Emerging Importance of Companion Diagnostics in Drug Development

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Emerging Importance of Companion Diagnostics in Drug Development

Tuesday, September 22, 2009

The New York Academy of Sciences

Molecular diagnostics is a rapidly growing field in the management of many diseases. Technological advancements, understanding of disease pathophysiology, and emergence of personalized medicine are putting new demands on drug development. The old paradigm of one blockbuster drug for everyone is becoming ancient history. As the medical field evolves to recognize the uniqueness of each individual’s disease, there is a growing certainty that particular drugs work better in subsets of patients we could not previously identify or segregate. In almost every clinical trial ever conducted, there have been subsets of patients that either derived no benefit or were harmed by the drug under study. Today, as molecular diagnostics improves the use of already approved drugs, the industry is looking to understand how to jointly develop new technological assays as diagnostics to be used with the new generation of targeted agents currently in development in order to be able to preselect those patients most likely to benefit from and exclude those likely to be harmed by a new drug. This advanced approach to drug development and use is fueled by tools coming out of basic research, welcomed by reimbursers, and endorsed by the regulatory sector, but industry is still figuring out how to efficiently combine the development of a drug with a new, companion diagnostic test. We propose to bring together some of these elements to highlight the demands, challenges, and successes in this exciting new era of disease management.

Agenda


1:00 PM

Introduction
George B. Zavoico, PhD, Westport Capital Markets LLC

1:10 PM

Rationale for Biomarkers and Surrogate End Points in Mechanism-driven Oncology Trials
Gary Kelloff, MD, National Cancer Institute

1:55 PM

AVN316, A Model for Gene Expression-based Biomarker Strategies for Drug Discovery and Development
Ken Carter, PhD, Clinical Data, Inc.

2:40 PM

Coffee Break

3:15 PM

Tumor Gene Expression Predicts Response to Cetuximab in Patients with KRAS Wild-type Metastatic Colorectal Cancer
Joffre Baker, PhD, Genomic Health, Inc.

4:00 PM

Three Chasms Facing Innovative Predictive Biomarkers
Bruce Quinn, MD, PhD, Foley Hoag LLP

4:45 PM

Panel Discussion
Global Adoption of Companion Diagnostics and Comparative Effectiveness – Is the U.S. Ahead or Behind?
All Speakers and Jorge Torres, Fish & Richardson P.C.

Speakers

Organizers

Carol Reed

Clinical Data, Inc.

Carol R. Reed, MD, FACP, FCCP, Executive Vice President and Chief Medical Officer – Dr. Reed joined Clinical Data in October 2005 as Chief Medical Officer following the completion of the Company’s acquisition of Genaissance Pharmaceuticals. Dr. Reed leads a team of experts in drug development, biology, chemistry and genetics dedicated to the clinical and pre-clinical research and development of both therapeutic and diagnostic products. She has successfully guided vilazodone to the completion of 2 Phase III registration trials. Following a successful career in the practice of internal medicine and pulmonary and critical care medicine, Dr. Reed joined the clinical drug development team at Bayer Pharmaceuticals prior to joining Genaissance Pharmaceuticals. Dr. Reed received an MD from Rush Medical College in Chicago and an MS in biology (molecular genetics) from the University of Illinois at Chicago.

George Zavoico

Westport Capital Markets, LLC

George B. Zavoico, PhD, has been affiliated with Westport Capital Markets, LLC since January 2009.  Before joining Westport Capital Markets, he was an Equity Research Analyst, specializing in the Life Sciences sector, with Cantor Fitzgerald since December 2005.  His focus is on privately-held and publicly traded (micro to mid-cap) biotechnology, specialty pharmaceuticals, and molecular diagnostics companies engaged in the discovery and development of therapeutics and value-added diagnostics for the treatment of cancer, cardiovascular, autoimmune, and inflammatory diseases.  Prior to Cantor Fitzgerald, Dr. Zavoico was a founder and President of Cronamere Consulting Group, L.L.C., an independent biotechnology and pharmaceutical industry consulting and medical writing and media company that was established in 1997.  Dr. Zavoico was a research program director at Alexion Pharmaceuticals from 1992 to 1993 and T Cell Sciences in 1995.  From 1988 to 1992, Dr. Zavoico was a Senior Research Scientist in the Cardiovascular Biochemistry division at Bristol-Myers Squibb.  Dr. Zavoico received a Bachelor of Science in biology from St. Lawrence University (1974), and a doctorate degree in physiology from the University of Virginia (1981).  He held post-doctoral positions at the University of Connecticut Health Center and Brigham & Women’s Hospital (Harvard University).

Speakers

Joffre Baker

Genomic Health, Inc.

Joffre Baker, PhD, has served as Chief Scientific Officer since December 2000. From March 1997 to October 2000, Joffre served as Vice President for Research Discovery at Genentech, Inc. From March 1993 to October 2000, Joffre oversaw Research Discovery at Genentech, which included the Departments of Cardiovascular Research, Oncology, Immunology, Endocrinology, and Pathology. From July 1991 to October 1993, he served as Genentech’s Director of Cardiovascular Research. Prior to joining Genentech, Joffre was a faculty member in the Department of Biochemistry at the University of Kansas. He holds a BS in Biology and Chemistry from the University of California, San Diego and a PhD in Biochemistry from the University of Hawaii.

Ken Carter

Clinical Data, Inc.

Kenneth C. Carter, PhD, is the Senior Vice President for Strategic Partnerships - Avalon Group for Clinical Data, Inc. As a co-founder and CEO of Avalon for ten years, Dr. Carter oversaw the Company’s rapid growth and ultimate acquisition by Clinical Data, Inc. in May 2009. After opening its doors in January 2000, Avalon established drug discovery programs in colon, breast, pancreatic and hematological cancers; garnered partnerships with Merck, Novartis, Sanofi-Aventis and AstraZeneca/MedImmune; completed an IPO in 2004; and merged with Clinical Data, Inc. in 2009. Prior to co-founding Avalon, Dr. Carter was at Human Genome Sciences, Inc., where he directed the company’s gene mapping initiative. In this capacity, he played a role in the discovery, cloning, and chromosomal mapping of dozens of novel human genes. Dr. Carter has also been involved in the formation and early stage development of several other companies as a co-founder, consultant, or member of the board of the directors. He has also served on the boards of directors or advisory boards for several biotechnology industry organizations including the Maryland Health Care Product Development Corporation; the National BIO Industry Organization Board of Directors; and the Maryland Governor’s Life Sciences Advisory Board Dr. Carter has more than 50 published scientific articles and holds multiple patents related to health care and biotechnology.

Gary Kelloff

National Cancer Institute/NIH

Gary J. Kelloff, MD, has had over 35 years in cancer research at the National Cancer Institute (NCI), authoring more than 400 publications. Dr. Kelloff is a graduate of the University of Colorado (BS and MD degrees). He began his NCI career as an intramural scientist and section head in viral immunology. In 1983, he transferred to what is now the Division of Cancer Prevention (DCP), where he developed an extramural basic science, translational research, and clinical development program in chemoprevention. Since 2001, he has been a special advisor for the NCI Division of Cancer Treatment and Diagnosis working on strategies for developing imaging-based and clinical biomarkers for oncology drug development. He currently leads several collaborations with FDA and the pharmaceutical industry on drug development strategies and co-chairs on-going efforts under NCI/FDA Intraagency Oncology Task Force and the Foundation for the National Institutes for Health Biomarkers Consortium to define biomarker use in cancer drug development and patient management. This effort has included consideration of functional and molecular imaging (FDG-PET, DCE-MRI, molecular probes), tumor burden markers (PSA-doubling time prostate cancer, Ca-125 in ovary), precancerous histopathology (colorectal adenomas), gene expression and proteomic biomarkers. This work has been preceded by collaboration with leaders in industry, academia, and the pharmaceutical industry to evaluate strategies for biomarker use in oncologic drug development resulting in many publications addressing specific biomarkers and general strategies.

Bruce Quinn

Foley Hoag LLP

Bruce Quinn, MD, PhD, served as a senior regional Medicare medical director from 2008. He is currently a senior policy strategist in the Government Strategies practice of Foley Hoag LLP, where he focuses on Medicare coverage and payment matters for new technologies. He is a national leader in the areas of Medicare coverage and payment, claims and billing, and Medicare contractor reform processes. Dr. Quinn works with companies, providers and venture capital investors to develop strategies for Medicare payment for new technologies. He focuses, in particular, in the emerging field of molecular diagnostics and personalized medicine. Before managing the Medicare Part B program, Dr. Quinn was a physician executive in the Health & Life Sciences division of Accenture, a global consulting organization, and a physician-scientist at Northwestern University, leading pathology research for Northwestern’s NIH-funded Alzheimer Research Center. He also held academic positions at the NYU School of Meidcine and UCLA Center for Health Sciences. Foley Hoag LLP is a leading national law firm in the areas of dispute resolution, intellectual property, and corporate transactions for emerging, middle-market, and large-cap companies. With a deep understanding of clients’ strategic priorities, operational imperatives, and marketplace realities, the firm helps companies in the biopharma, high technology, energy technology, financial services and manufacturing sectors gain competitive advantage. For more information visit www.foleyhoag.com.

Panelist

Jorge M. Torres

Fish & Richardson P.C.

Jorge M. Torres is an attorney who works in the New York office of global intellectual property law firm Fish & Richardson P.C. As a patent litigator, Jorge has focused his practice over the least seven years on representing technology, pharmaceutical, and consumer goods companies in complex disputes concerning the rights to use patented technologies. Jorge also counsels clients on intellectual property issues that arise in non-adversarial contexts, such as the investment due diligence of pharmaceutical and biotechnology companies . Before assuming his current position, Jorge served as a law clerk to the Honorable Raymond C. Clevenger, III of the U.S. Court of Appeals for the Federal Circuit, where he was directly involved in the disposition of over 50 different cases involving patent infringement, international trade, and other matters within the court’s jurisdiction. Jorge holds a law degree from the University of Pennsylvania Law School and a Bachelor of Science degree in Molecular Biophysics & Biochemistry from Yale, where he studied the structure and function of transmembrane proteins.

Abstracts

Rationale for Biomarkers and Surrogate Endpoints in Mechanism-driven Oncology Trials

Gary J. Kelloff, MD, 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 unexpected safety issues or difficulty determining efficacy, including confounded outcomes. 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.

Evidence-based and practical criteria for validating biomarkers have been developed including considerations of mechanistic plausibility, available methods and technology, and clinical feasibility. New promising tools for measuring biomarkers have also been developed and are based on genomics and proteomics, 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). The identification and evaluation of potential surrogate endpoints and other biomarkers require access to and analysis of large amounts of data, new technologies and extensive research resources. Further, there is a requirement for convergence of research, regulatory and drug developer thinking—an effort that will not be accomplished by individual scientists or research institutions. Research collaborations are needed to foster development of these new endpoints and other biomarkers and, in the US, include on-going efforts among the NCI, FDA, academia, and industry.

Regarding the topics above, this presentation will include: activities of the NCI/FDA Interagency Oncology Task Force; opportunities under the Oncologic Biomarker Qualification Initiative (OBQI) and establishing public/private partnerships; validation/qualification studies of imaging and molecular target assays; how the NCI is working with industry including development of combination therapies; and the potential impact of the NCI's Cancer Genome project, the HapMap, and other projects on how the pharmaceutical and biotechnology industries will develop new cancer therapies.

AVN316, A Model for Gene Expression-based Biomarker Strategies for Drug Discovery and Development

Kenneth C. Carter, PhD, Clinical Data, Inc.

AVN316 is a drug candidate that targets the beta-catenin cellular regulatory pathway, which is frequently mis-regulated in colorectal cancers and other malignancies. Despite massive efforts in the pharmaceutical and biotechnology industries, no drugs have been discovered targeting this key oncogenic regulatory network. We have used a unique approach to identifying small molecule inhibitors of the beta-catenin pathway by tracking gene expression-based biomarkers. This discovery approach provides advantages over conventional drug discovery and development, including concomitant identification of companion diagnostics for accelerating and enhancing clinical and commercial development of the drug.

Tumor Gene Expression Predicts Response to Cetuximab in Patients with KRAS Wild-type Metastatic Colorectal Cancer

Joffre B. Baker, PhD, Genomic Health, Inc.

The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab is an active drug in metastatic colorectal cancer (mCRC), but those mCRC patients who carry tumor mutations in KRAS receive little benefit from cetuximab. A recent study of metastatic tumors indicates that high expression of the EGFR ligand genes EREG and AREG predicts benefit from cetuximab treatment. In order to determine whether gene expression-based markers add predictive value to the KRAS mutation status, we evaluated multiple clinical endpoints in a large set of primary mCRC tumors. Experimental Design: Specimens of 226 formalin-fixed paraffin-embedded primary tumors from three cetuximab advanced mCRC monotherapy studies were retrospectively assayed for KRAS mutations and expression of 110 other genes using quantitative reverse transcription-polymerase chain reaction. Results were correlated with disease control, objective response, and progression-free survival (PFS). Results: Relative to patients with KRAS mutant tumors patients with KRAS wild-type tumors (144 of 226 total; 74%) had comparatively (P < .001) high frequencies of disease control (60% versus 23%) and objective response (22% versus 1%). In these KRAS wild-type cases the expression of several biologically relevant genes, including EREG and AREG, strongly associated with disease control, objective response, and PFS. An exploratory multi-gene classifier was developed to identify patients with KRAS wild-type tumors who may derive greater benefit from cetuximab treatment. Conclusion: A test that incorporates the expression of certain genes and KRAS mutation status may have predictive value beyond that provided by KRAS status alone and could be developed to optimally select mCRC patients for cetuximab therapy.

Three Chasms Facing Innovative Predictive Biomarkers

Bruce Quinn, MD, PhD, Foley Hoag LLP

New biomarkers entering mainstream medical care must bridge a great distance, from basic science to clinical trials to physician acceptance and finally payment from insurers. Many developers, physicians, and the public have little knowledge regarding how complex the final step, insurer acceptance, can be. "Chasms" at this final step include legacy approaches to coding, coverage, and reimbursement rates for diagnostic tests, which place a legacy generic test industry in collision with far more complex, research-driven biomarkers. The status of the current system and approaches to dealing with it are discussed.

Panelist Abstract

Jorge M. Torres, Fish & Richardson P.C.

Jorge Torres will address intellectual property issues that arise in the negotiation and performance of joint development and other collaboration agreements that involve research conducted by biopharmaceutical firms.

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