title: Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future.
abstract: The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). However, against this backdrop, there have been some notable disappointments in drug development. Here we use these as case studies to emphasize the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies, and the value of the deep phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of "omics" technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency.
authors.affiliation: Department of Medicine, Imperial College London, W12 0NN, United Kingdom.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Lythgoe
authors.affiliation: Department of Medicine, Imperial College London, W12 0NN, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rhodes
authors.affiliation: Department of Medicine, Imperial College London, W12 0NN, United Kingdom.
authors.forename: Pavandeep
authors.initials: P
authors.lastname: Ghataorhe
authors.affiliation: Department of Medicine, Imperial College London, W12 0NN, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Attard
authors.affiliation: Department of Medicine, Imperial College London, W12 0NN, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Wharton
authors.affiliation: Department of Medicine, Imperial College London, W12 0NN, United Kingdom. Electronic address: m.wilkins@imperial.ac.uk.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Wilkins
mesh_terms: D000818:Animals; D015415:Biomarkers; D000068456:Clinical Studies as Topic / Q000379:methods*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008090:Lisuride / Q000031:analogs & derivatives / Q000494:pharmacology; D010641:Phenotype; D010646:Phentolamine / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C006208:dironyl; D014660:Vasoactive Intestinal Peptide; C438273:aviptadil; D008090:Lisuride; D011505:Protein-Tyrosine Kinases; D010646:Phentolamine
keywords: Drug development; Imatinib; Pulmonary arterial hypertension; Serotonin; Statins; Vasoactive intestinal polypeptide