Protein changes may signal side effects in drug trials
Protein changes in blood can provide early warning of potential harmful side effects from experimental drug candidates
In an article published “early online” in the American Heart Association journal Circulation, researchers at Pfizer, the Karolinska Institute, the University of California, San Francisco and SomaLogic describe how the measurement of blood-based protein changes in response to treatment with an experimental drug candidate may improve the efficiency and safety of clinical drug development. The published study used a nine-protein-based risk score to detect potential cardiovascular problems with a drug candidate (torcetrapib) well before significant adverse symptoms manifested themselves in patients in the drug’s clinical trial. Their analysis also identified changes in approximately 200 additional proteins that help describe the biology behind those adverse symptoms, which is applicable more broadly in cardiovascular disease management.
Pfizer’s phase three clinical trial (named “ILLUMINATE”) of torcetrapib, a drug candidate that had been shown to raise levels of “good” cholesterol and lower levels of “bad” cholesterol, was expected to confirm its blockbuster potential in reducing the risk of serious cardiovascular events such as heart failure and stroke. Instead, ILLUMINATE was halted abruptly in 2006 due to an unexpected increase in deaths and cardiovascular problems in trial subjects receiving the new drug candidate. At the time the trial was halted, Pfizer had invested 15 years and nearly a billion dollars in developing torcetrapib.
The Circulation study describes an attempt to determine if the problems from torcetrapib treatment could have been detected earlier, and thus at a lower cost. In this study, the researchers used the SOMAscan® assay to measure changes in the levels of over 1,000 proteins in blood samples from ILLUMINATE trial participants. Using a previously validated, nine-protein cardiovascular risk score, they found that they could successfully predict the harmful effects of torcetrapib in specific patients after only three months of treatment—much earlier than the point at which the ILLUMINATE trial was terminated (18 months).
In addition, a wider analysis of approximately 200 blood proteins that significantly changed in torcetrapib-treated patients revealed that the drug candidate had widespread, unexpected effects on normal immune and inflammatory processes. In addition, changes in only eight of the proteins measured were sufficient to explain the biology underlying the hypertension side effect seen in clinical trials. Beyond torcetrapib, these insights can also provide additional guidance for more personalized and targeted prescribing of currently marketed cardiovascular drugs, such as statins and ACE inhibitors.
Torcetrapib is just one member of a promising class of cardiovascular disease-prevention drugs, cholesteryl ester transferase (CETP) inhibitors, that have garnered considerable interest from the pharmaceutical industry. In addition to Pfizer, both Eli Lilly and Roche had candidate CETP inhibitors that were dropped late in development due to lack of efficacy. However, Merck recently announced that their drug candidate anacetrapib successfully completed the longest CETP clinical trial to date.
Expanding the work described in the Circulation paper to include comparative analyses from all of these drug candidate trials from different companies could provide, not only enhanced understanding of critical protein changes related to side effects, but could also reveal early signs of “positive” protein changes that would help accelerate the successful development of more promising candidates from not only this drug, but across many different classes and even disease types.
Reference: Williams, SA et al. (2017) “Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib” Circulation (published early online October 3, 2017).
Fintan R. Steele, Ph.D.
Chief Communications Officer
SomaLogic is committed to helping people worldwide receive timely, accurate, trustworthy and actionable information that helps them manage their personal health and wellness. To realize this vision, we are creating and delivering the ”SOMAscan Platform,” a clinically useful and affordable health information system based on comprehensive and personalized protein measurement, delivered broadly through a global ecosystem of partners and users.