15-18 2013

.
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DECLARATION OF INTEREST

NO INTEREST

 &

Mipomersen
(previously ISIS 301012, trade name Kynamro)

Is a cholesterol-reducing drug
It is an antisense oligonucleotide inhibitor of apoB100

Crosses the hepatocyte & nuclear membranes that

targets the m-RNA for apoB100 apolipoprotein B

Is significally distributed to liver where apoB100 is

synthesised

PLoS One. 2012;7(11):e49006 Epub 2012 Nov

Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy McGowan MP, Tardif JC, Ceska R, Burgess LJ, Soran H, Gouni-Berthold I, Wagener G, ChasanTaber S.

PLoS One. 2012; 7(11. Published online 2012 November

PLoS One. 2012; 7(11): e49006. Published online 2012 November

36%

PLoS One. 2012; 7(11): e49006. Published online 2012 November

PLoS One. 2012

PLoS One. 2012

Kynamro (mipomersen) Now FDA Approved - January 29, 2013

PCSK-9 inhibitors
(proprotein convertase subtilin/kexin 9)

PCSK-9 blinds to LDL-Receptors leading to

their accelerated degradation

Increase LDLc levels

The PCSK-9 inhibitors decrease the LDL-Rs
degradation

Effect of a monoclonal antibody to PCSK-9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial
Prof, Dr Evan A Stein, MD, et al

LANCET July 2012, Pages 2936

 Multicentre, randomised, placebo-controlled phase 2 trial done at 16 lipid clinics in the USA and Canada (Jan 18, 2011& Nov 7, 2011) Adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 26 mmol/L or higher on stable diet and statin dose, with or without ezetimibe Pts were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg / 4 weeks, or 150 mg/ 2 weeks, or placebo / 2 weeks (ratio 1:1:1:1:1) Randomisation was stratified by concomitant use of ezetimibe at baseline Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing The primary endpoint was mean % in LDL-C from baseline at week 12 Was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group

LANCET July 2012,

Mean % change in baseline LDL-C (A) & ApoB (B) vs week during treatment & follow-up period. Data are mean % LDL-C & ApoB

MTP inhibitors

MTP (Microsomal triglyceride transfer protein )

mediates TGs absorption & chylomicron secretion from the intestine & VLDL secretion from the liver by linking lipid molecules with apolipoprotein B (apoB) including LDL

Phase 3 study of lomitapide (AEGR-733) to lower LDL-c for the treatment of pts with (HoFH )
November 16, 2009 Aegerion Pharmaceuticals

22 pts enrolled in the ongoing Phase 3 trial 14 of the pts for a min of 26 & 7 pts for 56 weeks Pts are titrated >to a max tolerated dose of lomitapide (up to 60 mg/day) The 14 pts treated with lomitapide for 26 weeks experienced a mean reduction in LDL-C of 49% on top of maximum tolerated background therapy. Average baseline LDL-C levels in this trial were 351 mg/dl &6 of the 14 patients achieved an LDL-C level below 100 mg/dl At 26 weeks, pts experienced a modest in hepatic fat from 1.0% to 7.8% All pts that have reached 56 weeks have seen their hepatic fat levels 7% at 56 weeks Mild -moderate gastrointestinal adverse events have been the most commonly reported side effect 2 of the 14 pts experienced transaminase which required a dose None of the ps required drug discontinuation due to liver function test elevations

 Lomitapide (INN, marketed as Juxtapid) is a

drug for the treatment of HoFH

It has been tested in clinical trials as single

treatment and in combinations with atorvastatin, ezetimibe & fenofibrate

The US Food and Drug Administration (FDA)

approved lomitapide on 21 December 2012, as an orphan drug to reduce LDL-C, total cholesterol, apolipoprotein B, & non-HDL-C in patients with (HoFH)

HPS2-THRIVE: Treatment of HDL to Reduce the Incidence of Vascular Events

25,673 high-risk pts with occlusive arterial disease from China, Scandinavia and UK
Randomized comparison: ER niacin/laropiprant (ERN/LRPT) 2g daily versus placebo

Primary end point: Major vascular events after median follow-up of 4 years
Pre-specified safety analyses: Median follow-up of 3.4 years (to January 2012) Background LDL-lowering therapy with: Simvastatin 40mg (+/- ezetimibe 10mg)/daily

Lipid levels by region: effect of 8 weeks ERN/LRPT during pre-randomization run-in

N
LDL cholesterol mmol/L Baseline Mean (SD) Change Absolute

China
Europe All

10932
14741 25673

1.51 (0.41)
1.74 (0.43) 1.64 (0.44) 1.06 (0.24)

-0.32
-0.36 -0.34 +0.15

-20%

HDL cholesterol mmol/L China 10932

Europe All 14741 25673

1.19 (0.31) 1.14 (0.29)

+0.20 +0.18

+17%

HPS2-THRIVE

20-12-12 H Merck - - ( ) Tredaptive

LIPOTEST
(75 g 25 g 10 g ) 4

FTT 89 180 mg/dl

FTT 220 mg/dl
Consensus Athens Feb. 2010

Risk of DM development during statin treatment

Recent meta-analyses have identified a slightly increased risk of development of DM in pts treated with statins.

Meta-analysis of 13 statin trials (n=91,140), 9% increase in incident DM during 4 yrs follow-up in pts receiving a statin versus placebo or standard care. In absolute terms, this equates to one additional case of
However, clinicians need to bear in mind that this absolute risk is low when compared with the reduction in coronary events achieved with statin therapy. Moreover, a definitive mechanism of action has not yet been elucidated
Naveed A Sattar, Institute of Cardiovascular& Medical Sciences, University of Glasgow, UK Atheroscler Suppl 2012

diabetes per 255 (95% CI, 150852) patients over 4 years

Fish Oil a No-Go, Nada Effect

(Maria Carla Roncaglioni (Mario Negri Institute of Pharmacological Research, Milan, Italy)

12 513 pts

6244 randomly assigned to 1gr of -3 fatty acids 6269 patients randomized to placebo
The primary end point of the trial was initially a
composite that included death, nonfatal MI, and nonfatal stroke Was revised to death from CVD causes / hospital admissions for CVD causes.
After a median follow-up of five years
May 9, 2013 New England Journal of Medicine

Primary and Secondary End Points

Outcome
Primary end point Death from CVD Hospitalizations for CVD Death or nonfatal MI or stroke Death from CVD cause or nonfatal MI/stroke Fatal/nonfatal coronary event Death from coronary cause
SD from cardiac cause or major ventricular arrhythmia

3 n=6239 (%)

Placebo, n=6266 (%)

11,7 2,3 9,9 7,8 4,6 5,0 1,3

11,9 2,2 10,1 7,5 4,4 5,2 1,2

p 0,64 0,80 0,68 0,64 0,59 0,51 0,66

1,0 0,8

0,8 0,6

0,22 0,36

SD from cardiac causes

 &

Drugs for Treatment of Hypercholesterolaemia