Cambridge Healthtech Institute’s 13th Annual

Advances in Drug Metabolism & Safety Testing
( 藥物代謝與安全性測試的進步 )

藥物代謝優化、藥物毒性預測、新藥模態評估

2020年6月2日~4日


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

Recommended Short Course*

SC4: Optimizing Drug Metabolism, Drug Clearance and Drug-Drug Interactions

*Separate registration required.

6月2日 (二)

10:00 am Main Conference Registration Open

EARLY METABOLISM & SAFETY ASSESSMENTS

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

ASSESSING NEW DRUG MODALITIES

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 In vitro ADME Challenges in Assessing New Modalities

Zhengyin Yan, PhD, Principal Scientist, Department of Drug Metabolism and Pharmacokinetics, Genentech Inc.

New modalities, such as covalent modulators, macrolides, macrocyclic peptides, and antibody-drug conjugates, have distinct physicochemical properties, and they pose a variety of unique challenges in assessing various ADME properties, including metabolic stability, plasma protein binding, and CYP inhibition. As a result, inaccurate in vitro ADME data can be reported unnoticedly. Some case studies, as well as alternative strategies on how to overcome those technical challenges and safeguard data quality, will be discussed.

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


PLENARY KEYNOTE SESSION

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

6月3日 (三)

7:30 am Registration Open and Morning Coffee

IDENTIFYING OFF-TARGET DRUG TOXICITY

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 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.

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

STRATEGIES FOR EARLY RISK ASSESSMENTS

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


PLENARY KEYNOTE SESSION

1:45 - 3:15

Lgr5 Stem Cell-Based Organoids in Human Disease

Hans Clevers, MD, CSO, Director of Research, Princess Máxima Center for Pediatric Oncology, University Medical Center Utrecht; Principal Investigator, Hubrecht Institute for Developmental Biology and Stem Cell Research

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

3:15 Refreshment Break in the Exhibit Hall with Poster Viewing

USE OF AI/ML FOR ADME/Tox PREDICTIONS

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

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

6月4日 (四)

8:00 am Registration Open and Morning Coffee


PLENARY KEYNOTE SESSION

8:30 - 9:40 Applications of Artificial Intelligence in Drug Discovery – Separating Hype from Utility

Patrick Walters, PhD, Senior Vice President, Computation, Relay Therapeutics

9:40 Coffee Break in the Exhibit Hall with Poster Viewing

OVERCOMING TRANSLATIONAL CHALLENGES

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

* 活動內容有可能不事先告知作更動及調整。

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6月2日~4日

加速標靶發現

擴大化合物與Druggable空間

新小分子標靶

新適應症與模態

癌症免疫療法進步

疾病模型

腫瘤治療領域臨床前研究策略的模式與工具

藥物代謝與安全性測試的進步

癌症免疫療法生物標記

臨床與轉譯生物標記

新藥發現與開發的AI

6月3日~4日

新藥發現的技術


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