02270nas a2200313 4500000000100000000000100001008004100002260001200043653001800055653002100073653002300094653001900117653001100136653003100147653001800178653003100196653001700227100002400244700001900268700001800287700001500305700002200320700001900342245007500361300001200436490000800448520148600456022001401942 2023 d c2023-0810aDrug Approval10aDrug development10aGerm-Line Mutation10aHuman Genetics10aHumans10aMolecular Targeted Therapy10aRare Diseases10aTherapies, Investigational10aTime Factors1 aKaterina Trajanoska1 aClaude Bhérer1 aDaniel Taliun1 aSirui Zhou1 aJ. Brent Richards1 aVincent Mooser00aFrom target discovery to clinical drug development with human genetics a737-7450 v6203 aThe substantial investments in human genetics and genomics made over the past three decades were anticipated to result in many innovative therapies. Here we investigate the extent to which these expectations have been met, excluding cancer treatments. In our search, we identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants. Large biobank-based genetic studies have the power to identify and validate a large number of new drug targets. Genetics can also assist in the clinical development phase of drugs-for example, by selecting individuals who are most likely to respond to investigational therapies. This approach to drug development requires investments into large, diverse cohorts of deeply phenotyped individuals with appropriate consent for genetically assisted trials. A robust framework that facilitates responsible, sustainable benefit sharing will be required to capture the full potential of human genetics and genomics and bring effective and safe innovative therapies to patients quickly. a1476-4687