Scientific Advisory Board
Andrew L. Hopkins, Ph.D., Associate Research Fellow, Knowledge Discovery, Pfizer Global R&D
Phillips Kuhl, MBA, President, Cambridge Healthtech Institute
Christopher A. Lipinski, Ph.D., Scientific Advisor, Melior Discovery Inc.
Louis A. Tartaglia, Ph.D., Advisor to Gene Logic Inc.
Marcel van Duin, Ph.D., Executive Director and Head, Department of Pharmacology, NV Organon
Wednesday, October 10
8:00 am Pre-Conference Short Course Registration
|9:00am Pre-Conference Short Course
|Filing a 505 (B)(2) Application and Strategies for Gaining Approval
||Kenneth V. Phelps, President and Chief Executive Officer, Camargo Pharmaceuticals Services, LLC
|Obtaining FDA product approval via the 505(B)(2) route can be a terrific business strategy, but you must understand the benefits, risks and development steps. This course takes you, step-by-step, through the 505(B)(2) approval process. Equally important, this course provides the historical, legal and practical background you need for go/no go decisions. This 3-hour short course will greatly enhance your ability to identify 505(B)(2) candidates and pursue them with confidence.
Key learning goals:
- Define 505(B)(2)
- Compare and contrast 505(B)(2) with NDA/ANDA
- Identify 505(B)(2) opportunities (based on dosage form, strength, formulation, NME’s)
- Evaluate the benefits and risks of 505(B)(2)
- Explain key legal challenges and their potential implications
- Describe the 505(B)(2) drug development steps and application process (Phases 1-4 and Submission)
12:00 pm Conference Registration
1:00 Chairperson’s Opening Remarks
Christopher A. Lipinski, Ph.D., Scientific Advisor, Melior Discovery Inc.
1:15 Drug Repurposing via Phenotypic Screening
Christopher A. Lipinski, Ph.D.
Screening of mechanistically defined targets accounts for 95% of today’s drug discovery efforts and lack of efficacy is a major cause of current clinical failure. These two phenomena are linked if there is a flaw in the logic for the target mechanism. In the 1970’s, phenotypic screening was the rule rather than the exception and failure rates were arguably better than today. So there is merit in a “back to the future” approach. Namely, capitalize on the known success of in vivo mouse phenotypic screening but do it much more efficiently than in the 1970’s. An intriguing, and only partly understood, phenomenon is the incredibly high success rate ranging from 10-90% in the initial stage in searching for a new use for an old drug, especially for an orally active drug that succeeded quite far into the clinic before failing for efficacy as opposed to safety. Partial explanations include the non diversity of biologically active chemistry space; the non diversity in ligand binding protein motifs; the great restriction in the properties of compounds advanced in clinical study and the orders of magnitude improvement in target opportunity space that phenotypic screening holds over mechanistic screening. An additional success increment can be added if the compound to be repurposed is subjected to absolutely brutal chemical examination so that nothing in the chemistry suggests even the slightest possibility of a medicinal chemistry or drug metabolism problem.
1:45 The Use of Integrative Pharmacology in Drug Repositioning
Thomas Barnes, Ph.D., Senior Vice President of Discovery, Gene Logic Inc.
Reduced hurdles in lead identification are resulting in the screening of druggable targets with weaker disease hypotheses, increasing the risk and thus incidence of programs that fail in the intended therapeutic area due to lack of efficacy. Nevertheless, the high-quality chemical matter that results can be used to probe target function and thereby link the corresponding compounds to new therapeutic utility. What is required is sufficiently high throughput methodologies to make de novo links between specific compounds and disease.
We have integrated a set of technologies that provide the means of efficiently associating compounds with potential new therapeutic utility. This is in contrast to the unsystematic observations classically relied upon to reveal alternative or new drug indications. The promise of these technologies is to expeditiously reduce pipeline gaps within a pharmaceutical industry whose growth is threatened by reduced (and increasingly costly) new product flow.
2:15 Integration of “Indications Discovery” Efforts within Pfizer
Donald E. Frail, Ph.D., Head, Global Indications Discovery Unit, Pfizer Global Research and Development (PGRD), Pfizer Inc.
Beyond “drug repositioning”, the Pfizer Indications Discovery Unit seeks to identify additional indications for active clinical candidates. A coordinated, systematic approach is being developed and implemented. The unit is dependent on extensive internal and external partnerships. Challenges and opportunities will be discussed.
2:45 Product Life Cycle Management: Drug Repositioning
Mr. Edward Grieff, Partner, Intellectual Property, Venable LLP
Corporations need to provide the maximum patent protection for commercial products. Several methods for life cycle management include FDA pediatric exclusivity, new formulations, and drug respositioning. Drug repositioning is an excellent way to maximize the life cycle of a product without changing the original dosage and formulation of a compound that is or will soon be off patent.
3:15 Poster Session, Exhibit Viewing and Refreshment Break
3:45 Chairperson’s Remarks
Thomas Bames, Ph.D.
3:50 Relating Protein Pharmacology by Ligand Chemistry
Michael Keiser, Biological & Medical Informatics, University of California, San Francisco
The identification of protein function based on biological information is an area of intense research. Here we consider a complementary technique that quantitatively groups and relates proteins based on the chemical similarity of their ligands. We begin with 65,000 ligands annotated into sets for hundreds of drug targets. The similarity score between each set is calculated using ligand topology. A statistical model was developed to rank the significance of the resulting similarity scores, which are expressed as a minimum spanning tree to map the sets together. Although these maps are connected solely by chemical similarity, biologically sensible clusters nevertheless emerged. Links among unexpected targets also emerged, among them methadone, emetine, and loperamide, which may antagonize muscarinic M3, α2 adrenergic, and neurokinin NK2 receptors, respectively. These predictions were subsequently confirmed experimentally. Relating receptors by ligand chemistry organizes biology to reveal unexpected relationships that may be tested directly by the ligands themselves.
4:20 In Silico Approach to Drug Repurposing
Ruben Abagyan, Ph.D., Professor, Molecular Biology, Scripps Research Institute
Repurposing known and tested small molecule drugs for new indications or molecular targets is an extremely appealing strategy from multiple points of view. We developed an in silico approach that identifies the secondary activities of the marketed drugs for a given new target  or for a panel of targets . This strategy led us to identifying anti-androgen activity of marketed anti-psychotic drugs and re-purpose them into promising new androgen receptor antagonists .
- Bisson W, Cheltsov A, Bruey-Sedano N, Bing Lin, Chen J, Goldberger N, May L, Christopoulos A, Dalton J, Sexton P, Zhang XK, Abagyan R. Discovery of Antiandrogen Activity of Non-steroidal Scaffolds of Marketed Drugs, PNAS, 2007, in press
- Schapira M, Abagyan R, Totrov M. Nuclear hormone receptor targeted virtual screening. J Med Chem. 2003 Jul 3;46(14):3045-59
4:50 Indications Discovery Using in Vivo Pathways as Targets
Scott Turner, Ph.D., Vice President, Research, KineMed Inc.
The flow of molecules through intact metabolic pathways represents a unique and potentially powerful therapeutic target, in that pathways combine complexity (and its emergent, unpredictable properties) with intrinsic functional significance and physical measurability. New methods utilizing stable isotopes and mass spectrometry now allow the effects of interventions on the activity of integrated metabolic pathways to be measured directly. KineMed has developed a repertoire of in vivo assays of pathways that are critical in disease or therapeutic action, and is using these assays to discover new indications for shelved drug candidates. "Dynamic" targets of this type have been applied to cardiovascular disease, neurobiology, fibrosis, arthritis, and diabetes. In addition to preclinical discovery, the modulation of these targets can be assessed in clinical settings as well, enabling rapid translational studies in man.
5:20 Orphan Drugs Challenges, Strategies, and Opportunities
Ramaiah Muthyala, Ph.D., Associate Director, Center for Orphan Drug Research, University of Minnesota
The drug development process for orphan diseases is the same as that for any other disease. In general, it is very expensive and time consuming. Major pharmaceutical companies show little or no interest in developing orphan-designated products due to a lack of anticipated return on their investment. However, biotech and smaller pharma companies are enticed by incentives such as market exclusivity, tax credits, grants for clinical trials, etc., that accrue once a biologic or chemical entity reaches the preclinical stage. Since 1983, 227 orphan products have been developed for more than 6,600 known orphan diseases. A majority of these orphan products are the result of finding new uses for existing approved drugs the so-called “low-hanging fruit” approach. In recent years, this approach has slowed considerably. The success rate is less than 30% due to the difficulties of linking pharmacological properties of an approved drug to an orphan disease. With the recent emphasis on genomics, a large number of targets have been identified but only a few disease-specific druggable targets have been identified. The systematic scientific understanding of how to translate chemical and biological discoveries into safe and effective orphan products is missing. In this presentation, some of our experiences will be presented from an academic point of view: challenges, strategies, and opportunities for developing orphan drugs.
5:50 Networking Reception
7:00 Close of Day One