Cambridge Healthtech Institute 第13回

Advances in Drug Metabolism & Safety Testing
( 薬物代謝・安全性試験の進歩 )

薬物代謝の最適化、薬物毒性の予測、臨床段階へと向かうトランスレーショナル研究の改善

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 (火)

OPTIMIZING DRUG METABOLISM

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

早期代謝と安全性評価

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

Di_LiLi 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

Van_Vleet_TerryTerry 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_GanJinping 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

医薬品の新たなモダリティの評価

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

Peterson_WardWard 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

Rycroft_DanielDaniel 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.

Sarwar_NadeemModerator: 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 (水)

PREDICTING DRUG TOXICITY

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

医薬品の標的外毒性の同定

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

Sheltzer_JasonJason 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

Tsui_KimberlyKimberly 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

Huang_RuiliRuili 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

早期リスク評価のための戦略

11:00 Using DILIsym to Predict Hepatotoxicity Risk during Preclinical Development

Michalski_PaulPaul 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

Markossian_SarineSarine 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

Clevers_HansHans 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

Fesik_StephenStephen 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

人工知能と機械学習を利用した薬物動態と毒性の予測

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

BHHATARAI_BarunBarun 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_SwamidassJoshua 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

6月4日 (木)

IMPROVING TRANSLATION INTO CLINIC

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


PLENARY KEYNOTE SESSION

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

Walters_PatrickPatrick 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

トランスレーショナル研究の課題克服

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_GintantGary 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

Mohamed_TamerTamer 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_HickmanJames 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

Lal_MadhuMadhu 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

Tagle_DaniloDanilo 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

Wagoner_MattMatthew 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

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。

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更新履歴
2020/03/06
アジェンダ・講演者・スポンサー更新


6月2日~4日

創薬ターゲット探索の加速

化合物空間とドラッガブル空間の拡大

新たな低分子薬の標的

新たな適応症とモダリティ

がん免疫療法の進歩

疾患モデル

腫瘍治療の分野における前臨床研究戦略のモデルとツール

薬物代謝・安全性試験の進歩

がん免疫療法に対応するバイオマーカー

臨床バイオマーカーとトランスレーショナルバイオマーカー

創薬と開発のためのAI

6月3日~4日

創薬のための技術


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