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Drug Safety Strategies to De-Risk Compounds Agenda
Drug Discovery & Development Week 2009: August 3-6, 2009· The World Trade Center Boston and Seaport Hotel · Boston, MA
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Pre-Conference Workshop - Tuesday, August 4, 2009
Drug-Induced Mitochondrial Dysfunction
2:00
Workshop Chair Opening Remarks
Yvonne Will, Ph.D., Senior Principal Scientist, Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer Global R&D
2:05
Mitochondrial Function and Failure: An Emerging Model for Idiosyncratic Drug Toxicity
Mitochondria produce almost all the energy in cells, but also chronically expose the cell to cytotoxic free radicals. Many widely prescribed therapeutics undermine mitochondrial function by interfering with DNA replication or expression, and more acutely, by uncoupling or inhibiting oxidative phosphorylation, leading to a variety of organ toxicities such as hepatic, cardiac, muscle, kidney and CNS. This talk will focus on fundamental mechanisms of mitochondrial physiology and failure, and so provide a foundation for subsequent talks.
James A. Dykens, Ph.D., Associate Research Fellow, Drug Safety R&D, Pfizer, United Kingdom
2:45
Strategies to Reduce NCE Attrition Due to Mitochondrial Toxicity-Novel Screening Methods
Early identification of new chemical entities (NCEs) that perturb mitochondrial function is of significant importance in drug discovery if attrition due to toxicity is to be avoided. We have tested oxygen sensors to measure mitochondrial respiration in isolated mitochondria and cells, immunocapture of individual electron transport chain proteins that can identify inhibitors of mitochondrial electron transport and metabolic profiling using solid oxygen and pH measurements. We discuss the strength and limitations of new HTS applicable screens and provide recommendations of where to position these assays within drug development.
Yvonne Will, Ph.D., Senior Principal Scientist, Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer Global R&D
3:15
Networking Break in Exhibit & Poster Hall
3:45
A Systems Biology Approach to Mitochondrial Toxicity and Mitochondrial Function
To investigate how mitochondrial function and regulation are integrated within cells, we systematically combined four cell-based assays of mitochondrial physiology with multiplexed measurements of nuclear and mtDNA gene expression across 2,490 small-molecule perturbations in cultured muscle. Our screening compendium can be used as a discovery tool both for understanding mitochondrial biology and toxicity and for identifying novel therapeutics.
Vamsi Mootha, M.D., Associate Professor of Systems Biology and Medicine, Massachusetts General Hospital and Harvard Medical School
4:15
Mitochondrial Toxicity in Drug Development: The Heart of the Matter
The development of kinase inhibitors as drug candidates also generates many opportunities for toxicity, not only as a result of the inhibition of desired targets but, also because of inhibition of off-target kinases. Mitochondrial dysfunction and energy depletion seem to be a common theme in these toxicities, and the heart seems to be a prominent target organ. We are currently working with a large library of kinase inhibitors in order to identify assays predictive of cardiotoxicity and more importantly have a mechanistic understanding of how specific kinase inhibitors lead to mitochondrial toxicity and loss of cardiac function.
Hirdesh Uppal, Ph.D., Research Scientist, Investigative Toxicology, Non-Clinical Drug Safety, Roche Pharmaceuticals Palo Alto
Strategic Discussion Group
4:45
Mitochondrial Dysfunction and Drug Safety
- Is all idiosyncratic toxicity a result of mitochondrial dysfunction?
- What high-throughput approaches are emerging to explore the complexity of mitochondrial biology and drug safety?
- Organ toxicities and in vitro testing methodologies
- Systems biology approaches to mitochondrial dysfunction
- How to fill the gap on SAR studies of mitochondrial toxicity
Moderator: Yvonne Will, Ph.D., Senior Principal Scientist, Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer Global R&D
Plenary Keynote
5:20
Keynote Introduction
Osamu Sato, Ph.D., Director & Head of Medical Writing Group, Daiichi-Sankyo Co., Ltd., Japan
5:25
Global Pharma Innovator: Daiichi Sankyo's Challenge to Build a Competitive Pharmaceutical Company in the Global Market
The current challenge for Japanese pharmaceutical companies to stay competitive in the global marketplace, is to expand product offerings and sales and increase R&D and clinical development capabilities in the U.S., Europe and other markets outside of Japan. This presentation will discuss Daiichi Sankyo's vision and strategy for transforming itself from a Japan-based pharmaceutical company to a truly global pharmaceutical player. Recent implementations of this strategy including the incorporation of Ranbaxy (India) and U3 Pharma (Germany) into the Daiichi Sankyo family will be discussed.
Takashi Shoda, President and CEO, Daiichi Sankyo Co., Ltd., Japan
6:00
Cocktail Reception in Exhibit & Poster Hall
Main Conference - Wednesday, August 5, 2009
7:30
Registration and Coffee
8:10
Conference Chair Opening Remarks
Vivek (Vic) Kadambi, Ph.D., Senior Director, Drug Safety Evaluation, Millennium, The Takeda Oncology Company
Improving Hepatotoxicity Models
8:15
Non-Clinical Findings Predicting for Human Liver Injury (Including Idiosyncratic)
Mechanisms postulated for liver toxicity in humans are not unique to humans. A review of the non-clinical liver findings and structural alerts for over 20 prototypical agents inducing liver injury enables identification of a series of non-clinical risk factors predicting for hepatotoxicity in the clinic. Ultimately, hepatocyte in vitro test systems with application of select molecular probes will provide earlier stage guidance for the medicinal chemist in synthesizing molecules with low likelihood of induction of chemical structure based liver injury. New interpretations of non-clinical findings are requisite for success in the predictive toxicology paradigm.
Carl L. Alden, DVM, Vice President, Drug Safety Evaluation, Millennium, The Takeda Oncology Company
8:40
Novel Approaches for Drug Development Using Mice with Humanized Livers
We run a "liver-humanized mouse factory' for investigating drug metabolism and the propagation of human hepatitis viruses (HV). The hitherto data support that the mice are powerful to predict the metabolic patterns of medicines and efficacy of anti-HV drugs, and could be used for drug toxicity tests.
Katsutoshi Yoshizato, Ph.D., Guest Professor, Osaka City University and Academic Advisor, Phoenixbio Co., Japan
9:05
Engineering Microscale Liver Models for Drug Development
Here, we present miniaturized, multi-well human and rodent liver tissue models with optimized microscale architecture that maintain phenotypic functions for up to 12 weeks in vitro. We demonstrate model utility via characterization of global gene expression profiles, phase I-II metabolism, bile canalicular transport, secretion of liver-specific products, drug-drug interactions, species-specific drug metabolism, and susceptibility to a panel of hepatotoxins. In the future, the combination of microtechnology and tissue engineering may spur development of other tissue models and their integration towards the so-called ‘human-on-a-chip'.
Salman R. Khetani, Ph.D., Director of Research, Hepregen Corporation
9:30
Imaging Techniques for Assessing Toxicity in Primary Human Hepatocytes
Hepatotoxicity is a major cause of late stage attrition for drug candidates. Image-based discovery and predictive toxicology assays are a quantitative approach that correlates highly with accepted gold-standard toxicity tests and provides a mechanism to accurately assess safety concerns early in the development process.
Eric Tien, Ph.D., Senior Scientist, Pfizer, Inc.
Conference Keynote
(open to all attendees and exhibit hall visitors)
9:55
Skirting Drug Safety Potholes in the Critical Path to POC
The last thing drug developers want is an ambiguous set of preclinical safety data that clouds their chances for achieving proof-of-concept for a new therapy. At the same time, eliminating projects likely to cause cardiovascular, liver, renal and other toxic events at an early stage is crucial to efficient drug development. This presentation will discuss the need for and progress towards translational and biomarker strategies that improve preclinical-clinical toxicity predictions and allow for safe and efficient transitions to clinical POC studies.
William B. Mattes, Ph.D., Director of Toxicology, The Critical Path Institute
10:20
Networking Refreshment Break in Exhibit & Poster Hall
Biomarker Development: Regulatory Perspectives
11:00
Biomarker Development and their Clinical Qualification
A biomarker is characteristic that is objectively measured and evaluated as an indicator of normal biologic process, pathogenic processes, or pharmacologic responses to a therapeutic intervention (Biomarkers Definition Working Group, Clin. Pharmacol. Ther. 2001 69:89-95). In this regard, the spectrum of uses for biomarkers ranges from diagnostic tools (early identifiers of disease, target identification), patient identification/triage (e.g. Her-2-Nu positive for treatments with Herceptin), tools in assessing response to therapy (mechanistic biomarkers and imaging modalities) and biomarkers that are used for staging disease progression. This presentation will describe some of the biomarker development efforts underway at FDA and in partnership with FDA, and will list some of the benefits obtained to date.
Wendy R. Sanhai Ph.D., Senior Scientific Advisor, Office of the Commissioner, FDA
11:25
Regulatory Perspective on Qualification & Implementation of PET & Radiolabeled Imaging Biomarkers in Multicenter Clinical Trials
This presentation will review the regulatory needs assessment and other elements to address through a centralized IND to introduce investigational PET imaging agents in large multicenter clinical trials to support investigational drug and biologic development. It will describe the implementation of the Centralized IND to facilitate early "Go-No Go" decision making in Early Phase 1 (Exploratory IND) clinical trials and describe regulatory imaging standardization needs and processes, implementation of centralized PET imaging phantoms and the regulatory challenges and risks associated with distributed, multicenter manufacture of PET and radiopharmaceuticals.
George Q. Mills, M.D., Vice President, Medical Imaging Consulting, Perceptive Informatics (PAREXEL) and Former FDA Division Director, Medical Imaging and Hematology Products, Office of Oncology Drug Products, CDER, FDA
Strategic Discussion Group
11:50
What Is Needed From Biomarkers for Preclinical and Clinical Testing?
- Biomarkers in toxicity prediction and disease assessment
- Lessons learned from the FDA biomarker qualification process
- Surrogate biomarkers and diagnostic biomarkers
- Improving and translating toxicity prediction from preclinical to man
Moderator: Shawnmarie Mayrand-Chung, Ph.D., NIH Program Director, The Biomarkers Consortium Public-Private Partnership Program, National Institutes of Health
Wendy R. Sanhai Ph.D., Senior Scientific Advisor, Office of the Commissioner, FDA
George Q. Mills, M.D., Vice President, Medical Imaging Consulting, Perceptive Informatics (PAREXEL) and Former FDA Division Director, Medical Imaging and Hematology Products, Office of Oncology Drug Products, CDER, FDA
William B. Mattes, Ph.D., Director of Toxicology, The Critical Path Institute
12:30
Networking Luncheon in Exhibit & Poster Hall
Improving Models of Cardiovascular Toxicity
2:00
Pure Murine Embryonic Stem Cell-derived Cardiomyocytes: A Predictive Tool for the Assessment of Cardiotoxicity
Pure murine embryonic stem cell-derived Cor.At cardiomyocytes present a new and highly predictive cellular model to assess efficacy and cardiotoxicity of compounds. Provided as frozen stocks, the primary-like cells recover completely after thawing and are ready-to-use for the application in manual and automated patch clamping as well as label-free detection systems or common endpoint assays.
Ralf Kettenhofen, Ph.D., Senior Scientist, Axiogenesis AG, Germany
2:35
QTempo: A More Sensitive, Accurate Alternative to the hERG Assay Utilizing Pluripotent Stem Cell-derived Beating Cardiomyocytes
Drug-induced QT interval prolongation (DIQTIP) can lead to sudden cardiac death and is a major safety concern for the drug industry and regulating agencies. To reduce the risk of DIQTIP, drug candidates are routinely assayed for in vitro electrophysiological properties using cell-based assays. Here we report the development of QTempo (QT prolongation Examination with Myocardia derived from Pluripotent cell), a significantly improved assay that incorporates beating cardiomyocytes derived from stem cells.
Yasuyuki Asai, Ph.D., Chief Technology Officer, ReproCELL, Inc., Japan
3:10
Therapeutic Benefit Versus Cardiovascular Toxicity with Anticancer Therapy
Given that the probability of morbidity/mortality in cancer progression is higher than that of adverse cardiovascular effects, the threshold for tolerance and risk management in oncology should be considered. Although cardiovascular safety pharmacology studies are not required for an IND submission in oncology, using these studies to weed out molecules with cardiovascular liabilities that are not mechanism based, will offer pharmaceutical companies a competitive advantage. This presentation will include an oncology discovery based screening strategy to nonclinically evaluate the cardiovascular liabilities of anticancer therapeutics followed by case studies of adverse effects of molecularly targeted anticancer therapeutics on cardiac hemodynamics, mechanical and electrical function.
Vivek (Vic) Kadambi, Ph.D., Senior Director, Drug Safety Evaluation, Millennium, The Takeda Oncology Company
3:45
Networking Refreshment Break in Exhibit & Poster Hall
Emerging Technologies and Models to Improve Predictivity from Preclinical to Clinical
4:30
Application of Omic Technologies to Identify Biomarkers of Toxicity
Drug-induced toxicity remains an area of great concern and the lack of a complete mechanistic understanding is hampering our search for biomarkers to enable better preclinical and clinical detection. Identification of biomarkers using pharmacogenomics, metabolomics and proteomics has the potential to move us closer to the promise of personalized medicine.
Donna L. Mendrick, Ph.D., Director, Division of Systems Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration
4:55
Human Proximal Tubule Cell Monolayers: A New Approach to Understand Renal Drug-drug Interactions
Understanding renal drug handling has been severely hampered by the lack of a suitable experimental model. Current animal models show poor correlation with human in-vivo data. Here we describe a human proximal tubule cell model that provides a robust and reproducible model of human renal drug handling and drug-drug interactions.
Colin D A Brown, Ph.D., Associate Professor, Institute for Cell & Molecular Biosciences, Medical School, University of Newcastle, United Kingdom
POINT/COUNTERPOINT
POINT: Animal models have limitations in predicting human safety
COUNTERPOINT: Animal models are useful today in predicting human safety
5:20
Are Animal Models of Disease Predictive of Human Drug Safety?
This session will debate the merits of current animal models of cardiovascular toxicity and hepatotoxicity. Panelists will address both sides of the question including the following issues:
- What are the current models and how are they performed?(eg. species/normal or genetically modified etc.)
- What are the plusses and limitations of current models? Which are predictive and which are not?
- Can one translate results (positive or negative) into people?
- Do animal models provide too much information?
- What are the regulatory requirements and considerations when using animal safety models?
- What is the impact of the European guidance on use of animals for predicting dose in humans.
Panelists:
Alain Stricker-Krongrad, Ph.D., Chief Scientific Officer, Preclinical Sciences, Charles River Laboratories, Inc.
Vivek (Vic) Kadambi, Ph.D., Senior Director, Drug Safety Evaluation, Millennium: The Takeda Oncology Company
Lauren E. Black, Ph.D., Senior Scientific Advisor, Charles River Laboratories
Tim MacLachlan, Ph.D., Associate Director of Nonclinical Safety Assessment, Genzyme Corporation
Jim Murray, Principal Research Associate, Nonclinical Safety Assessment, Genzyme Corporation
6:00
Attendee Networking Dinner
Join fellow attendees of the Drug Safety Strategies to De-Risk Compounds conference for dinner. Space is limited and an additional fee applies. Check box on registration form to sign up.
Main Conference - Thursday, August 6, 2009
8:30
Conference Chair Opening Remarks
Eric A.G. Blomme, Ph.D., Director, Investigative Toxicology and Pathology, Global Preclinical Safety, Abbott Laboratories
Case Studies of Translational Approaches from Preclinical Models to Man
8:40
Strategic Application of Preclinical Toxicity Data in Assessing Drug Safety
Safety issues remain a significant cause of late-stage attrition. Thus the ability to improve the translation of preclinical toxicity data to predict clinical safety remains of critical importance. The utility of early screening for ADME/PK properties has significantly reduced the attrition rate due to PK issues. More recently, there has been increasing emphasis on the development and implementation of toxicity screens at earlier stages in the drug discovery paradigm. This presentation will discuss approaches for the early assessment and optimization of compound safety, the integration with ADME/PK data, and the utility of preclinical data to predict clinical safety outcomes.
Alan G.E. Wilson, Ph.D., Fellow ATS, Vice President, Drug Metabolism, Pharmacokinetics, Toxicology and Pathology, Lexicon Pharmaceuticals
9:10
Leveraging Clinical Hepatoxicity Information to Better Understand Mechanisms for Early Drug Discovery
A set of marketed drugs showing hepatotoxicity was identified using textmining and related approaches. These compounds have been screened in early Tox assays and some of them turn up as false negatives. We use a published in-house method to better understand related mechanisms to guide future development of better predictive assays.
Josef Scheiber, Ph.D., Research Investigator, Knowledge Engineering Consultant, Novartis Pharma, Switzerland
9:40
Drug-Induced Delay in Cardiac Conduction - An Elixir Pharmaceuticals Case Study to Identify Mechanism and De-Risk Backups
This talk will present a brief background on the issues surrounding drug induced cardiotoxicity. An Elixir Pharmaceuticals case study in cardiac safety will then be discussed. This historical perspective will illustrate strategies used to identify mechanisms underlying these events, and how they were successfully placed into the testing funnel to screen backup compounds for this liability.
Rory Curtis, Ph.D., Director of Research, Elixir Pharmaceuticals
Michael R. Gralinski, Ph.D., Chief Executive Officer, CorDynamics
10:10
Networking Refreshment Break
10:40
Safety Assessment of Proarrhythmic Potential of Cardiac Drugs
Using a female rabbit heart model with reduced repolarization reserve, we have demonstrated a way of assessing the risk of proarrhythmic activities of drugs that acts on cardiac ion channels. Detection of proarrhythmic activities caused by low risk QT-prolonging drugs will be described.
Lin Wu, M.D., Senior Scientist, Pharmacological Sciences, CV Therapeutics, Inc.
11:10
Three Case Studies of Strategic Use of Novel Technologies in Toxicology to De-risk Compounds
Toxicity represents an important cause of failure in drug development, and identification of toxic liabilities at early stages can decrease R&D costs. Novel technologies can help de-risk compounds by improving the predictive value of preclinical models. In this presentation, we use 3 real case studies to illustrate strategies that leverage carefully selected methodologies to improve hepatoxicity prediction, species-difference extrapolation in toxic response and positioning the data for clinical relevance and the final case study is about how a mechanistic understanding of cardiotoxicity can lead to selection of safer compounds.
Eric A.G. Blomme, Ph.D., Director, Investigative Toxicology and Pathology, Global Preclinical Safety, Abbott Laboratories
11:40
An in vitro and in vivo Evaluation of the Off-Target Profile of the CETP Inhibitor, Torcetrapib
Abstract not available at time of print.
Michael J. Forest, Director of Cardiovascular Pharmacology, Merck
12:10
Networking Luncheon with Attendee/Speaker Chat Sessions
Informal roundtable discussions during the luncheon will be led by conference speakers. Grab your lunch, pick a topic, join a table and meet fellow attendees and conference speakers. Additional topics will be added. To suggest a discussion topic, Please contact us.
Drug-Induced Mitochondrial Dysfunction
Yvonne Will, Ph.D., Senior Principal Scientist, Compound Safety Prediction, Worldwide Medicinal Chemistry, Pfizer Global R&D
Progress in the Development of Human Models of ADMET via Humanized Mice or Human Based Systems
Discussion Leader: Colin D A Brown, Ph.D., Associate Professor, Institute for Cell & Molecular Biosciences, Medical School, University of Newcastle, United Kingdom
Predicting for Human Cardiovascular Toxicity
Discussion Leaders:
Vivek (Vic) Kadambi, Ph.D., Senior Director, Drug Safety Evaluation, Millennium: The Takeda Oncology Company
Lin Wu, M.D., Senior Scientist, CV Therapeutics, Inc.
Applying "Omics' Technologies to Identify Toxicity Biomarkers
Discussion Leader: Donna L. Mendrick, Ph.D., Director, Division of Systems Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration
in silico Methods in Drug Safety
Discussion Leader: Josef Scheiber, Ph.D., Research Investigator, Knowledge Engineering Consultant, Novartis Pharma, Switzerland
Imaging for Hepatotoxicity
Discussion Leader: Eric Tien, Ph.D., Senior Scientist, Pfizer, Inc.
How Can Systems Biology Help in De-risking Molecules?
Discussion Leader: David Cook, Ph.D., Associate Director, Safety Informatics and Modeling, Global Safety Assessment, AstraZeneca, United Kingdom
1:30
A 28-Day Mechanistic Safety Study in Rhesus Monkeys on Hepatitis C Virus Protease Inhibitor BILN 2061: A Case Study of Lessons Learned from One Compound's Attrition Due to Toxicity that Aided Decisions on Follow-up Compound Selections
BILN 2061 is a potent, novel, orally available, reversible inhibitor of the hepatitis C virus NS3/NS4A serine protease required for viral replication. The early successful clinical proof of principle with BILN 2061 was offset by later preclinical safety studies in Rhesus monkeys that demonstrated a cardiotoxicity, myocardial vacuolation that corresponded to swollen mitochondria ultrastructurally. Here we describe an experiment designed to investigate the nature, onset and reversibility of the lesion and explore biomarkers for the change.
James H. Stoltz, Director, Experimental Pathology, Boehringer Ingelheim Pharmaceuticals, Inc.
2:00
Early Preclinical and Clinical Studies with Raptiva® and Managing the First Dose Response
This presentation will discuss the early nonclinical safety evaluation and clinical development of Raptiva® (efalizamab), focusing on the predictive value of animal studies to the clinical situation, and how the first dose infusion reactions were managed. Raptiva is an immunosuppressive recombinant humanized IgG1 kappa isotype monoclonal antibody that binds a human CD11a, thus reducing T cell activation, adhesion and migration. Raptiva is indicated for the treatment of adult patients with chronic moderate to severe plaque psoriasis.
Kathleen Meyer, Ph.D., Director, Preclinical Safety Evaluation, XOMA
Making Better Decisions on Compound Selection and De-Selection from Preclinical Safety Data: Systems Biology, Computational and in silico Approaches
2:30
Incorporating Real-time Experience into Early Drug Development Decisions: A Learning Paradigm
Individual drug development candidates are commonly selected against a set of static criteria of unsubstantiated importance, and advance through a linear series of increasingly complex experiments until further progression is deemed futile. The overall probability of success of any individual candidate selected in this manner is understandably small. An alternative is to advance a diverse collection of candidates against a chosen target in a non-equitable manner, continuously reprioritizing until a selected milestone (e.g., clinical proof-of-concept) or investment limit is reached. The model used for real-time comparison between candidates should be dynamic, changing in response to the relevant knowledge being generated.
William M. Kluwe, Ph.D., VP & Global Head of Safety Assessment, Translational Sciences, Preclinical Safety, Novartis Institutes for Biomedical Research
3:00
Developing Computational Biology in Toxicology: Predictions, Data and Culture
Developing new approaches to the prediction, translation and understanding of toxicological signals is critical to reducing the current rate of failure of new medicines due to unacceptable safety liabilities. I will describe the approaches we are taking in AstraZeneca to develop computational biology to underpin new approaches to the detection and understanding of potential adverse events. I will discuss the challenges in exploiting prior knowledge in toxicology, developing models and changing cultures.
David Cook, Ph.D., Associate Director, Safety Informatics and Modeling, Global Safety Assessment, AstraZeneca, United Kingdom
3:30
Networking Refreshment Break
4:00
A Systems Biology Approach to Identifying Biomarkers for Efficacy and Toxicity of Drugs
Systems biology can effectively convert complex molecular data into detailed molecular mechanisms that define efficacy and toxicity. Correspondingly, through the knowledge of these molecular mechanisms, mechanism-based biomarkers can be readily identified. Molecular mechanisms of compounds that cause idiosyncratic drug-induced liver toxicity have been determined using transcriptomic profiling data from rats treated with drug. Biomarker candidates are readouts of these identified molecular mechanisms contributing to idiosyncratic drug-induced liver injury.
Keith O. Elliston, Ph.D., Co-Founder, President and CEO, Genstruct
4:30
Early Risk Identification Using Novel Multidimensional Data Mining Technology
Predictive risk management in drug safety has to overcome the challenges of analyzing heterogeneous data and relatively small number of measurements and patient data. The capacity to exhaustively mine the data for novel hypothesis is an essential tool for early signal detection. Applications of a novel logic based technology are presented using several real examples in predictive preclinical risk analysis, toxicology/clinical safety correlates, and the design of new composite efficacy/safety clinical endpoints.
Mohammad Afshar, M.D., Ph.D., Ariana Pharma, France
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