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Focus Feature: Tox Screening
February 2020
by Jeffrey Bouley  |  Email the author
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Focus Feature: Tox Screening

Q&A: Transgenic rasH2 mice and the 3Rs are transforming drug safety testing
 
Besides the typical drug discovery constraints of time and money, when it comes to drug safety screening there is usually a desire to use fewer animals in keeping with Russell & Burch’s 3Rs (replacement, reduction and refinement) philosophy. Being able to conduct the required drug safety screening in less time, with fewer animals and at a lower cost, can be a significant advantage.
 
According to Taconic Biosciences Inc., the transgenic rasH2 mouse model is transforming ADME-Tox testing by replacing the traditional two-year carcinogenic assessment with a 26-week study that uses fewer animals. The potential utility of this model also extends to new applications, including an eight-week dermal carcinogenic risk assessment that can be utilized prior to laborious, time-consuming regulatory studies.
 
Additionally, a few new studies are showing rasH2 in combination with error-corrected, next-generation sequencing (EC-NGS) as a predictive tumorigenic assay that can be utilized in a one-month study and implemented much earlier in the drug development process. DDNews recently spoke with Terry Receveur, associate director of product management at Taconic Biosciences, about how the rasH2 model is enhancing drug safety testing.
 
DDNews: What is a rasH2 mouse?
 
Terry Receveur: The rasH2 mouse was developed in the laboratory of Tatsuji Nomura of the Central Institute for Experimental Animals (CIEA) in Kawaski, Japan. The rasH2 mice carry the human c-Ha-ras oncogene in addition to the endogenous murine Ha-ras oncogene. The presence of the human c-Ha-ras gene makes hemizygous rasH2 mice highly susceptible to tumor development when exposed to compounds that cause cancer in humans.
 
DDNews: Why has the industry adopted the use of the rasH2 for carcinogenicity studies so readily?
 
Receveur: Compared to the traditional two-year study, the rasH2 model provides a more accurate and faster result that is regulatory approved and accepted, at a lower cost. Companies looking to comply with Russell & Burch’s 3Rs also find the rasH2 model aligns well.
 
The six-month rasH2 carcinogenicity study is approved by The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the FDA as a substitute for the traditional two-year rodent carcinogenicity studies. It reduces the in-life testing timeline by 75 percent, has extremely low incidence of spontaneous tumors, and provides more rapid onset and higher incidence of more malignant tumors.
 
Using only 25/sex/group (versus 50 to 60) means less test article required and a huge decrease in post-study pathology. The rasH2 also has a robust historical control database to support decisions on carcinogenicity susceptibility, displays low mortality, shows no drift in tumor incidence, and experiences stable body weight data among groups. Over 75 percent of mouse carcinogenicity studies are now conducted in the rasH2.
 
DDNews: How does the rasH2 support Russell & Burch’s 3Rs?
 
Receveur: Russell and Burch originated the concepts of replacement, reduction and refinement (3Rs) in their 1959 book, The Principles of Humane Experimental Technique (Principles), proposing a new applied science to improve treatment of laboratory animals and advance the quality of science in studies that use animals. The 3Rs were put forward to help investigators find and use available techniques and encourage developing new tools and methodologies.
 
The rasH2 model applies to two of the Rs. By using only 25/sex/group, the number of animals per study is reduced by 250 to 300 (a more than 50-percent reduction). Use of the rasH2 also considerably reduces the number of mice euthanized due to senescence-related morbidity typically found near the end of two-year studies. The number of repeat studies needed due to inconclusive evidence related to false positives that result from spontaneous tumors is considerably reduced, reflecting refinement in animal use.
 
DDNews: How is the rasH2 mouse continuing to transform drug safety testing?
 
Receveur: Three initiatives underway involving the rasH2 can benefit drug safety testing and drug discovery.
 
In 2011, Dr. Frank Sistare and colleagues posited that researchers could retrospectively analyze two-year rat bioassay data and, in tandem with six-month rasH2 carcinogenicity studies, predict negative outcomes of two-year rat studies with 80-percent accuracy. They estimated that use of such predictions could reduce the number of required two-year rat carcinogenicity studies by 40 to 50 percent without additional risk to human safety. The ICH’s extensive efforts to validate the theory has shown a two-year rat carcinogenicity study provides little value if a compound lacks histopathological risk factors for neoplasia in chronic toxicity studies, does not cause hormonal perturbation, and is negative for genotoxicity. ICH S1 Guidelines are expected to undergo a revision that would allow waiving the requirement for a two-year rat bioassay under certain conditions. The proposed changes could take effect by late 2021. The impact to the 3Rs is significant: fewer animals used, for a shorter time.
 
Second, a recent article (“Establishment and Validation of an Ultra-Short-Term Skin Carcinogenicity Bioassay Using Tg-rasH2 Mice”) confirmed the effectiveness of rasH2 in predicting skin carcinogenicity. This is a follow-up to a 2013 paper (“Tumor Promotion by 12-O-tetradecanoylphorbol-13-acetate in an Ultra-Short-Term Skin Carcinogenesis Bioassay Using rasH2 Mice”), which concluded that skin promotion effects could be detected in only eight weeks in rasH2 mice. This paper validates the rasH2 carcinogenicity bioassay as a tool for assessing the carcinogenicity potential of topically applied chemicals. This new assay reduces the time animals are on study and may replace the use of more sentient species.
 
Third, there is strong evidence in emerging research for using rasH2 with EC-NGS as a predictive tumorigenic assay that can be utilized in a one-month study and implemented much earlier in the drug development process. Though in the early stages of development and validation, there is compelling information to support its use.
 
This approach could enable testing for genotoxic and non-genotoxic carcinogenicity in just four weeks. It also adds predictive utility in the drug discovery pipeline in a pre-IND application, allowing organizations to de-risk earlier in the process, saving time and money and enabling screening of more potential life-saving compounds. The assay results also identify mutations in both the murine and human ras gene/transgene without the need for pathology. With this approach, animals are on study for less time, and since compounds that may have caused tumors in the traditional carcinogenicity testing scenario are eliminated, there may be less pain or distress.
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Terry Receveur is the associate director of product management at Taconic Biosciences Inc. He has been in the laboratory animal industry for over 30 years and has held positions in animal production, vivarium management and operational excellence.
 

Prospects for global ADME-Tox: High need but potential roadblocks
 
MOUNTAIN VIEW, Calif.—According to the report “Global ADME-Tox Screening Systems dynamics comprehensive analysis business growth prospects and opportunities 2025” from QY Research, North America is expected to dominate the ADME-Tox screening system market due to the presence of a large number of biopharmaceutical companies in this region.
 
The European and Asia-Pacific regions come after North America for the ADME-Tox screening system market. In the Asia-Pacific region, India and China are expected to be the fastest-growing market over the forecast period, owing to increased focus by leading biopharmaceutical manufacturers to expand their subsidiaries in these countries. 
 
The increasing focus of drug manufacturer to reduce the development cost of drug with least toxicological issue is the major factor driving the growth of ADME-Tox screening system market, as reliable and accurate ADME-Tox testing increases the potential of a drug by increasing the efficiency of the drug to target the desired tissue.
 
Moreover, increasing demand for specialized drugs due to rising prevalence of various chronic diseases will also boost the growth of the ADME-Tox screening system market, says QY Research. High installation and maintenance cost of such systems, though, could hamper growth, and a lack of skilled professionals to operate such systems could contribute to sluggish growth in  this market.
 
ADME-Tox screening involves an integrated workstation for describing of the absorption, distribution, metabolism and excretion (ADME) properties of drug molecules. ADME-Tox screening systems include a biochemical assay tester that measures the physicochemical properties of a drug molecule. This system also supports permeability assays testing, which measures the drug's affinity toward metabolic enzyme.
 
ADME-Tox screening systems are enabled with highly integrated software that has an inbuilt protocol for the sample testing. The protocol feed in the software can be edited as per the customized need of sample testing. ADME-Tox screening systems also are connected to a multi-mode reader which allows runs the wide range of protocol on primary and secondary screen. The system thus provides accurate toxicity tests for drug development and biopharmaceutical production.
 

 
Toxicity predictions
 
BOSTON—When evaluated with eight previously studied drugs, Emulate Inc.’s Liver-Chip was able to accurately model and predict human toxicity, the company announced in late 2019. In addition to predicting liver toxicity differences between humans, dogs and rats, the Liver-Chip was also able to model the mechanism of action for hepatotoxicity and measure relevant clinical biomarkers. This research examined drugs that had advanced to human trials with no signs of toxicity in animal studies, but that were then halted during in-human studies due to safety concerns. The Liver-Chip accurately predicted the drugs that demonstrated human toxicity despite not showing any hepatotoxicity concerns in animal studies. The results, published in Science Translational Medicine, were co-authored by researchers from AstraZeneca, Janssen Research & Development, LLC, the Wyss Institute for Biologically Inspired Engineering at Harvard University, and Emulate.
 
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SOT/ToxExpo 2020 Show Preview: A taste of toxicology
 
When it comes around, March will bring with it the 59th Society of Toxicology (SOT) Annual Meeting and ToxExpo, held this year in Anaheim, Calif. The meeting is expected to include over 6,000 scientists from countries all over the world. DDNews spoke with Ronald N. Hines, SOT president 2019-2020, and George Daston, SOT vice president 2019-2020, to learn what the meeting has in store for its attendees.
 
 “The SOT Annual Meeting and ToxExpo is the largest gathering of toxicologists in the world, featuring more than 2,000 presentations and 80 featured and scientific sessions. We also connect attendees with 300-plus service providers through the ToxExpo and offer hundreds of events designed to foster networking and engagement with colleagues,” says Hines. “As a result, the SOT Annual Meeting is a place where people showcase the best in toxicological research while also sowing the seeds for future research and collaborations. The SOT membership is diverse in its interests and specialties, and the SOT meeting reflects this diversity.”
 
“As usual, the SOT annual meeting will have many sessions that are highly relevant for scientists who develop or regulate pharmaceuticals,” notes Daston. “This includes sessions on development of protein degradation therapies, relevance of lysosomal dysregulation in adverse responses, and predicting adverse effects related to cancer immunotherapy. The meeting will also feature continuing education courses on gene therapy, cancer immunotherapy and options for treatment of ocular diseases.”
 
“To help ensure that the SOT meeting focuses on topics and issues of interest to a global audience, the society has partnerships with other toxicology associations and organizations that result in special sessions during the meeting each year,” adds Hines. “This tradition continues in 2020 with the SOT/EUROTOX Debate on individual toxicity in risk assessment, a symposium session on oxidative stress with the Japanese Society of Toxicology, an award lecture exchange with EUROTOX, and the featured Medical Research Council lecture by Dame Amanda Fisher on epigenetics and inheritance.”
 
The SOT/EUROTOX debate, “Individual Toxicity Is the Future of Risk Assessment,” will be debated by Syril D. Pettit of the Health and Environmental Sciences Institute and Alan R. Boobis of Imperial College London. The “Oxidative Stress in Multiple Manifestations of Toxicity” session features speakers Yoshito Kumagai of the University of Tsukuba, Yoshiro Saito of Tohoku University, Alicia R. Timme-Laragy of the University of Massachusetts Amherst, and Dean P. Jones of the Emory University School of Medicine.
 
The meeting will take place from March 15-19. For more details, visit www.toxicology.org or click here read our full show preview feature for SOT/ToxExpo 2020 (of which this is an exceprt).
 
Code: E022035

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