|
Friday, March 28
8:30 Chairperson's Remarks
Mark D. Lindner, Ph.D., Consultant, McArthur and Associates GmbH
8:35 How Do in Vitro Preclinical Results Translate into
in Vivo Models: What Do We Lose or Gain in Translation to Patients?
Berengere Dumotier, Ph.D., Safety Profiling and Assessment, Novartis Pharma AG
The main problem in preclinical safety is how to best combine advantages of different assays to reliably predict drug QT liability/torsadogenic potential. The predictive value of preclinical tests for clinical QT prolongation in man is usually considered as not sufficient. On the other hand, from retrospective data analysis, the combination of in vitro ion channel data and in vivo animal (telemetry) data show good results in correctly predicting QT liability in man. In this context, what do the follow up studies bring us in terms of information and for which specific disease area is it beneficial? How predictive are these assays? In this presentation, you will hear about the reliability of the preclinical assays and about the correlation with ECG (including human) data.
9:05 Optimizing Preclinical Assessment and Decision-Making
Mark D. Lindner, PhD, Consultant, McArthur and Associates GmbH
Lack of efficacy is the single biggest reason why compounds fail in the clinic and failures due to lack of efficacy continue to increase despite tremendous technological advancements and scientific achievements. Lack of efficacy in clinical trials is usually attributed to limitations in the predictive validity of the preclinical models, but preclinical models are not worse now than they were 20 years ago. In fact, preclinical models and measures of potential efficacy continue to be developed and refined, so it is especially puzzling that the productivity of drug discovery efforts continues to decline. One component of the process that has been neglected is the human element. Years of clinical research have shown that different forms of bias must be carefully controlled, or they will inflate and exaggerate the therapeutic potential of the treatment being assessed. This talk will present evidence that preclinical assessments of potential efficacy are at least as vulnerable to bias as clinical trials, and controls for potential bias are not part of the standard of practice for preclinical assessments. Furthermore, the shift to 𩾷arget-based discovery�Eand other changes in management may be increasing the effects of bias on preclinical assessment and decision-making processes. The possibility that biases may be affecting preclinical assessments of potential efficacy must be recognized before it can be addressed, but procedures to control and limit the effects of bias are available, and even modest improvements in preclinical assessments could produce dramatic increases in clinical success rates and the return on investment in drug discovery research.
9:50 Q&A
10:05 Technology Spotlight
(Sponsorship Available)
10:20 Coffee Break in the Foyer
11:00 Translational Medicine Approaches in CNS Drug Development: Buy Down the Risk?
Hong Wan, Ph.D., Associate Director, Clinical Translational Medicine, Wyeth Research
CNS drug development presents unique challenges, such as complexity of the target system, chronic disease with incomplete understanding of pathogenesis, inaccessibility of target tissue for biomarker analysis and possible CNS-related side effects of drug candidates. Translational medicine strategies are needed in preclinical discovery and clinical development to 弎uy down�Ethe risk and select the 𢘛inners�E Examples and case studies will be provided to illustrate:
-
Use of disease biomarkers to demonstrate proof of concept: evidence of modulating underlying neurobiology of the disease;
-
Use of compound biomarkers to demonstrate proof of mechanism: pharmacodynamic biomarkers of target engagement and target pathway modulation
Use of experimental human models and innovative animal models to bridge the gap between preclinical discovery and clinical development
11:30 Assessment of CNS Penetration: Preclinical-Clinical Correlations and Relationships between Protein Binding, CSF Distribution, and Target Receptor Occupancy
Elizabeth Shang, Ph.D., Manager, Clinical Pharmacology - CVMED, Pfizer Inc
This presentation will discuss the utility of translational approaches for assessing the extent of human brain penetration and PK/PD relationships for target receptor occupancy - a critical but challenging aspect of contemporary CNS drug development. Twenty proprietary CNS compounds were reviewed to characterize the translatability of preclinical to human CSF distribution characteristics, and to investigate the utility of CSF pharmacokinetic data as predictors of target receptor occupancy (RO). A moderate correlation between CSF distributional characteristics in animals and humans was found, with human CSF distribution being successfully predictable from the plasma unbound fraction for compounds without active efflux mechanisms or physicochemically driven diffusion limitations. Additionally, predicted human RO values were within two-fold of the observed values from PET/SPECT CNS imaging studies for the majority of compounds, supporting the overall conclusion that human plasma protein binding, CSF distribution, and preclinical CSF distribution information are useful quantitative predictors of human brain penetration for compounds lacking active efflux mechanisms. The value of PK/PD modeling of CNS RO data from imaging studies to guide dose selection and understand the molecular determinants of therapeutic index will also be discussed using case studies and illustrative simulations.
12:00pm Luncheon Workshop
(Sponsorship Available) or Lunch on Your Own
1:00 Chairperson's Remarks
Kohkan Shamsi, M.D., Ph.D., President & CEO, Acunova Life Sciences Inc. and Director, Symbiotic Pharma Research
1:05 Imaging Biomarkers in Early Clinical Development of Novel Therapeutic Agents
Jeffrey L. Evelhoch, Ph.D., Executive Director, Medical Sciences, Imaging, Amgen Inc.
Over the past decade, biomarkers (objectively measured indicators of a biological/ pathobiological process or pharmacologic response to treatment) have been recognized as a critical element to improve predictability and efficiency in the process of developing more effective, more affordable, and safer therapeutics for patients. In the early clinical development of novel therapeutics, biomarkers can provide information critical to internal decision-making (i.e., establish presence of target, evaluate biological/clinical activity, dose selection for later phase trials, stratify study populations, conduct interim analysis of efficacy and/or safety). Imaging is a powerful biomarker that can provide information about genetic, biochemical, physiological and anatomic processes in many diseases including multiple sclerosis, cancer, arthritis, atherosclerosis, Alzheimer's disease, and others. This talk will explain how imaging is used as a biomarker and give several examples of how it can impact decision-making in early clinical development.
1:35 Imaging in Phase
II/III Clinical Development
Haren Rupani, M.D, FACR, FACNP, Global Head, Oncology Imaging, Novartis Pharmaceuticals Corporation
-
Standard or Validated Imaging Modalities
-
RECIST and McDonald Criterias
-
Role of Exploratory Imaging in Phase II/III
2:05 Imaging as a Biomarker in Oncology Drug Trials and Improving Cancer Patient Care
Gary Kelloff, M.D., Advisor, Cancer Imaging Program, Division of Cancer Treatment and
Diagnosis, National Cancer Institute
Although several new oncology drugs have reached the market, more than 80% of drugs for all indications entering clinical development do not get marketing approval, with many failing late in development often in Phase III trials, because of difficulty in determining efficacy, including confounded outcomes, as well as unexpected safety issues. These factors contribute to the high costs of oncology drug development and clearly show the need for faster, more cost-effective strategies for evaluating oncology drugs and better definition of patients who will benefit from treatment. Remarkable advances in the understanding of neoplastic progression at the cellular and molecular levels have spurred the discovery of molecularly-targeted drugs. This progress along with advances in imaging and bioassay technologies are the basis for describing and evaluating new biomarker endpoints as well as for defining other biomarkers for identifying patient populations, potential toxicity, and providing evidence of drug effect and efficacy. Science-based and practical criteria for validating biomarkers have been developed including considerations of mechanistic plausibility, available methods and technology, and clinical feasibility. New promising imaging tools for measuring biomarkers have also been developed and are based on direct visualization by microscopy (e.g., confocal microscopy and computer-assisted image analysis of cellular features), nanotechnologies, and direct and remote imaging (e.g., fluorescence endoscopy and anatomic, functional and molecular imaging techniques). Definitions and classifications of these biomarkers for use in oncology drug development are presented, as are activities of the NCI/FDA Interagency Oncology Task Force; opportunities under the Oncologic Biomarker Qualification Initiative (OBQI) and Biomarkers Consortium for establishing public/private partnerships; and validation/qualification studies of imaging-based biomarkers.
2:35 The Promises and Realities of Imaging as a Translational Biomarker in Drug Development
Timothy J. McCarthy, Ph.D., Senior Director and Head of Imaging, Translational and Molecular Medicine, Pfizer Global R&D
-
Overview of the use of non-invasive imaging in drug development
-
Identification of issues around translational imaging
-
Opportunities for future technical innovations
3:05 Close of Conference
|
Japanese
Korean
English