Paradim Shift in cholesterol behandeling: van LDL-C target naar - - PowerPoint PPT Presentation

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Paradim Shift in cholesterol behandeling: van LDL-C target naar - - PowerPoint PPT Presentation

Oct 19, 2022 156 likes •725 views

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 Risk and profit

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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

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Risk and profit

https://www.ausbanking.org.au/subsites/smarterinvesting/risks.html

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High risk CVD patients

Risk and profit

https://www.ausbanking.org.au/subsites/smarterinvesting/risks.html

CVD risk Patient

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Patient “at risk”

Inflammation Lipids Thrombosis Glucose

LDL lp(a) Remnants

CVRM in the years to come.....

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5 LP252041

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6 LP252041

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7 LP252041

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  • Affected family members with:
  • Total cholesterol in 90th

percentile,Tendon xanthomas, CHD Early MI Stroke

PCSK9- a major breakthrough

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Raal Hovingh. Lancet 2015;385:331–340.

Evolocumab significantly reduces LDL-C in patients with heterozygous FH

Placebo Q2W (n=54) Evolocumab 140 mg Q2W (n=110)

Study week Mean % change in LDL-C from baseline

10 8 12 20

  • 20
  • 40
  • 60
  • 80

Baseline 2

60% vs placebo

  • 1%
  • 61%
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Therapeutics...

Small molecules

hydrophobic organic, typically act by deactivating or inhibiting target proteins through competitive binding. downside: only 2–5% of the protein- coding human genome has these sites

RNA drugs

siRNA, ASO, CRISPR9Cas extremely specific, exome skipping, knockdown

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

Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Fire A, Mello CC

  • Nature. 1998 Feb 19; 391(6669):806-11.
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Alirocumab Evocumab

Aantallen papers (pubmed hits) per jaar “evolocumab” en “alirocumab”

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Alirocumab Evocumab

en nu zonder reviews....

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Dadu and Ballantyne. Nat Card Rev 2014

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Boekholdt SM, Hovingh GK, JACC 2015

Achieved LDL-C matters

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Giugliano R et al. Lancet oct 2017; 1962-1971

Evolocumab- FOURIER: achieved LDL-C

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Giugliano R et al. Lancet oct 2017; 1962-1971

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0.5 1 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Giugliano R et al. Lancet oct 2017; 1962-1971

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Dec 2017:1385

2034 with LDL-C <70mg/dL at baseline !!

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Conclusions Odyssey (preliminary...._

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An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Trial Design

Evolocumab SC

140 mg Q2W or 420 mg QM

Placebo SC

Q2W or QM LDL-C ≥70 mg/dL (1.8 mmol/L) or non-HDL-C ≥100 mg/dL (2.6 mmol/L)

Follow-up Q 12 weeks Median f/up 2.2 yrs

Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)

RANDOMIZED DOUBLE BLIND

Sabatine MS et al. Am Heart J 2016;173:94-101

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Therapeutics...

Small molecules

hydrophobic organic, typically act by deactivating or inhibiting target proteins through competitive binding. downside: only 2–5% of the protein- coding human genome has these sites

RNA drugs

siRNA, ASO, CRISPR9Cas extremely specific, exome skipping, knockdown

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

Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Fire A, Mello CC

  • Nature. 1998 Feb 19; 391(6669):806-11.
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Kaczmarek Genome Med. 2017; 9: 60.

Current clinical RNA delivery trials

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Phase II ORION-1 Study

Study design

Completed (n=483) Screening (Day -14 to Day -1) Randomization (Day 1, n=501) Treated (n=497)

Day 1 Study drug given Day 14 1st follow-up visit Monthly follow-up visits Day 30 Day 90 Day 180 Day 210 End of study visit Primary evaluation Day 360 Extended follow-up

One dose starting regimen 200 mg

N=60

Placeb

  • N=65

500 mg

N=65

300 mg

N=61

Day 1 Study drug given Day 14 1st follow-up visit Monthly follow-up visits Day 30 Day 90 Day 180 Day 210 End of study visit Primary evaluation Day 360 Extended follow-up

Two dose starting regimen 100 mg

N=61

Placeb

  • N=62

300 mg

N=61

200 mg

N=62

Study drug given

Randomized (n=501)

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

No safety concerns

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300 mg 50.9% reduction

Efficacy: One dose starting regimen LDL-C reductions – 300 mg optimal

300 mg 38.4% reduction

P-value for all comparisons to placebo <0.0001

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Efficacy: Two dose starting regimen

Individual patient responses (%) at day 180

Mean 52.6% Max 80.9%

Placebo Percent reduction Inclisiran 300 mg Percent reduction All patients responded

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PCSK9 targeted therapy

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Selective Thyroid Receptor Agonist(s)

Cholesterol Triglycerides Lipoprotein(a) Reverse cholesterol transport Metabolic rate

Side effects Metabolic effects TR beta TR alpha

Heart Bone Skeletal muscle

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“how low can you go?”

CVD risk LDL risk

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“how low can you go?”

CVD risk LDL risk

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PCSK9i in heFH

Hartgers et al. accepted

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PCSK9i in heFH

Hartgers et al. accepted J CLin Lipidol

Without CVD

No Rx

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PCSK9i in heFH

Hartgers et al. accepted J CLin Lipidol

Without CVD

No Rx Statin and Eze

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PCSK9i in heFH

Hartgers et al. accepted J CLin Lipidol

Without CVD

No Rx Statin and Eze and PCSK9i

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“all that good?”

https://nl.surveymonkey.com/r/YCFPY89

Adverse events and inefficacy of PCSK9 Inhibition with evolocumab or alirocumab in hypercholesTeraemic pAtients. (AKITA trial)

(March 2018)