Clinical OMICS

JAN-FEB 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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14 Clinical OMICs January/February 2018 www.clinicalomics.com inhibiting the pathway could cause severe acne and/or high cholesterol. Although the two approaches complement one another, there's a reason why the Director of Drug Discov- ery at 23andMe, Erik Karrer, called PheWAS the company's "secret sauce" in a recent Nature News & Comment article. The ability not only to validate drug targets but also to predict potential adverse reactions early on could save pharmaceutical companies from following futile leads. "If it's not going to work, don't spend millions or billions [of dollars] getting there," remarked David Mosedale, Ph.D., chief scientific officer at Total Scientific, a small contract research organization in the U.K. "You kill it early, and you move on to something else." Total Scientific began offering PheWAS as a contract service to current clients after developing its own cohort. Despite its size, the 1,300-individual cohort already has helped detect potential toxicology issues that could threaten a drug program. For example, one study identified an unlikely association between a candidate drug target- ing an unrelated disease and thrombosis. "In some sense, PheWAS is like performing a knockout study in man with- out the impossible ethical hurdle," wrote Total Scientific Executive Director and Founder, David Grainger, Ph.D., in DrugBaron.com. By bringing potential safety concerns to the forefront, PheWAS gives drug companies an opportunity to add addi- tional parameters to animal studies, design clinical trials that exclude patients genetically predisposed to adverse reactions, or if the concern is serious enough, kill a drug program and move on—avoiding any surprises in Phase III. Of course, drug developers will need to perform additional studies to confirm adverse associations, since the hypoth- esis-generating nature of PheWAS functions a bit like the Cheshire Cat—answering questions with more questions. However, "[PheWAS] tells you something about your [drug] target and where you're going," said Mosedale. Pharmaceutical companies may not have to go far to find new treatments for disease either. Systematically examining the broad range of phenotypes associated with a particular gene can not only signpost adverse drug effects, but can also lead to new indications for approved drugs. Repurposing drugs can significantly accelerate the process of finding a drug that might work in a particular disease—especially for rare diseases, where the challenges associated with clinical studies are magnified as a consequence of the lim- ited number of patients available for recruit- ment. Cashing In on Biobanks Despite the promising story unfolding around genetics and drug development, the protagonists still have many challenges left to overcome. Excavating phenotypic informa- tion from sometimes hundreds of thousands of individual records demonstrates one of the challenges to successfully implementing PheWAS. While the proof-of-concept study published by Denny et al., addressed the need for a high-throughput method to extract clinical phenotypes from medical records by developing algo- rithms that map ICD-9 billing codes to diseases of interest, the field will need to move beyond billing codes to gain greater granularity from phenotypes. The main conflict, however, arises from the astro- nomical upfront costs and legwork required to collect phenotypic information from thousands of individuals and link that data to genotypes. Only a handful of large biobanks with linked phenotype data currently exist, and, according to Daniel Rader, M.D., professor of (continued from previous page) David Mosedale, CSO, at work with staff member at Total Scientific.

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