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More than 90% compounds entering clinical trials fail to demonstrate safety and efficacy in human, despite evidence of safety and effectiveness in pre-

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Presentation on theme: "More than 90% compounds entering clinical trials fail to demonstrate safety and efficacy in human, despite evidence of safety and effectiveness in pre-"— Presentation transcript:

1 More than 90% compounds entering clinical trials fail to demonstrate safety and efficacy in human, despite evidence of safety and effectiveness in pre- clinical models High failure rates indicate the limited ability of pre-clinical models to predict patient benefit in human populations. Limitations in drug discovery 1

2 Human genetics as “Experiment of nature” to prioritize molecular targets in drug discovery => naturally occurring conditions (mutations) that modulate (gain- or loss-of–function) a biological target (gene) with reproducible effect (decreased or increased risk) on human physiology (trait = appropriate proxy for drug efficacy) -> mimic the effect of therapeutic modulation of a target -> serve as estimate of dose-response curves (function-phenotype curves) Potential of Human genetics to overcome limitations in drug discovery 2

3 PCSK9, LDL levels and coronary heart disease 1. PCSK9 GOF alleles: increased LDL levels 2003 1 3

4 PCSK9, LDL levels and coronary heart disease 1. PCSK9 GOF alleles: increased LDL levels 2003 2. PCSK9 LOF alleles: decreased LDL levels 2005-2006 1 2 4

5 PCSK9, LDL levels and coronary heart disease 1. PCSK9 GOF alleles: increased LDL levels 2003 2. PCSK9 LOF alleles: decreased LDL levels 2005-2006 1 2 5

6 PCSK9, LDL levels and coronary heart disease 1. PCSK9 GOF alleles: increased LDL levels 2003 2. PCSK9 LOF alleles: decreased LDL levels 2005-2006 1 2 6

7 PCSK9, LDL levels and coronary heart disease 1. PCSK9 GOF alleles: increased LDL levels 2003 2. PCSK9 LOF alleles: decreased LDL levels 2005-2006 3. PCSK9 LOF alleles: protect against CHD 2006 4. 1 2 3 7

8 PCSK9, LDL levels and coronary heart disease 1. PCSK9 GOF alleles: increased LDL levels 2003 2. PCSK9 LOF alleles: decreased LDL levels 2005-2006 3. PCSK9 LOF alleles: protect against CHD 2006 4. PCSK9 LOF alleles: no obvious adverse events 2006 1 2 3 4 8

9 PCSK9, LDL levels and coronary heart disease 1. PCSK9 GOF alleles: increased LDL levels 2003 2. PCSK9 LOF alleles: decreased LDL levels 2005-2006 3. PCSK9 LOF alleles: protect against CHD 2006 4. PCSK9 LOF alleles: no obvious adverse events 2006 1 2 3 4 LDL levels Risk of CHD lowhigh low high PCSK9 GOF alleles PCSK9 LOF alleles 9

10 1. PCSK9 GOF alleles: increased LDL levels 2003 2. PCSK9 LOF alleles: decreased LDL levels 2005-2006 3. PCSK9 LOF alleles: protect against CHD 2006 4. PCSK9 LOF alleles: no obvious adverse events 2006 5. Clinical trials: monoclonal antibody to PCSK9 2012 PCSK9, LDL levels and coronary heart disease LDL levels Risk of CHD lowhigh low high PCSK9 GOF alleles PCSK9 LOF alleles 1 2 3 4 5 10

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