Wednesday, March 29

11:00 - 1:00 Conference Registration

1:00 - 1:10 Welcoming Remarks from Conference Director
Julia Boguslavsky, Cambridge Healthtech Institute

Translational Medicine: 
Decision Making at the Preclinical/Clinical Interface

1:10 – 1:15 Chairperson’s Opening Remarks
Dr. Dominic G. Spinella, Global Head of Oncology Translational Medicine, Pfizer Inc.

1:15 – 1:45 Translational Oncology: Hitting the Right Target in the Right Patient at the Right Dose 
Dr. Samuel E. DePrimo, Clinical Research Scientist, Translational Medicine, Pfizer Global R&D
The Translational Medicine (TM) approach to drug discovery and development relies on the early preclinical identification of biomarkers and pharmacodynamic endpoints and their adaptation to the clinic for use as “internal surrogates” of safety and efficacy. The adoption of this approach in Oncology is both especially powerful and particularly challenging. Tumors vary enormously in their expression of molecular targets, underscoring the critical need for patient selection biomarkers. Early development is usually done in patients rather than healthy volunteers, and often relies pre- and post-treatment biopsy samples for target biomarker evaluation – limiting TM studies to patients with “biopsiable” tumors. These challenges have led to concerted efforts to apply technologies as diverse as molecular imaging and –omics profiling to patient studies, all of which fall squarely within the responsibility of Translational Medicine. This talk will outline the Translational Medicine processes in place at Pfizer as specifically applied to the discovery and development of anti-cancer drugs, and describe several case studies that illustrate both the power and the challenges inherent in Translational Oncology.

1:45 – 2:15 Organizational, Procedural and Scientific Changes to Incorporate Translational Medicine Concepts within R&D
Ms. Cynthia S. Cheesman, Assistant Vice President, Preclinical Project Management, Wyeth 
Translational Medicine (TM) is a set of activities aimed to optimize the transition of products leaving discovery research and entering clinical development. Specific focus is given to the development of biomarker strategies, plans and biomarker validation. TM activities provide an organization with the additional tools to manage its innovative portfolio and provide several benefits to discovery and development, including reducing risk, producing higher quality candidates, increasing the value of compounds, shortening cycle times, increasing success rates, and determining probable failures earlier. A case study will present the organizational and procedural changes made within R&D, as well as the increased scientific expectations that have been incorporated into our research programs.

2:15 - 2:45 Search for Biomarkers at Preclinical, Translational, and Clinical Level to Support Development of a Novel, First-in-Class Drug 
Dr. Juan A. Leal, Senior Director, Translational Medicine, Exelixis, Inc.
The era of targeted therapeutics has launched intensive research efforts on biomarker discovery and validation. The general consensus is measurable bona fide biomarkers can expedite the drug development process (e.g. monitors drug exposure and/or stratify patients into responders and non-responders). The true value of a biomarker for a specific drug (or class of drug) is never certain, for instance, biomarkers have been clearly beneficial for the development of drugs such as Trastuzumab (measure levels of tumor HER2 expression) and Erlotinib (monitoring exposure to EGFR inhibitors by skin rash); however, in many cases biomarkers have not been crucial for successful drug development. (e.g. Bevacizumab, Gefitinib). This presentation will illustrate how our Translational Medicine Department is approaching pharmacodynamic (PD) biomarker challenges during the development of spectrum selective kinase inhibitors (SSKI) which are currently in Phase 1 and 2 clinical trials. While for some targets there is a good mechanistic understanding and appropriate PD markers from the development of similar compounds, an intensive exploratory survey for biomarkers is being undertaken to support development of several first-in-class drugs. Examples of bridging preclinical discovery with clinical development (bench to bedside), as well as from clinical development to preclinical (bedside to bench) will be presented. As a case report, the biomarkers strategy for a first-in-class Met inhibitor with antiangiogenic properties (VEGFR, PDGFR and Tie-2) will be discussed, including: a) Preclinical xenograft models for efficacy and PD end-points, b) Translational studies in preclinical models to identify potential surrogate markers, and c) Phase 1-biological sample analyses to assess the validity of surrogate markers.

2:45 - 4:00 Networking Refreshment Break

Biomarkers for Clinical Safety Assessment and 
Predicting Adverse Effects

3:55 – 4:00 Chairperson’s Opening Remarks

4:00 – 4:30 Update on Her-2 Directed Therapy
Dr. Dennis J. Slamon, Chief, Division of Hematology/Oncology, David Geffen School of Medicine, UCLA

4:30 – 5:00 Genetic Approaches for Enhancing Drug Safety
Dr. Koustubh Ranade, Associate Director, Pharmacogenomics & Human Genetics, Pharmaceutical Research Institute, Bristol-Myers Squibb Co.
Genetic approaches to understand the mechanistic basis of adverse effects, and the application of this knowledge to enhancing drug safety will be discussed.

5:00 – 5:30 New Emerging Predictive and Diagnostic Biomarkers of Renal and Hepatic Toxicity and Safety
Dr. Rakesh Dixit, Senior Director, Toxicology, Johnson & Johnson Pharmaceutical R&D
Prediction of toxicities is an important objective for all drug development programs. This presentation will discuss the current state of knowledge in development and application of innovative biomarkers of hepatic and renal damage. The biomarkers based on system biology approach with case studies will be presented. 

5:30 – 6:00 Discovery of a Biomarker Profile of Drug-Induced Musculoskeletal Syndrome by Metabonomics and Proteomics
Dr. Feng Wang, Principal Scientist, Procter & Gamble Pharmaceuticals
The presence of diagnostic biomarkers of the onset of musculoskeletal syndrome (MSS) in osteoarthritis (OA) patients treated with an inhibitor of matrix metalloproteinases (MMPI) was explored using proteomics and metabonomics. MSS is a drug-induced adverse condition characterized by stiffness of the joints, inflammation, and pain in hands, arms and shoulders. Patients that developed MSS upon drug exposure could be identified by characteristic metabolic and protein profiles. Preliminary findings suggest a pre-existing condition that sensitizes OA patients to develop drug-induced MSS, and a protein biomarker profile of progression of MSS was also identified. Upon validation in a larger population, these profiles could potentially be used to identify patients prone to MSS prior to exposing them to MMPIs.

6:00 Close of Day One