Stimulation of cholecystokinin-A receptors with Gl181771X: a failed clinical trial that did not test the pharmacogenetic hypothesis for reduction of food intake.
There are two interacting components in a clinical trial: the drug and the study design. When a trial does not work, we blame the drug--and the study is usually not published. This Commentary provides a context for the use of efficacy pipeline pharmacogenetics (PGx) in therapeutic programs. Jordan et al. published the results of an obesity trial with a cholecystokinin-A (CCK-A) receptor agonist and concluded that CCK-A by itself does not have a central role in long-term energy balance. The conclusions were sound, the report accurate, and the journal commendable for publishing a negative study, but the trial design was misdirected--it did not build on phase IIA information and did not test the proposed mechanism of action. The hypotheses should have been based on the original putative role of a central mechanism affecting appetite, which had been validated using efficacy PGx in phase IIA.
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Deane Drug Discovery Institute, Institute for Genomic Sciences and Policy, Duke University School of Medicine and Fuqua School of Business, Durham, North Carolina, USA. allen.roses@duke.edu
D001569:Benzodiazepines / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D010597:Pharmacogenetics / Q000379:methods*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D043886:Receptor, Cholecystokinin A / Q000819:agonists / Q000235:genetics*; D015431:Weight Loss / Q000235:genetics*
C488719:GI 181771X; D043886:Receptor, Cholecystokinin A; D001569:Benzodiazepines