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Oligonucleotide Therapeutics - From Concept to Implementation Agenda
Drug Discovery & Development Week 2009: August 3-6, 2009· The World Trade Center Boston and Seaport Hotel · Boston, MA
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Main Conference - Monday, August 3, 2009Main Conference: Monday | Main Conference: Tuesday
7:30
Registration and Coffee
8:30
Conference Chair Opening Remarks
James D. Thompson, Ph.D., Vice President, Pharmaceutical Development, Quark Pharmaceuticals
Featured Presentations
8:40
RNAi: The Next Big Thing after Monoclonal Antibodies?
With the advent of RNAi as a potential therapeutic modality, the same types of questions and problems that have stymied the development of antisense oligonucleotides may well be visited. What, if anything, has been learned after that 20 year development effort that can be applied to RNAi therapeutics? This lecture will attempt to present an overview of where we have been, as a prelude to where we may be going.
Cy Stein, M.D., Professor, Urology & Molecular Pharmacology, Albert Einstein College of Medicine
9:10
Thirty Years of Targeting RNA: A Retrospective
Thirty years ago Paul Zamecnik treated mammalian cells with antisense oligonucleotides. Since this seminal work, various mechanisms for blocking RNA function in cells have been employed (blocking, RNase H cleavage, ribozymes cleavage and RISC-mediated cleavage) each with practical advantages and disadvantages. A vast array of modified oligonucleotides chemistries have been explored, but a surprisingly few modified chemistries have gained general use. This core group of modified chemistries (2' modified, phosphorothioate, neutral backbones) can be used in a great variety of configurations to impart favorable characteristics on therapeutic oligonucleotides. The affect of mechanism and chemistry on specificity, toxicity and potency on RNA targeting oligonucleotides will be discussed.
Tod Woolf, Ph.D., President and CEO, RXi Pharmaceuticals Corporation
Delivery Challenges and Novel Delivery Systems
9:40
Development of SNALP Formulated siRNA-based Drugs
Using the modular lipid nanoparticle siRNA delivery platform known as SNALP (Stabilized Nucleic Acid Lipid Particles), Tekmira has confirmed RNAi medicated efficacy in several models of oncology, infectious and metabolic disease. SNALP are expected to enter Phase I clinical trials in the first half of 2009.
Ian MacLachlan, Ph.D., Executive Vice President & Chief Scientific Officer, Tekmira Pharmaceuticals Corp.
10:05
Efficient GeRP-Mediated Oral Delivery of siRNA to Macrophages to Modulate Inflammation in Mice
To accomplish targeted oral delivery of siRNA to macrophages we have developed a new delivery technology based on the synthesis of Glucan encapsulated siRNA Particles (GeRPs). The outer glucan shell of provides for efficient receptor-mediated oral bioavailability and macrophage targeting of the encapsulated siRNA. siRNA is formulated inside GeRPs by complexation with cationic polymers to trap, protect and provide for siRNA release in macrophages.
Gary R. Ostroff, Ph.D., Research Professor, University of Massachusetts Medical School
10:30
Networking Refreshment Break
11:00
Polymeric siRNA Nanoparticles for Systemic Cancer Therapy
Calando is developing polymer-based, transferrin-targeted siRNA nanoparticles for the systemic treatment of cancer. The lead siRNA candidate CALAA-01 targeting ribonucleotide reductase subunit M2 (RRM2) is in clinical development. The presentation will give a complete program update covering pre-clinical safety and efficacy, CMC, as well as clinical status.
Thomas Schluep, Ph.D., Chief Scientific Officer, Calando Pharmaceuticals
11:25
RNAi Therapeutics: Delivery and Mechanism
Our DiLA2 platform has demonstrated efficient uptake into hepatocytes, and RACE assays have confirmed RNAi as the mechanism for message knockdown. While fundamental in nature, for each new mRNA target and cell type of interest these steps are required for evaluation of delivery platforms and selection of siRNA development t candidates.
Michael V. Templin, Vice President, Discovery Research and Pharmaceutical Development, MDRNA Inc.
11:50
Nanoparticle-Enhanced and Multi-Targeted siRNA Therapeutics for Critical Human Diseases
Multi-targetd siRNA cocktails provide a novel therapeutic approach to realize advantage of RNAi drugs. We have developed a series of polymer and liposome based siRNA delivery systems to further enhance the delivery of siRNA API into animal disease models of respiratory infection, ocular diseases, skin wounds, spinal cord injury and cancer, etc. The successes of those protocols inspired our effort to move them into IND enabling studies.
Patrick Lu, Ph.D., President & CEO, Sirnaomics, Inc.
12:15
Meet & Greet Networking Luncheon
Specificity & Toxicity Considerations in Developing Oligonucleotide Therapeutics
1:55
Chairperson's Remarks
Patrick Lu, Ph.D., President & CEO, Sirnaomics, Inc.
2:00
Strategies for Developing RNAi Therapeutics(tentative title)
Abstract not available at time of print.
Satish Chandran, Ph.D., Chief Technology Officer, Pfizer RTC
2:25
Strategies for Designing Antisense Oligonucleotides with Improved Therapeutic Margins
Identification of critical biopharmaceutical properties that optimize potency, reduce off-target or non-hybridization toxicities, and improve pharmacokinetic & PK/PD behavior of antisense oligonucleotides will be presented. Medicinal chemistry strategies that take advantage of the knowledge base gained from phosphorothioate based oligonucleotides have shown great progress.
Richard S. Geary, Ph.D., Senior Vice President, Development, Isis Pharmaceuticals, Inc.
2:50
Are Target and Off-Target Regulation by RNAi Therapeutics Conserved Across Species?
Abstract not available at time of print.
Aimee Jackson, Ph.D., Director Drug Discovery, Regulus Therapeutics
3:15
Talk TBD
Speaker TBA
3:40
Networking Refreshment Break
4:15
Attendee/Speaker Chat Sessions
These informal chat sessions will be led by conference speakers or industry leaders. Attendees can pick a topic, join a table and meet fellow attendees and speakers. Additional topics will be added. To suggest a discussion topic, Please contact us.
Regulatory - What's the Status, Relationship & Treatment of RNAi Compound?
Maximizing Therapeutic Oligo Manufacturing Efficiency via Customer and CMO Partnerships
Discussion Leader: Paul Metz, Ph.D., Senior Director, Manufacturing Operations, Agilent Technologies Inc
Survey of the IP Landscape
Discussion Leader: Brian Johnston, Ph.D., Chief Executive Officer/Chief Scientific Officer, SomaGenics, Inc
Current & Future Developments of miRNA
Discussion Leader: Aimee Jackson, Ph.D., Director Drug Discovery, Regulus Therapeutics
Delivery Innovations and Breakthroughs
RNAi for Target Validation
Challenges and Limitations of In Vivo Models for Oligo Therapeutics
5:15
Chat Sessions Round-Up
6:00
Attendee Networking Dinner in Boston
Join fellow attendees of Oligonucleotide Therapeutics: From Concept to Implementation conference for an evening networking dinner. Space is limited and an additional fee applies. Check box on registration form to sign up.
Main Conference - Tuesday, August 4, 2009Main Conference: Monday | Main Conference: Tuesday
8:30
Conference Chair Opening Remarks
William S. Marshall, Ph.D., President and Chief Executive Officer, miRagen Therapeutics, Inc.
The Different Stages of Drug Development (Discovery to PreClinical to Clinical) for siRNA, miRNA, Antisense and Aptamers
8:40
Development of Liposomal siRNA (Atuplex) For RNAi Mediated Therapeutic Applications
Functional RNAi in vivo requires the functional delivery of siRNA to the cytoplasm of the desired cell type within the body. Consequently, delivery remains the main obstacle for the development of RNAi-based therapeutics. For functional uptake of siRNA molecules, appropriate formulation strategies might facilitate the siRNA to overcome several cellular barriers in vivo and confer pharmacological properties. We have developed a cationic liposomal siRNA formulation (siRNA-lipoplex/AtuPLEX) for "systemic RNAi'. The AtuPLEX (liposomal siRNA) can be used for RNAi in the vascular endothelium, when applied intravenously. Therefore, an RNAi-mediated modulation of the vascular endothelium in vivo would offer many opportunities for developing new therapeutic interventions. The AtuPLEX technology is the basis of our current therapeutic program Atu027 in oncology. Pre-clinical research data will be discussed and an update on the status of our current drug candidate Atu027 will be provided.
Klaus Giese, Ph.D., CSO & Vice President, Research, Silence Therapeutics AG
9:05
Design and Development of Synthetic siRNAs for Clinical Applications
Quark Pharmaceuticals' pipeline includes a synthetic siRNA licensed by Pfizer in Phase 2 clinical studies and another synthetic siRNA in Phase 1/2 studies for two renal indications. This talk will include an update on Quark clinical studies and provide a case study on development of the first siRNA administered systemically to man. An overview of the strategies Quark is using to optimize synthetic siRNAs for clinical applications while avoiding off-target effects will also be presented.
James D. Thompson, Ph.D., Vice President, Pharmaceutical Development, Quark Pharmaceuticals
9:30
Development of Novel RNAi Therapeutic Compounds and In Vivo Delivery Approaches
Potency, specificity, endonuclease stability and ease of manufacture are the essential characteristics of RNAi therapeutic compounds. In addition, effective delivery of synthetic compounds is critical for the successful use of RNAi as a therapeutic. We will describe the properties of our proprietary rxRNA™ (including single-oligo) compounds and the use of novel delivery technologies (including oral delivery to macrophages) for in vivo administration.
Dmitry Samarsky, Ph.D., Vice President, Technology Development, RXi Pharmaceuticals
9:55
Evaluating the Structure and Energy Contributions of Base Mismatches
To fully benefit from the actual sequence space in the prediction and rational design of small interfering RNAs, we developed a computational model (MC-Fold) to predict the structure and energy contributions of non-canonical base pairs that form at mismatched positions in RNA duplexes and higher-order structures. Substituting classical thermodynamic parameters by MC-Fold increases accuracy in estimating messenger RNA structure, stability, and accessibility, as well as guide-message duplex stability.
Francois Major, Ph.D., Professor, Computer Science, Institute for Research in Immunology and Cancer, Universite de Montreal
10:20
Networking Refreshment Break in Exhibit & Poster Hall
11:00
Novel, Highly Potent Designs for shRNAs Targeting Hepatitis C Virus
Current therapies for hepatitis C are of limited efficacy, and there is an urgent need for alternatives. We have identified short hairpin RNAs (shRNAs) that potently target a highly conserved HCV sequence, without inducing an interferon response. These shRNAs show similar or greater potency (low-picomolar IC50) than cognate siRNAs in human hepatocytes and HCV replicon systems, and also in a mouse reporter model. The position of the shRNA loop is important: unlike right-hand loop shRNAs, which require a 3' overhang and a loop sizes of at least 5 nt for optimal activity, left-hand loop shRNAs are effective with loops of 0-4 nt and no overhang. Highly potent shRNAs with stem lengths of 16-19 bp are not processed by Dicer. 5'-RACE analysis shows a normal target cleavage position. These findings are encouraging for the prospects of the therapeutic use of direct-delivered shRNAs.
Brian Johnston, Ph.D., Chief Executive Officer/ Chief Scientific Officer, SomaGenics, Inc.
11:25
A Novel Dual Inhibitory Function Anti-HIV Envelop Aptamer-siRNA Chimera
HIV Infection is a major problem world wide and there is a constant need for new therapeutic approaches. RNA interference is a powerful mechanism that can be used to inhibit HIV replication and has therapeutic potential for treatment of HIV/AIDS. We have develop a novel anti-HIV aptamer that blocks HIV virion infectivity, but also delivers an anti-HIV siRNA into HIV infected cells. We show both in vitro and in a humanized mouse model that this aptamer-siRNA isa potent anti-HIV agent with long lasting inhibitory activity. Finally, a new modular aptamer-siRNA strategy allowing mixing and matching of different siRNAs with a given aptamer will be discussed.
John Rossi, Ph.D., Professor and Chairman, Molecular Biology, Beckman Research Institute of the City of Hope, City of Hope Graduate School of Biological Sciences
Industry Leadership Forum
(open to all attendees and exhibit hall visitors)
11:50
RNA Therapeutics - Are We Leveraging on the Promise?
- Current state of development of siRNA, miRNA, antisense and aptamars
- How are companies capitalizing on the promise of the field?
- What's the vision and potential for the field?
Moderator:
James D. Thompson, Ph.D., Vice President, Pharmaceutical Development, Quark Pharmaceuticals
Panelists:
Paul Burke, Ph.D., Executive Director, RNA Therapeutics, Merck & Co., Inc.
Klaus Giese, Ph.D., Chief Scientific Officer, Vice President, Research, Silence Therapeutics AG
Tod Woolf, Ph.D., President and CEO, RXi Pharmaceuticals Corporation
12:30
Networking Luncheon in Exhibit & Poster Hall
The Different Stages of Drug Development (Discovery to PreClinical to Clinical) for siRNA, miRNA, Antisense and Aptamers (continued)
1:55
Chairperson's Remarks
Dmitry Samarsky, Ph.D., Vice President, Technology Development, RXi Pharmaceuticals
Technology Workshop
2:00
Spiegelmers® advance towards clinical trials
Spiegelmers® are L-aptamers that bind to a given target and inhibit its function. They possess unique properties that solve the development challenges presented by stability and delivery. NOX-E36 and NOX-A12, targeting MCP-1 and SDF-1, respectively, are in preclinical development. Data demonstrating the compounds' discovery, efficacy, and safety will be presented.
Sven Klussmann, Ph.D., Chief Scientific Officer, NOXXON Pharma AG
2:25
microRNA Manipulation as a Therapeutic Strategy for Cardiovascular Disease
Cardiovascular disease is the number one global killer and represents a major area of unmet medical need. Alterations in specific microRNAs have been observed in several cardiovascular disease models and human clinical samples, providing an exciting potential for therapeutic intervention. An update on relevant microRNA identification and efforts toward therapeutic development will be presented.
William S. Marshall, Ph.D., President and Chief Executive Officer, miRagen Therapeutics, Inc.
2:50
Therapeutic Applications of Tumor Suppressor miRNAs
Let-7, miR-15/16, miR-34, and several other miRNAs apparently function as tumor suppressors by regulating the expression of key oncogenes and the activities of important cancer-related pathways. Reduced expression of these important miRNAs appears to contribute to the development of both primary and metastatic tumors in a significant number of cancer patients. We have developed synthetic mimics for six tumor suppressor miRNAs and evaluated the capacity of the small RNAs to inhibit tumor development and metastasis following IV injections in mouse models of cancer. We are now proceeding with the development of miRNA-based therapies that can be tested for safety and efficacy in advanced animal models.
Matt Winkler, Ph.D., Chief Executive Officer, Asuragen/Mirna Therapeutics
3:15
LNA Antimirs - Pioneering miRNA Therapeutics
Short, single stranded LNA oligonucleotides delivered systemically as naked molecules are able to potently and safely inhibit miRNAs in a range of tissues in experimental animals. The presentation will provide an update on the unique features of LNA oligonucleotides in miRNA therapeutics with particular emphasis on the pre-clinical and clinical development of SPC3649, an LNA AntimiR targeting miRNA-122.
Henrik Ørum, Ph.D., Chief Scientific Officer, Santaris Pharma A/S
3:40
Networking Refreshment Break in Exhibit & Poster Hall
4:25
Antisense Oligonucleotide GED-0301 Against Smad7 for the Oral Treatment of Crohn's Disease
We are developing a novel oligonucleotide-based therapeutic approach for management of active Crohn's disease. The compound, named GED-0301 targets Smad7. We developed an oral dosage form of GED-0301 that affords delivery to small intestine and right colon thus achieving a "topical' effect. Toxicology and safety pharmacology in mice and no-human primates indicate that the orally administered drug is well tolerated.
Mario Germano Giuliani, Ph.D., President & CEO, Giuliani SPA, Italy
4:50
Recent Advances in Aptamer Therarpeutics: Discovery and Initial Characterization of an Anti-hepatocyte Growth Factor Aptamer
The function of the HGF:Met axis is important during development, homeostasis, and tissue regeneration. Dysregulation of the HGF:Met pathway has been shown to play a critical role in tumorigenesis and promotes aggressive cellular invasiveness that is linked to tumor metastasis. Mouse and human cell lines that overexpress HGF and/or c-Met become tumorigenic and metastatic in nude mice. Additionally, a wide range of solid and hematological malignancies overexpress HGF and c-Met and their misexpression often correlates with poor prognosis thus interruption of the HGF:c-Met signaling axis represents an attractive target for the treatment of cancer. Anti-HGF aptamers were generated through the process of SELEX (Systematic Evolution of Ligands by Exponential enrichment) using nuclease resistant oligonucleotide pools. These aptamers and polyethylene glycol (PEG) conjugated derivatives bind human HGF with high affinity and are potent inhibitors of HGF-dependent signaling in vitro. These aptamers block HGF-mediated proliferation of endothelial and epithelial cells as well as HGF-mediated endothelial cell migration. These aptamers are intriguing leads for the development of novel HGF specific cancer therapies.
Kristin M. Thompson, Ph.D., Associate Director, Aptamer Discovery, Archemix
5:15
Close of Oligonucleotide Therapeutics Conference and Proceed to Plenary Keynote
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
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