Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib
Background—Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE, a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15,067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days due to significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine: 1) whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and 2) whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial using proteomics.
Methods—A nested case-control analysis of paired plasma samples, at baseline and at 3-months, was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls, 1:1. Main outcomes were: 1) a survey of 1,129 proteins for discovery of biological pathways altered by torcetrapib, 2) a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure or death.
Results—Plasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the two treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared to the atorvastatin only arm by +1.08% (p=0.0004). Thirty-seven proteins changed in the direction of increased risk out of 49 proteins previously associated with cardiovascular and mortality risk.
Conclusions—Heretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00134264.
- precision medicine
- personalized medicine
- drug safety
- drug development
- cardiovascular disease
- drug surveillance
- pathway analysis
- Received March 4, 2017.
- Revision received August 21, 2017.
- Accepted September 8, 2017.