Genetic Engineering & Biotechnology News

APR15 2017

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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8 | APRIL 15, 2017 | | Genetic Engineering & Biotechnology News Predict Drug Toxicity without Guesswork The initial laboratory testing itself is an expensive, time-consuming task. The human body is a physiologically complex machine, and any introduction of new drug compound has the potential to cause multiple organ sys- tems to malfunction and, in extreme cases, to shut down completely. If such adverse results could be prevented in the early stages, expen- sive road trips to nowhere could be cut short, or suitable detours could be mapped. To help drug developers avoid bad road trips, cell biologists, safety pharmacologists, toxicologists, and other scientists will pres- ent some cutting-edge research at Predicting Drug Toxicity, a conference to be held June 13–14 in Boston. At this event, presenters and attendees will gather to discuss their com- mon goal: minimizing drug-induced toxicity in new drug candidates. They will also recon- sider the place of ADME/DMPK (absorption, distribution, metabolism, and excretion/drug metabolism, and pharmacokinetics) assess- ments in drug development. DILISym Heading up the big show in Boston as keynote speaker is Paul Watkins, M.D., di- rector of the University of North Carolina Institute for Drug Safety Sciences and profes- sor of medicine, pharmacy, and public health at the University of North Carolina, Chapel Hill. Dr. Watkins, an expert on drug-induced liver injury (DILI), has developed a computer model called DILISym. The model can be used to assess the toxic- ity potential of drugs at various developmen- tal stages before they reach clinical trials. It can also help developers explain and reduce toxicity that emerges in the clinic. Systems with such capabilities are valu- able in the drug development arena. What sets DILISym apart from other systems is that it has been developed with the guidance of many brilliant minds from most of the top 20 pharmaceutical companies, as well as the FDA. Keeping an open door for the latest de- veloping drugs to run through the DILISym system allows pertinent information about liver safety to come to the forefront quickly. "This model utilizes a 'middle-out' tech- nique," says Dr. Watkins. It starts with or- Drug Discovery Feature Dwain Dsouza The road from a drug's conception in the laboratory to its arrival in the pharmacy is long and arduous. It can also take over 12 years and cost over $350 million before a drug finds a place on pharmacy shelves. Given the global demand for safe and efficacious new medicines to treat cancer, metabolic disorders, mental illness, and other diseases, the biopharmaceutical indus- try drug pipeline continues to grow. However, drug de- velopment is an expensive, long process involving high rates of new molecule attrition. It is imperative, therefore, to be able to advance new compounds that have a lower risk of failure. This is the essence of de-risking—the intel- ligent application of relevant early testing to help miti- gate major drug development risks such as toxicity, com- plex clinical development, nonapproval, and postmarket withdrawal. Key areas of focus for early de-risking include the sus- ceptibility a new drug may have to suffer from drug-drug interactions (DDIs), genotoxicity, cardiotoxicity, neurotox- icity, and drug-induced liver injury (DILI). If liability in any of these major risk areas is detected early enough, it is possible to make changes to the drug's structural chem- istry. Such changes should retain the drug's pharmaco- phore but reduce its safety liability. Over the past decade, in vitro models have become increasingly sophisticated with primary human cell function and differentiation being maintained for several weeks. Indeed, integrated culture systems that incorporate multiple primary cell types have led to the concept of "humans on a chip." Such chips can allow efficacy and safety risks to be assessed on multiple hu- man cell types. Other new in vitro technologies include 3D bioprinting, genetic modification of primary human cells to evoke proliferation, co-culturing, and hanging- drop technology (liquid surface tension) to enhance 3D cell culture. All of these new in vitro technologies play a crucial role in advancing de-risking strategies using human cells. The primary aim of Envigo's de-risking strategy is to pro- vide a comprehensive and rigorous data set in early drug development that facilitates rational, scientifically based assessments to identify particular characteristics of drugs that result in failure. n De-Risking Drug Development Using Nonanimal Technologies A comparison of carcinogenicity study timelines for Taconic Biosciences' rasH2 model and a traditional mouse model. The faster tumorigenic response in the rasH2 model allows studies to be completed relatively quickly (in about six months instead of two years). In addition, since a higher proportion of mice will respond to carcinogen exposure, fewer animals are required for study completion compared to lifetime rodent assays. Developed by CIEA

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