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WEDNESDAY, APRIL 13
12:30 pm Registration
1:30 Chairperson’s Opening Remarks
Michael Sofia, Ph.D., Vice President, Chemistry, Pharmasset
1:40 Updates on Three Nucleoside Polymerase Inhibitors in Clinical Trials
Bill Symonds, Pharm. D., Vice President, Clinical Pharmacology, Pharmasset
This presentation will describe the early clinical development of 3 nucleoside/tide NS5b polymerase inhibitors including RG7128, PSI7851/7977 and PSI-352938. I will discuss Phase 1 safety, pharmacokinetics and pharmacodynamics of this compounds from single and multiple ascending dose studies. This will include a review of the monotherapy HCV RNA response data from studies ranging from 3 to 14 days with these compounds.
2:10 INX-189, a Highly Potent Nucleotide HCV Polymerase Inhibitor
John Vernachio, Ph.D., Vice President, Biology, Inhibitex, Inc.
This presentation will review the available Phase 1 clinical data for INX-189, which includes pharmacokinetics, viral kinetics, safety, and tolerability.
2:40 Solving Developability Issues with a Novel “Traceless” Prodrug Approach - Application to a Replicase/NS5B Inhibitor Series
Martin Leivers, Ph.D., Chief Scientist, GlaxoSmithKline, Inc.
A series of Replicase / NS5B inhibitors was successfully optimized to reduce their hERG liability, but the solubility of the series was also reduced. A novel prodrug approach was developed which greatly increased exposure, allowing for further progression of compounds from the series.
3:10 The uPA Chimeric Mouse Model for HCV Drug Discovery
Garry Lund, Ph.D., Project Manager, KMT Hepatech, Inc.
The KMT MouseTM is the first small animal model of HCV infection. The uPA/scid-beige chimeric mouse provides for infection of human hepatocytes in vivo with clinically relevant strains and titres of virus, and has demonstrated the ability to generate infectious virus that can be transmitted to other chimeric mice – in short, the full viral life cycle. The model has been validated with a wide range of therapeutic agents and the correlation between KMT MouseTM results and clinical outcomes is confirmed. PK, toxicity, efficacy of single agents or combinations, and resistance studies have all proven helpful in generation and design of clinical trials. The study of infection facilitated by a mouse with a chimeric human liver is not limited to hepatitis viruses, and extension to other pathogens with obligate life cycles in the liver could greatly broaden the impact of the model.
3:25 Sponsored Presentation (Opportunity Available)
3:40 Networking Refreshment Break in the Exhibit Hall with Poster Viewing
4:20 The Discovery of BMS-790052, a First-in-Class HCV NS5A Inhibitor with Potent Clinical Antiviral Effects
Makonen Belema, Prinicipal Scientist, Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development
This presentation will describe the optimization of a screening lead discovered by high-throughput screening using a genotype 1b HCV replicon screen and for which resistance mapped to the NS5A protein. During the initial SAR investigation, it became apparent that minor high molecular weight species derived by dimerization of the parental compounds contributed to the antiviral activity. Based on a preliminary understanding of the SAR, a novel stilbene-based lead NS5A inhibitors was designed that exhibited 2300-fold increased potency compared to the initial HTS hit. Subsequent iterative optimization focusing on potency and ADME properties culminated in the discovery of the highly potent analog BMS-790052 (1a/1b EC50 = 50 pM/9 pM), that is currently in Phase II clinical studies.
4:50 Nonclinical Profile and Phase I Results for the Novel and Potent HCV NS5A Inhibitor GS-5885
John O. Link, Ph.D., Senior Director, Medicinal Chemistry, Gilead Sciences
HCV NS5A has emerged as an important target for small molecule antiviral drugs. GS-5885 is a highly potent HCV NS5A inhibitor in replicon cell lines with an EC50 of 41 picomolar (pM) for GT 1a, and 5 pM for GT 1b, and is under development for the treatment of HCV infection. Here we describe the nonclinical profile, phase I safety data, pharmacokinetic data in healthy subjects, and antiviral activity for GS-5885 in HCV infected patients. The pharmacokinetic profile and antiviral activity of GS-5885 are consistent with once daily dosing.
5:20 Breakout Discussions:
Topic: Animal Models for HCV
Moderator: Alexander Ploss, Ph.D., Research Assistant Professor, Center for the Study of Hepatitis C, The Rockefeller University
• Advances and challenges with animal models for HCV
• Where are we and where do we need to be?
• (How) Can development of HCV therapeutics be improved/accelerated using small animal models?
Topic: Protease Inhibitors -- 2nd Generation Challenges
Moderator: Jeremy Green, Ph.D., Director of Chemistry, VertexWhat will HCV therapy look like in 5-10 years time?
Topic: Finding New HCV Host Targets
Moderator: Kai Lin, Ph.D., Group Head, Virology, Novartis
What are host targeting antivirals (HTAs) and how to identify novel targets?
Pros and cons of HTAs vs. DAAs
Specific challenges in developing HTAs
6:30 End of Day
*Dinner Short Course*, 6:30 - 9:00pm
SC 6 HCV Biology and Drug Development Fundamentals
- Virology of HCV -- emphasis on drug targets and viral characteristics promoting development of drug resistance
- Immunology/host factors and HCV
- In vitro HCV replication systems
- Novel HCV therapies- clincal trials and drug resistance issues
David Wyles, M.D., Assistant Professor, Infectious Diseases, UCSD
*Separate Registration Required
Day 1 | Day 2 | 2011 Download Brochure | 2011 Archive