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Limitations in drug discovery

Limitations in drug discovery. 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

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Limitations in drug discovery

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  1. Limitations in drug discovery • 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.

  2. Potential of Human genetics to overcome limitations in drug discovery • 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)

  3. PCSK9, LDL levels and coronary heart disease 1 1. PCSK9GOFalleles: increased LDL levels 2003

  4. PCSK9, LDL levels and coronary heart disease 1 1. PCSK9GOFalleles: increased LDL levels 2003 2. PCSK9LOFalleles: decreased LDL levels 2005-2006 2

  5. PCSK9, LDL levels and coronary heart disease 1 1. PCSK9GOFalleles: increased LDL levels 2003 2. PCSK9LOFalleles: decreased LDL levels 2005-2006 2

  6. PCSK9, LDL levels and coronary heart disease 1 1. PCSK9GOFalleles: increased LDL levels 2003 2. PCSK9LOFalleles: decreased LDL levels 2005-2006 2

  7. PCSK9, LDL levels and coronary heart disease 1 1. PCSK9GOFalleles: increased LDL levels 2003 2. PCSK9LOFalleles: decreased LDL levels 2005-2006 3. PCSK9LOFalleles: protect against CHD 2006 4. 2 3

  8. PCSK9, LDL levels and coronary heart disease 1 1. PCSK9GOFalleles: increased LDL levels 2003 2. PCSK9LOFalleles: decreased LDL levels 2005-2006 3. PCSK9LOFalleles: protect against CHD 2006 4. PCSK9LOFalleles: no obvious adverse events 2006 2 3 4

  9. PCSK9, LDL levels and coronary heart disease 1 1. PCSK9GOFalleles: increased LDL levels 2003 2. PCSK9LOFalleles: decreased LDL levels 2005-2006 3. PCSK9LOFalleles: protect against CHD 2006 4. PCSK9LOFalleles: no obvious adverse events 2006 high PCSK9 GOF alleles 2 3 Risk of CHD 4 PCSK9 LOF alleles low low high LDL levels

  10. PCSK9, LDL levels and coronary heart disease 1 1. PCSK9GOFalleles: increased LDL levels 2003 2. PCSK9LOFalleles: decreased LDL levels 2005-2006 3. PCSK9LOFalleles: protect against CHD 2006 4. PCSK9LOFalleles: no obvious adverse events 2006 5. Clinical trials: monoclonal antibody to PCSK9 2012 high PCSK9 GOF alleles 2 3 Risk of CHD 4 PCSK9 LOF alleles 5 low low high LDL levels

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