Paradim Shift in cholesterol behandeling: van LDL-C target naar LDL-C eradicatie

Transcription

1 Paradim Shift in cholesterol behandeling: van LDL-C target naar LDL-C eradicatie Prof. G.Kees Hovingh, MD PhD MBA Dept. Vascular Medicine Academic Medical Center Amsterdam, the Netherlands

2 Risk and profit

3 High risk CVD patients Risk and profit CVD risk Patient

4 CVRM in the years to come... LDL Inflammation Lipids Remnants lp(a) Patient at risk Thrombosis Glucose

5 LP252041

6 LP252041

7 LP252041

8 PCSK9- a major breakthrough Affected family members with: Total cholesterol in 90th percentile,tendon xanthomas, CHD Early MI Stroke

9 Mean % change in LDL-C from baseline Evolocumab significantly reduces LDL-C in patients with heterozygous FH % % vs placebo % -80 Baseline Study week Placebo Q2W (n=54) Evolocumab 140 mg Q2W (n=110) Raal Hovingh. Lancet 2015;385:

10 Therapeutics... Small molecules hydrophobic organic, typically act by deactivating or inhibiting target proteins through competitive binding. downside: only 2 5% of the proteincoding human genome has these sites Protein based antibody/ enzyme high specificity to a variety of targets / replacement of mutated or missing proteins (e.g., insulin for diabetes) -: cost, size, stability RNA drugs sirna, ASO, CRISPR9Cas extremely specific, exome skipping, knockdown Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Fire A, Mello CC Nature Feb 19; 391(6669):

11 Aantallen papers (pubmed hits) per jaar evolocumab en alirocumab Alirocumab Evocumab

12 en nu zonder reviews... Alirocumab Evocumab

13 Dadu and Ballantyne. Nat Card Rev 2014

14 Achieved LDL-C matters Boekholdt SM, Hovingh GK, JACC 2015

15 Evolocumab- FOURIER: achieved LDL-C Giugliano R et al. Lancet oct 2017;

16 Giugliano R et al. Lancet oct 2017;

17 Giugliano R et al. Lancet oct 2017;

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19 2034 with LDL-C <70mg/dL at baseline!! Dec 2017:1385

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30 Conclusions Odyssey (preliminary..._

31 Trial Design 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) LDL-C 70 mg/dl (1.8 mmol/l) or non-hdl-c 100 mg/dl (2.6 mmol/l) Evolocumab SC 140 mg Q2W or 420 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Follow-up Q 12 weeks Median f/up 2.2 yrs Sabatine MS et al. Am Heart J 2016;173:94-101

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35 Therapeutics... Small molecules hydrophobic organic, typically act by deactivating or inhibiting target proteins through competitive binding. downside: only 2 5% of the proteincoding human genome has these sites Protein based antibody/ enzyme high specificity to a variety of targets / replacement of mutated or missing proteins (e.g., insulin for diabetes) -: cost, size, stability RNA drugs sirna, ASO, CRISPR9Cas extremely specific, exome skipping, knockdown Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Fire A, Mello CC Nature Feb 19; 391(6669):

36 Current clinical RNA delivery trials Kaczmarek Genome Med. 2017; 9: 60.

37 Phase II ORION-1 Study Study design Screening (Day -14 to Day -1) Randomization (Day 1, n=501) One dose starting regimen Randomized (n=501) Two dose starting regimen Placeb o N= mg N= mg N= mg N=65 Treated (n=497) Placeb o N= mg N= mg N= mg N=61 Day 1 Day 14 Day 30 Day 90 Study drug given 1 st follow-up visit Monthly follow-up visits Day 1 Day 14 Day 30 Day 90 Study drug given 1 st follow-up visit Monthly follow-up visits Study drug given Day 180 Day 210 Primary evaluation End of study visit Completed (n=483) Day 180 Day 210 Primary evaluation End of study visit Day 360 Extended follow-up Day 360 Extended follow-up

38 No safety concerns No thrombocytopenia No neuropathy No immunogenicity (no anti-drug antibodies) No pro-inflammatory symptoms or elevated markers

39 Efficacy: One dose starting regimen LDL-C reductions 300 mg optimal 300 mg 50.9% reduction 300 mg 38.4% reduction P-value for all comparisons to placebo <0.0001

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41 Efficacy: Two dose starting regimen Individual patient responses (%) at day 180 Placebo Percent reduction Inclisiran 300 mg Percent reduction Mean 52.6% All patients responded Max 80.9%

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44 PCSK9 targeted therapy

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47 Selective Thyroid Receptor Agonist(s) TR alpha TR beta Side effects Heart Bone Skeletal muscle Metabolic effects Cholesterol Triglycerides Lipoprotein(a) Reverse cholesterol transport Metabolic rate

48 how low can you go? CVD risk LDL risk

49 how low can you go? CVD risk LDL risk

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51 PCSK9i in hefh Hartgers et al. accepted

52 PCSK9i in hefh No Rx Without CVD Hartgers et al. accepted J CLin Lipidol

53 PCSK9i in hefh No Rx Statin and Eze Without CVD Hartgers et al. accepted J CLin Lipidol

54 PCSK9i in hefh Statin and Eze and PCSK9i No Rx Without CVD Hartgers et al. accepted J CLin Lipidol

55 all that good? Adverse events and inefficacy of PCSK9 Inhibition with evolocumab or alirocumab in hypercholesteraemic patients. (AKITA trial) (March 2018)