100

Approved to reduce LDL‐C, apo B, TC, non‐HDL‐C in patients with homozygous familial hypercholesterolemia (HoFH)

Dosing: 200 mg once weekly subcutaneous injection .

Adverse effects:

injection site reactions (84%),

flu‐like symptoms (30%),

elevated hepatic transaminases

MTP Inhibition Lomitapide (Juxtapid)VLDL assembly as target of therapy

MTP Inhibition Lomitapide (Juxtapid) Approved December 24, 2012

MTP inhibitor decreases lipoprotein production

Microsomal Triglyceride Transfer Protein (MTP)

is responsible for transferring triglycerides onto apolipoprotein B within the liver in the assembly of (VLDL), the precursor to LDL.

In the absence of functional microsomal triglyceride transfer protein, as in the rare recessive genetic disorder abetalipoproteinemia, the liver cannot secrete VLDL, leading to the absence of all lipoproteins containing apolipoprotein B in the plasma.

used to reduce LDL‐C, TC, apo B, non‐HDL‐C in homozygous familial hypercholesterolemia (HoFM)

Dosing: capsules 5 & 10 mg daily titrated to a maximum of 60 mg daily

Adverse effects:

hepatic steatosis,

elevated hepatic transaminases;

GI adverse reactions (93%)

decreased absorption of vitamin E, ALA, linoleic acid, EPA, DHA (supplement recommended)

Increasing Lipoprotein Clearance

PCSK9 INHIBITOR (evolocumab) • Function of LDL receptor and life cycle

The role of PCSK9 in the regulation of LDL receptor expression

PCSK9 INHIBITOR (evolocumab) the gene PCSK9 proprotein convertase subtilisin/kexin

type 9 , serine protease mainly expressed in the liver and the intestine which regulates the levels of the LDL receptor in the liver.

It acts by reducing the amount of LDL-R in hepatocytes by 2 ways;

- Circulating PCSK9 binds the LDL-R on the cell surface and is co-internalised with the LDL-R promoting the degradation of the receptor in the lysozyme.

- Intracellularly, it can also bind to the LDL-R increasing its degradation rather than recycling to the plasma membrane

• LAPLACE-2 is a large phase III study of PCSK9 INHIBITOR (evolocumab)

The monoclonal antibody evolocumab produced highly significant reductions in low-density lipoprotein (LDL) cholesterol, the "bad cholesterol," as an add-on to statins in all treatment groups,

Evolocumab was well tolerated, with adverse event rates similar to those in placebo and ezetimibe-treated groups and no sign of liver damage or muscle problems.

• The ongoing FOURIER trial will assess whether additional lowering of LDL cholesterol with evolocumab, on top of high and moderate-intensity statin therapy, reduces the number of cardiovascular events over a period of years.

LDL apheresis

LDL apheresis• type of 'extracorporeal' procedure to remove low-

density lipoprotein (LDL) cholesterol from the blood

• removes the LDL cholesterol , lipoprotein (a) and triglycerides but has only a small effect on high-density lipoprotein (HDL).

• two needles (catheters) ,permanent catheters in the chest or formation of a shunt in the arm

• lower LDL level by 50 to 65 % after a single treatment.

• either every week or every two weeks

• Indications

refractory forms of homozygous familial hypercholesterolaemia (FH)

preventing the progression of coronary artery disease in heterozygotes and others with severe dyslipidaemia who are refractory to or intolerant of high doses of lipid-lowering drugs , despite the maximum amount of drug treatment and a cholesterol lowering diet

Extracorporeal methods for elimination of LDL cholesterol

1) Plasmapheresis

2) Cascade filtration

3) Immunoadsorption

4) Heparin-induced LDL precipitation (HELP)

5) Dextran sulfate LDL adsorption (liposorber-LA 15)

6) LDL hemoperfusion the direct adsorption oflipoproteins (DALI)

Side effects of LDL apheresis

•

Therapies for raising levels of anti-

atherogenic lipoproteins

Therapies for raising levels of anti

atherogenic lipoproteins

Therapies promoting Apo A1 productionAutologus Apo A1 (IV infusion)

Apo A1 mimetic peptidase inhibitors (IV)

Apo A1 mimetic peptidase inhibitors oral

Therapies promoting cholesterol efflux and RCT PPAR alpha agonistsPPAR gamma agonistsDUAL PPAR agonists

Therapies slowing removal of HDL from bloodCETP InhibitorsCETP vaccine

Therapies promoting Apo A1 production

Autologus Apo A1 (IV infusion)

Apo A1 mimetic peptidase inhibitors (IV)

Apo A1 mimetic peptidase inhibitors oral

Autologus Apo A1 (IV infusion)

• pateint’s own Apo A1

• Apo A1 is more effective at promoting cholesterol efflux from macrophages than mature HDL

• Selectively delipidate HDL in whole plasma ex vivo generating lipid poor Apo A1 then reinfused

• Promote cholesterol efflux and RCT thus slowing or regressing atherogenesis

Autologus Apo A I (IV infusion)

• Acute effects of bolus iv infusion of Apo A I in humans

• 5 weekly infusions of recombinant Apo A Imilano

• Resulted in a significant reduction of coronary atheroma volume as measured by IVUS.

rHDL (CSL-111)• CSL-111 is an apolipoprotein A-I isolated from human plasma and

phosphatidylcholine derived from soybean at 1:150 mol/mol

• Effect of rHDL (CSL-111) on Atherosclerosis Safety and Efficacy (ERASE) trial.

• patients needing coronary angiography were given infusions of reconstituted HDL cholesterol isolated from human plasma as 4 weekly infusions at 2 different strengths or placebo.

• Use of the high-dose infusion was discontinued early in the trial after biochemical and laboratory liver test abnormalities were detected, and these patients were moved into the low-dose infusion or placebo groups.

• At the end of the study, no significant differences in coronary atheroma volume were found between the groups. Those receiving the CLS-111 infusions also had significant changes in plaque characterization index.

Apo A I mimetic peptidase inhibitors

(IV)

• small synthetic peptides having properties similar to Apo A I including promotion of cellular cholesterol efflux

• Injection of Apo A I mimetic peptide (L-5F) into mice significantly reduced the progression of atherosclerosis

• ETC-642 (RLT peptides) in early trials .

• Parenteral administration is a logistical barrier to long term administration so in the clinical trials as “ acute induction therapy” for rapid plaque regression or stabilization in patients with ACS

Apo A I mimetic peptidase inhibitors

oral

• D-4F : oral Apo A I mimetic peptide

• Not recognized by gut peptidases so not degraded

• Showed dramatic reduction of atherosclerosis in mice

• Promoted macrophage RCT in vivo in mice

RVX-208 ( Resverlogix)• a novel small molecule that increases production

of ApoA-1, taken orally which raises HDL levels and is thought to enhance reverse cholesterol transport

• the ASSURE (phase 2b multicenter, double-blind, randomized, parallel group, placebo-controlled trial ) had failed to meet its primary endpoint.

• the trial did meet the secondary endpoints of regression of total (coronary) atheroma volume (TAV) and increases in Apolipoprotein A-I (ApoA-I) and HDL cholesterol The company said that results in the placebo arm of the study were stronger than expected.

Therapies promoting cholesterol

efflux and RCT

PPAR alpha agonists

PPAR gamma agonists

DUAL PPAR agonists

• macrophage cholesterol efflux involves the ABCA1 transporter promoting efflux to Apo A1

• Over expression of ABCA1 in mice leads to significant increase in HDL-C levels associated with significant reduction in atherosclerosis

• The major regulator of ABCA1 gene expression is the nuclear receptor liver X receptor (LXR) and retinoid X receptor (RXR)

Pleiotropic actions of balanced PPAR-α/γ agonists. FA = fatty acids; FFA = free fatty acids. Adapted from Fiévet et al, Balakumar et al, and Charbonnel

PPAR alpha agonists• Clofibrate ,Fenofibrate, Bezafibrate, Gemfibrozil

• PPAR-α is metabolically active in the liver, heart, kidney, skeletal muscle and brown fat.

• It is also present in all vascular cells, including endothelial cells, smooth muscle cells and monocytes/macrophages.

• The effects of PPAR-α include hypolipidemic action,an anti-inflammatory effect on the vascular wall and metabolic effects on the myocardium

• clinical trials of fibrates have demonstrated their beneficial effects on cardiovascular clinical outcomes, particularly in patients suffering with metabolic syndrome and diabetes.

• Treatment of macrophages in vitro with fibrates led to upregulation of ABCA1 and increased cholesterol efflux

selective PPAR-α agonist, LY518674

• (LY5) is similar to fenofibrate but pproximately10 000 times more potent.

• LY518674 and fenofibrate demonstrated evidence of increasing the serum creatinine levels; this effect was substantial in some cases.

• The novel PPAR-α agonist was not better than fenofibrate or statin monotherapy in achieving the intended improvement of the lipid profile, and it appeared to worsen renal function.

PPAR γ agonists

• macrophages also express PPAR - gamma

• Thiazolidendiones (TZDs) , agonists of PPAR –gamma promote macrophage cholesterol efflux in vitro

• Potentially also through up regulation of LXR , ABCA1 expression

• Troglitazone (Glaxo Smith Kline) Withdrawn from Market.

• Rosiglitazone ,Pioglitazone

PPAR α and γ agonist (Dual PPAR agonists)

• targeting both PPAR- alpha and PPAR- gamma promoting more macrophage cholesterol efflux

• Muraglitazar (Bristol Mayer, Merck) first developed , but data analysis suggested incraesedincidence of adverse CV events

• Naveglitazar increased risk of bladder cancer

• Tesaglitazar has risk of renal dysfunction

• Aleglitazar the latest and most promising , SYNCHRONY study showed decreased LDL , decreased glucose and incrased HDL.

Therapies slowing removal of HDL from

blood

CETP Inhibitors

CETP Vaccine

CETP inhibitors

• Cholesterol ester transport protein responsible for theexchange of cholesterol for TG in mature HDL to bechanged into LDL and VLDL

cholesteryl ester transfer protein (CETP) inhibitor

dalcetrapib, torcetrapib• Torcetrapib (from Pfizer) not only failed to show

a reduction in risk when HDL was increased, but actually showed an increase in cardiovascular risk.

• Dalcetrapib ( from Roche) was halted in May 2012 for lack of effectiveness.

• Both of these related drugs significantly increased HDL levels, but doing so did not result in any demonstrated clinical benefit.

evacetrapib &Anacetrapib

• cholesteryl ester transfer protein (CETP) inhibitor

• Produce dose-dependent increases in HDL-C

• When administered in combination with statin therapy, evacetrapib, increased HDL-C levels and resulted in greater reductions in LDL-C and non-HDL-C

• Both evacetrapib and anacetrapib give a more dramatic HDL elevation, and a sizeable LDL reduction .

CETP vaccine

• novel strategy using CETP based peptide for IMMUNIZATION to raise inhibiting auto antibodies against CETP ( anti CETP antibodies)

• Single injection of the CETP peptide can develop anti CETP antibodies

• Second injection of the active vaccine develop significant levels of anti CETP antibodies

• Interesting approach with the advantage of avoiding the need to take a daily pill

Gene therapy

Gene therapy• The adeno-associated virus serotype 1 (AAV1)

viral vector delivers an intact copy of the human lipoprotein lipase (LPL) gene

• In two Phase II/III clinical trials, LPLD patients received a series of injections into the thigh muscle, followed by several weeks of immunosuppressive drugs to blunt immune responses to the viral capsids

• fat concentrations in blood were reduced between 3 and 12 weeks after injection(IM) , in nearly all patients

• advantages of AAV include

lack of pathogenicity,

delivery to non-dividing cells,

non-integrating in contrast to retroviruses, which show random insertion with risk of cancer

very low immunogenicity, mainly restricted to generating neutralizing antibodies, and little well defined cytotoxic response.

Glybera))Alipogene tiparvovec

• 2012 became the first gene therapy treatment to be approved for clinical use in either EUROPE or the United States after its endorsement by the European Commission, as a treatment for a disease caused by a defect in a single gene, lipoprotein lipase.