Evaluaon of a Novel Graphical Display Tool for Visualizing & Analyzing Histopathology Data from Mulple Toxicology Studies Alan Brown, Philip Drew, Kevin Snyder, Sean Troth & Joyce Zandee FDA PhUSE Computational Sciences Nonclinical Topics Working Group The ability to aggregate and analyze histopathology data from mulple toxicology studies provides the opportunity to idenfy trends in target organ toxicies and lesions of concern, and to readily compare results across studies. This funconality is provided by HistoGraphic, a novel graphical display tool which ulizes a ‘sunburst’ format based on a hierarchical concentric ring structure. As proof-of-concept, histopathology data from mulple toxicology studies were obtained from the European Union’s Innovave Medicines Iniave (IMI) eTOX consorum, which constutes a database of legacy toxicity data from member pharmaceucal companies. HistoGraphic is highly interacve and provides the means for idenfying major target organs for each compound, and can be searched by organ or lesion descriptor to rapidly idenfy findings of interest. HistoGraphic is based on open-source soſtware. The histopathology data depicted in the above ‘sunburst’ plots have been obtained by aggregang data from 10 studies across two species for compound AZD2014. Color is used to differenate between organs with organ segment size indicang the frequency of lesion findings. These charts are interacvely zoomable. Citaon: Ondov, B. D., Bergman, N. H., & Phillippy, A. M. (2011). Interacve metagenomic visualizaon in a Web browser. BMC Bioinformacs, 12, 385. Citaon: Sanz, F., Pognan, F., Steger-Hartmann, T,. et al. Legacy data sharing to improve drug safety assessment: the eTOX project: Nature Reviews, Drug Discovery, Volume 16, December 2017 ,811 - Innovave Medicines Iniave (IMI). 3: What findings are present in these organs? Can we rank order them within target organ? 4: Can we search for a specific lesion or descriptor term? The HistoGraphic spreadsheet can be edited prior to graphing to answer quesons such as: Are there findings of high severity at relavely low incidence? How do the findings compare across compounds? Can we differenate stress- related findings (potenally remove/isolate these findings from analysis)? 1: What are the target organs? Can we rank order them based on frequency of findings? 2: What are the target organs? Can we rank order them by species within target organ? 5: Was there a dose rela- onship? Was there a difference between treated and controls? 6: Which species did these findings occur in? Was the finding present in both males and females? 7: Is there a relaonship with study duraon or necropsy day? Oral Toxicity studies of AZD2014 obtained from eTOX database for inclusion in HistoGraphic Study ID Number Species Study Dura- tion (days) Doses (mg/kg) 1 Rat 29 0, 2, 12, 18 2 Rat 29 0, 6, 12, 22 3 Rat 15 22, 25 4 Rat 14 22 5 Rat 28 0, 6, 12, 22, 25 8 Rat 15 22 10 Rat 29 22 11 Rat 5 25 12 Dog 29, 57* 0, 1, 3, 5 13 Dog 15 5, 10 Histopathology data were group summary and not indi- vidual animal data (non-SEND); Standardized tissue and lesion terms utilized; *Believed to be recovery phase. Citation: Pike, K., Malagu, K., Hummersone, M., et al. Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014: Bioorganic & Medicinal Chemistry Letters 23 (2013) 1212 - 1216 AZD2014 chemical structure: