Newly published research demonstrates the ability of BioMAP Systems, a unique set of primary human cell and co-culture assays that model human disease and pathway biology, to identify important safety aspects of drugs and chemicals more efficiently and accurately than can be achieved by animal testing. Data from BioMAP Systems analysis of 776 environmental chemicals, including reference pharmaceuticals and failed drugs, on their ability to disrupt physiologically important human biological pathways were published online this week in Nature Biotechnology. The results show that this in vitro approach can reproducibly identify potential toxicities and off-target drug effects, as well as pinpoint cellular mechanisms and specifically affected biomarker endpoints underlying specific types of adverse reactions in humans. DiscoveRx Corp’s BioSeek division conducted the analysis in collaboration with scientists from the U.S. Environmental Protection Agency as part of the EPA ToxCast Program.
Assessing the safety aspects of drugs, consumer products and environmental chemicals has been historically undertaken through animal testing. However, the vast number of chemicals needing such toxicological assessment and the fact that results in animals often do not translate well to results in humans require the development of alternative, faster, more accurate and humane testing approaches.
“This publication examines an unprecedentedly large data set in terms of number of chemicals, chemical diversity and types of assays screened phenotypically in BioMAP primary human cell models of tissue biology and disease,” said Ellen Berg, scientific director and general manager of DiscoveRx’s BioSeek division and an author of the publication. “In contrast to screening approaches aimed at understanding the actions of a single agent at the molecular and mechanistic level, this method harvests the collective knowledge embedded in reference chemicals with respect to their molecular targets, mechanisms of action, and animal and human toxicity and applies it to characterizing the biological activity of new chemicals or medicines.
“Our results show such systems to be a highly useful and reproducible tool for predictive toxicology that can identify potential chemical targets, toxicological liabilities and molecular mechanisms that elucidate specific adverse outcome pathways for drugs and other chemicals,” Berg continued. “Even using a limited set of primary human cell systems, we were able to recognize consistent patterns of activity that were closely correlated with diverse drug actions and toxicities. New chemicals falling into profile clusters with known activities suggest specific potential toxicities for more careful evaluation, greatly increasing the efficiency of toxicity testing by focusing resources for follow-up testing on the bioactivities of highest concern.”
For example, drugs and chemicals, including selective estrogen receptor modulators, tamoxifen and raloxifene, that are associated with thrombosis-related side effects, like deep vein thrombosis (DVT), were found to preferentially increase the levels of tissue factor in BioMAP models of vascular inflammation. Thus, the use of these models for screening earlier in the drug discovery process may help identify new medicines with reduced potential for this debilitating side effect.
“DiscoveRx’s vision now is to further build the BioMAP database with additional compounds, types of data, and cellular models, thus broadening the utility of this approach for both predictive toxicology and drug discovery research,” Berg said. “This includes annotated, collated public data of compound clinical effects combined with exposure and compound metabolism information on drugs and chemicals, as well as data on compounds at multiple testing concentrations. To that end, we are continuing the effort begun by the ToxCast Initiative to assemble a pharmaceutical industry consortium that will contribute compounds in order to generate an unprecedented industry resource that can help drug developers better understand the potential risks and benefits of their compounds and why they might succeed or fail, before entering the clinic.”
“Failed drugs, especially those that fail in costly later stages of clinical testing, represent a serious and expensive problem for pharmaceutical and biotechnology companies,” said Sailaja Kuchibhatla, executive vice president for DiscoveRx Corp. “Thus the ability to better predict and understand potential safety issues associated with drugs before they enter animal or human testing is an important industry need. DiscoveRx’s continued efforts to make BioMAP Systems an essential industry resource reflect our ongoing mission of providing drug developers with the best tools, information and expert services to meet the pharmaceutical and biotechnology industry’s most pressing needs, both today and tomorrow.”
Date: May 19, 2014
Filed Under: Drug Discovery