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Disciplined approach to drug discovery and early development

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Science Translational Medicine  27 Jul 2016:
Vol. 8, Issue 349, pp. 349ps15
DOI: 10.1126/scitranslmed.aaf2608

Figures

  • Fig. 1. A disciplined approach to identify drug targets and test therapeutic hypotheses.

    Four areas in translational medicine are causal human biology, therapeutic modalities that recapitulate human biology, biomarkers of target modulation, and next-generation clinical trial technologies. Connecting all four promises to improve the novelty, efficiency, and productivity of drug R&D.

    CREDIT: H. MCDONALD/SCIENCE TRANSLATIONAL MEDICINE
  • Fig. 2. Nature’s randomized clinical trial.

    Human epidemiology is a powerful observational method that establishes an association between a risk factor and disease (such as hormone replacement therapy and cardiovascular disease). On its own, however, epidemiology cannot establish causality and is, therefore, subject to spurious associations as a result of unmeasured confounding factors. Mendelian randomization is a method that uses human genetic variation to test for a causal effect between observational data and clinical outcomes. G, target genotype; I, intermediate biomarker; D, disease outcome; C, confounder variable.

    CREDIT: H. MCDONALD/SCIENCE TRANSLATIONAL MEDICINE

Tables

  • Table 1. Natural selection.

    Examples of approved drugs with causal support from tissue-specific human autoimmunity or human genetics. SOST, sclerostin; IL6R, interleukin 6 receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; GLP1R, glucagon-like peptide–1 receptor; IL23A, interleukin 23α; IL12B, interleukin 12β.

    Clinical disorderTissue-specific autoimmunityDrug
    EncephalitisDRD2Antipsychotics
    NarcolepsyOrexin neuronsSuvorexant
    DiabetesPancreatic beta cellsInsulin
    Myasthenia gravisAcetylcholine receptorsAcetylcholinesterase
    inhibitors
    Thrombotic thrombocytopenic
    purpura
    ADAMTS13 on plateletsCaplacizumab*
    Clinical disorderGene(s)Drug(s)
    SchizophreniaDRD2Antipsychotics
    Sclerosteosis and van Buchem
    disease
    SOSTRomosozumab*
    Rheumatoid arthritisIL6RTocilizumab
    High cholesterolPCSK9Evolocumab and alirocumab
    DiabetesGLP1RIncretin mimetics
    PsoriasisIL23A, IL23R, and IL12BUstekinumab
    Atopic dermatitisIL4RADupilumab*

    *Not yet approved.