Cambridge Healthtech Institute’s 13th Annual
Advances in Drug Metabolism & Safety Testing
Optimizing Drug Metabolism; Predicting Drug Toxicity; Improving Translation into Clinic
June 2-4, 2020
Lead compounds in drug discovery need to be optimized for both efficacy and safety. Unfortunately, some of the adverse events related to metabolism, clearance, transport and drug-drug interactions do not surface until much later in development. Similarly,
cardiotoxicity, hepatotoxicity and idiosyncratic drug toxicity continue to haunt the drug development process. While new screening technologies, in vitro assays, in vivo models and computational tools are being developed and used,
scientists are still unclear about when, where and which tools to use, how reliable the data is, and how predictive the translation is from in vitro to in vivo. Cambridge Healthtech Institute’s Advances in Drug Metabolism &
Safety Testing conference looks at the scientific and technological progress being made to optimize lead compounds and predict drug-induced toxicities early in drug discovery, and to better translate these findings to the clinic. The talks and discussions
highlight relevant case studies, recent research findings, and the use of innovative assays and technologies for improving drug safety.
Final Agenda
Day 1 | Day 2 | Day 3 | Download Brochure
Download Preclinical Program Brochure
SC4: Optimizing Drug Metabolism, Drug Clearance and Drug-Drug Interactions - Detailed Agenda
*Separate registration required.
Tuesday, June 2
Lead compounds need to be optimized for metabolism and safety early in the drug development process. Day 1 in the Advances in Drug Metabolism & Safety Testing conference looks at some innovative tools and strategies that are being utilized for lead optimization, particularly for drug metabolism, dosing, and drug-drug interactions. How to utilize these tools for evaluating and optimizing new drug modalities will also be discussed.
10:00 am Main Conference Registration Open
11:15 Chairperson’s Remarks
Li Di, PhD, Research Fellow, Pharmacokinetics, Dynamics and Metabolism, Pfizer
11:25 The Impact of Intracellular Free-Drug Concentration on Prediction of Clearance and Drug-Drug Interaction
Li Di, PhD, Research Fellow, Pharmacokinetics, Dynamics and Metabolism, Pfizer
A novel in vitro method has been developed to estimate in vivo live-to-plasma unbound partition coefficient (Kpuu). The method uses hepatocytes in 4% bovine serum albumin (BSA). BSA
plays an important role in maintaining transporter functional activities, similar to in vivo. In vitro-in vivo correlation (IVIVE) has been established
for liver Kpuu and clearance-mediated by both enzymes and transporters. Applications of the method to predict human clearance and drug-drug interaction (DDI) will be discussed.
11:55 Incorporating Complex in vitro Models in Drug Safety Assessment
Terry Van Vleet, PhD, DABT, Director, Investigative Toxicology, Department of Preclinical Safety, AbbVie
This talk will discuss some example applications of complex in vitro models in early drug safety assessments. A comparison of 2D and 3D model outcomes will be presented as well for perspective.
12:25 pm Complex In vitro Models for ADME Applications: Current Status and Future Perspectives
Jinping Gan, PhD, Senior Principal Scientist, Pharmaceutical Candidate Optimization, Research & Early Development, Bristol-Myers Squibb
The evolving landscape of biopharmaceutical R&D demands more predictive and flexible models for many aspects of preclinical sciences, including ADME applications. Complex in vitro models, typically of more physiological
nature, hold promise to improve translation from preclinical to clinical or from in vitro to in vivo. In this talk, key gaps in ADME translation will be reviewed, examples of
progress will be shared, along with future perspectives.
12:55 Transition to Lunch
1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:30 Session Break
2:00 Chairperson’s Remarks
Donglu Zhang, PhD, Principal Scientist, Drug Metabolism and Pharmacokinetics, Genentech, Inc.
2:05 Local Metabolism Leads to Better Understanding of Tissue Drug Concentration for New Modalities
Donglu Zhang, PhD, Principal Scientist, Drug Metabolism and Pharmacokinetics, Genentech, Inc.
For small-molecule drugs, the liver is the major organ for drug clearance. Liver in vitro systems can be used to predict in vivo PK. Plasma drug concentration is a good surrogate
for tissue concentrations. For new modalities, especially drug conjugates, there is a universal lysosomal degradation of proteins for clearance and generation of active drugs. The efficacy and toxicity is supported by the drug that is released
locally in the right form and concentration from a conjugate. This talk discusses the importance of tissue metabolism.
2:35 Novel Microbiome-Targeting Drugs to Improve the Therapeutic Window of Prescription Medicines
Ward Peterson, PhD, President & CEO, Symberix Inc.
The use of various classes of prescription medicines are frequently associated with dose-limiting intestinal sequelae. These drugs undergo glucuronidation by liver UDP-glucuronosyltransferases and subsequent de-glucuronidation by gut bacterial b-glucuronidases
(GUS), resulting in the production of toxic drug catabolites in the intestinal lumen. Symberix’s approach for ameliorating these toxicities is to selectively inhibit bacterial GUS with microbiome-targeting “symbiotic drugs” that
do not damage the endogenous microbiota.
3:05 Developing and Embedding an in vitro Capability to De-Risk Translational in vivo Attributes of Therapeutic Antibody Panels
Daniel Rycroft, Antibody Pharmacology Team Leader and GSK Associate Fellow, Biopharm Molecular Discovery, GSK
While it is well established that small sequence differences between therapeutic monoclonal antibodies cause a range of biophysical attributes which can affect the manufacturability potential of drug candidates, it is now becoming increasingly understood
that these same properties can impact in vivo suitability. By using a panel of orthogonal in vitro methods, it is however possible to de-risk antibody panels for in vivo properties without the need for iterative in vivo studies.
3:35 Sponsored Presentation (Opportunity Available)
4:05 Networking Refreshment Break and Transition to Keynote
4:25 - 6:05
Driving Entrepreneurial Innovation to Accelerate Therapeutic Discoveries
The life sciences community has an unprecedented scientific arsenal to discovery, develop and implement treatments, cures and preventions that enhance human healthcare.
Moderator: Nadeem Sarwar, President, Eisai Center for Genetics Guided Dementia Discovery (G2D2), Eisai Inc.
Panelists: Anthony Philippakis, Chief Data Officer, Broad Institute; Venture Partner, GV
Barbara Sosnowski, Vice President and Global Head, Emerging Science & Innovation Leads, WWRDM, Pfizer
John Hallinan, Chief Business Officer, Massachusetts Biotechnology Council
6:05 Welcome Reception in the Exhibit Hall with Poster Viewing
7:10 Close of Day
Day 1 | Day 2 | Day 3 | Download Brochure
Wednesday, June 3
Day 2 in the Advances in Drug Metabolism & Safety Testing conference focuses on innovative use of screening assays, computational and machine learning tools for better assessing and predicting drug-related toxicities. The talks highlight ways to use CRISPR screening, quantitative modeling, AI/ ML algorithms, and high-performance computing to make better and more accurate drug safety predictions early in the drug development process.
7:30 am Registration Open and Morning Coffee
8:10 Chairperson’s Remarks
Jason Sheltzer, PhD, Principal Investigator, Cold Spring Harbor Laboratory
8:15 Off-Target Toxicity is a Common Mechanism of Action of Cancer Drugs Undergoing Clinical Trials
Jason Sheltzer, PhD, Principal Investigator, Cold Spring Harbor Laboratory
We have recently applied CRISPR mutagenesis to demonstrate that many putative targeted inhibitors in clinical trials kill cancer cells independently of their reported targets. This off-target toxicity raises significant safety concerns and may contribute
to the frequent failure of new anti-cancer drugs. We discuss multiple genetic strategies to ensure on-target drug activity and to minimize potentially harmful off-target interactions.
8:45 CRISPR Screens Identify Regulators of Antibody-Drug Conjugate Toxicity
Kimberly Tsui, PhD, Postdoctoral Fellow, Laboratory of Dr. Andrew Dillin, Department of Molecular and Cell Biology, University of California, Berkeley
Using CRISPR-Cas9 screens, we have uncovered many known and novel endolysosomal regulators as modulators of Antibody-drug conjugate (ADC) toxicity. Through comparative analysis of screens with ADCs bearing different linkers, we show that a subset
of late endolysosomal regulators selectively influence toxicity of non-cleavable linker ADCs. These results reveal new regulators of endolysosomal trafficking, provide important insights for ADC design and identify candidate combination therapy
targets.
9:15 Application of Tox21 qHTS Data in Predicting Drug Toxicity
Ruili Huang, PhD, Group Leader, Tox21 Informatics, National Center for Advancing Translational Sciences, National Institutes of Health
Target-specific, mechanism-oriented in vitro assays post a promising alternative to traditional animal toxicology studies. The Tox21 program, a large-scale in vitro chemical toxicity
screening effort, has tested ~10K drugs and environmental chemicals in quantitative high-throughput screening (qHTS) format against a panel of ~70 assays, producing more than 100 million data points to date. Strategies will be discussed on applying
this rich set of in vitro activity profiles to assess potential drug toxicity.
9:45 Sponsored Presentation (Opportunity Available)
10:15 Coffee Break in the Exhibit Hall with Poster Viewing
11:00 Using DILIsym to Predict Hepatotoxicity Risk during Preclinical Development
Paul Michalski, PhD, Investigator, Systems Modeling and Translational Biology, GlaxoSmithKline
DILIsym is a quantitative systems toxicology (QST) model of drug-induced liver injury (DILI) developed primarily to provide mechanistic understanding of clinically observed hepatotoxicity. We recently evaluated DILIsym as a screening tool for preclinical
development. Here we will give an overview of DILIsym and discuss the results of our evaluation, highlighting where DILIsym can provide value in early development. We also provide practical advice on the steps required to industrialize DILIsym
as an in-house screening tool.
11:30 Accelerating Drug Discovery through Accurate Safety Predictions: One Goal of The ATOM Consortium
Sarine Markossian, PhD, Specialist, Department of Pharmaceutical Chemistry, University of California San Francisco
The Accelerating Therapeutics for Opportunities in Medicine (ATOM) consortium is an academia, industry, and government partnership with the goal of rapidly accelerating drug discovery by integrating high-performance computing and diverse biological
data. One of our goals in ATOM is to optimize preclinical safety predictions, so we can incorporate predictive toxicology early in the drug discovery process. Here we present our strategy and efforts towards reliably measuring and predicting drug-induced
liver injury (DILI).
12:00 pm Sponsored Presentation (Opportunity Available)
12:30 Transition to Lunch
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:05 Session Break
1:45 - 3:15
Lgr5 Stem Cell-Based Organoids in Human Disease
Hans Clevers, MD, PhD, Principal Investigator of Hubrecht Institute and Princess Máxima Center, CSO of HUB Organoids Technology
Organoid technology opens a range of applications in fields such as physiology, study of disease, drug development and personalized medicine. Human organoids represent excellent disease models, be it infectious, hereditary or malignant Eventually,
cultured mini-organs may be used to replace transplant organs from donors. I will describe how we originally created ‘mini-guts’ via 3D culture systems of stem cells of the small intestine and colon, and then expanded the technology
to virtually all human organs.
Systematically Drugging Ras
Stephen Fesik, PhD, Professor of Biochemistry, Pharmacology, and Chemistry, Orrin H. Ingram II Chair in Cancer Research, Vanderbilt University School of Medicine
K-Ras is a small GTPase that is mutated in pancreatic (90%), colon (50%), and lung (30%) carcinomas. Downregulation of activated Ras reverses the transformed phenotype of cells and results in the dramatic regression of tumors in murine xenograft models.
Thus, K-Ras inhibition represents an attractive therapeutic strategy for many cancers. In this presentation, I will discuss our efforts to directly target Ras at two sites and target SOS, a molecular partner of Ras, with activators and inhibitors.
3:15 Refreshment Break in the Exhibit Hall with Poster Viewing
4:00 Chairperson’s Remarks
Barun Bhhatarai, PhD, Investigator, Novartis Institute for Biomedical Research
4:05 ML and AI on ADME/Tox Accelerating Drug Discovery
Barun Bhhatarai, PhD, Investigator, Novartis Institute for Biomedical Research
ML- and AI-related approaches have been tested and applied in various areas within Novartis. In ADMETox, ML approaches are serving intended purposes and complementing experimental methods. With the advent of AI, ingenious deep learning algorithms,
and powerful micro-processors, we have explored its anticipated benefit in preclinical and clinical programs. Our various efforts on data digitization, ML and AI implementation, and collaborations will be discussed with specific examples from
ADMETox.
4:35 Artificial Intelligence and Small-Molecule Drug Metabolism
Joshua Swamidass, MD, PhD, Assistant Professor, Immunology and Pathology, Laboratory and Genomic Medicine; Faculty Lead, Translational Informatics, Institute for Informatics, Washington University
We have been building artificial intelligence (AI) models of metabolism and reactivity. Metabolism can both render toxic molecules safe and safe molecules toxic. The AI models we use quantitatively summarize the knowledge from thousands of published
studies. The hope is that we could more accurately model the properties of medicines to determine whether metabolism renders drugs toxic or safe. This is one of many places where artificial intelligence could give traction on the difficult
questions facing the industry.
5:05 Find Your Table, Meet Your Moderator
5:10 Roundtable Breakout Discussions - View Details
TABLE: Impact of Artificial Intelligence and Machine Learning on Drug Safety Assessments
Moderators: Barun Bhhatarai, PhD, Investigator, Novartis Institute for Biomedical Research
Joshua Swamidass, MD, PhD, Assistant Professor, Immunology and Pathology, Laboratory and Genomic Medicine; Faculty Lead, Translational Informatics, Institute for Informatics, Washington University
TABLE: Traditional and Advanced Models and Strategies for Early Risk Assessments
Moderators: Terry Van Vleet, PhD, DABT, Director, Investigative Toxicology, Department of Preclinical Safety, AbbVie
Paul Michalski, PhD, Investigator, Systems Modeling and Translational Biology, GlaxoSmithKline
5:45 Reception in the Exhibit Hall with Poster Viewing
6:45 Close of Day
Day 1 | Day 2 | Day 3 | Download Brochure
Thursday, June 4
Translation of preclinical findings to the clinical setting remains a formidable challenge in drug development. Day 3 in the Advances in Drug Metabolism & Safety Testing conference focuses on attempts being made to reduce those gaps in translation and to find better ways to accurately predict clinical outcomes. The talks will highlight scientific and technical innovations and applications that are making this possible.
8:00 am Registration Open and Morning Coffee
8:30 - 9:40 Applications of Artificial Intelligence in Drug Discovery – Separating Hype from Utility
Patrick Walters, PhD, Senior Vice President, Computation, Relay Therapeutics
Over the last few years, there has been tremendous interest in the application of artificial intelligence and machine learning in drug discovery. Ultimately, the success of any predictive model comes down to three factors: data, representation,
and algorithms. This presentation will provide an overview of these factors and how they are critical to the successful implementation and deployment of AI methods.
9:40 Coffee Break in the Exhibit Hall with Poster Viewing
10:25 Chairperson’s Remarks
James Hickman, PhD, Founding Director, NanoScience Technology Center and Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida
10:30 Lost in Translation: Challenges in Interpreting in vitro Studies Using Human-Derived Tissues
Gary Gintant, PhD, Senior Research Fellow, Department of Integrative Pharmacology, Integrated Science and Technology, AbbVie
With the advent of human-derived cells and tissues has come newfound challenges for the translation of in vitro study findings to guide drug development. This presentation will focus on biological and platform-related
challenges (and potential solutions) for nonclinical safety studies with human-derived tissues.
11:00 Human Heart Slices as a Reliable Platform for Predicting Cardiotoxicity
Tamer Mohamed, PhD, Assistant Professor of Medicine, Institute of Molecular Cardiology, University of Louisville
Culturing human heart slices is a promising model of intact human myocardium. This technology provides access to the complete 3D multicellular system that is similar to the human heart tissue that reflects the human myocardium in physiological
or pathological conditions, both functionally and structurally. Recently, we have developed a novel biomimetic culture system that maintains full viability and functionality of human and pig heart slices (300 µm thickness) for 6
days in culture.
11:30 Human-on-a-Chip Applications in ADME/Tox to Predict Clinical Outcomes
James Hickman, PhD, Founding Director, NanoScience Technology Center and Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida
Multi-organ human-on-a-chip platforms have been used to demonstrate concurrent measurement of efficacy and toxicity for therapeutic index estimation. Evaluation of drugs and compounds has shown similar responses to results seen from clinical
data, as well as demonstrated long-term (28-day) function. Applications for ALS, Alzheimer’s, rare diseases, diabetes, and cardiac mechanistic toxicity will be reviewed. The development of in vitro PDPK models that are being used to predict in vivo results will also be presented.
12:00 pm Sponsored Presentation (Opportunity Available)
12:30 Transition to Lunch
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:05 Dessert and Coffee Break in the Exhibit Hall with Poster Viewing
2:00 Chairperson’s Remarks
Madhu Lal-Nag, PhD, Program Lead, Research Governance Council, Office of Translational Sciences, Center for Drug Evaluation & Research, U.S. Food and Drug Administration
2:05 Emerging Microphysiological Systems for Drug Safety Testing: A Regulatory Perspective
Madhu Lal-Nag, PhD, Program Lead, Research Governance Council, Office of Translational Sciences, Center for Drug Evaluation & Research, U.S. Food and Drug Administration
There is a great need to understand the synergy between the areas of translational and regulatory science research as they pertain to microphysiological systems and their application in evaluating safety and efficacy for therapeutic indications
for different disease areas. My presentation will focus on identifying these areas of synergy and focus on the development of microphysiological systems that are a best fit for different applications.
2:35 Microphysiological Systems: Tissues on Chip for Safety, Toxicity, and Efficacy Tools in Precision Medicine
Danilo Tagle, PhD, Associate Director, Special Initiatives, National Center for Advancing Translational Sciences, National Institutes of Health
Microphysiological systems are bioengineered in vitro tools that mimic the 3D structure and function of human organ systems and have been developed to improve the predictive assessment of the safety and efficacy
of promising therapeutics. The use of human-derived cells and tissues have increased the utility of tissue chips towards modeling diseases and for clinical trials on chips to inform human trial design. The presentation will focus on the
latest advances in this promising technology.
3:05 Of Microtissues and Men: Applications of Advanced in vitro Systems in Toxicology
Matthew Wagoner, PhD, Director, Investigative Toxicology, Takeda Pharmaceutical
Advanced in vitro cell culture systems are transforming the way we design safer medicines. Here we share case studies of how neural, hepatic, and intestinal organoids are allowing us to more effectively detect
and de-risk toxicity, while reducing a reliance on animal models.
3:35 Close of Conference
Day 1 | Day 2 | Day 3 | Download Brochure