Antiviral Drug Discovery & Development Summit

Daria Hazuda, M.D., Ph.D.
Executive Director of Biological Chemistry
MERCK & COMPANY

8:25 - 9:00 - KEYNOTE ADDRESS: HCV Antivirals: Targets and Assays
The development of specific antivirals against HCV has been challenging. Recently, cell-based assays have been established to evaluate compounds targeting RNA replication and entry. I will review these systems and highlight some exciting new targets that have been discovered through basic studies.

Charles Rice, Ph.D.
Professor, Laboratory of Virology & Infectious Disease
THE ROCKEFELLER UNIVERSITY

9:00 - 9:35 - KEYNOTE ADDRESS: Attacking HIV Drug Resistance at its Source – Inhibiting the NRTI Resistance Phenotype
Two different strategies have been used to bypass the primer unblocking phenotype of HIV resistance to nucleoside inhibitors (NRTI). First, selective alterations of the NRTI sugar and phosphate backbone have provided NRTI refractory to the primer unblocking mechanism. Second, we have identified compounds that selectively inhibit excision of incorporated NRTI without affecting incorporation of the NRTI. These inhibitors restore antiviral activity of zidovudine (AZT) against AZT-resistant HIV strains.

Michael A. Parniak, Ph.D.
Professor of Medicine, Molecular Genetics and Biochemistry
Co-Director, Viral Diseases Unit
UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE

9:35 - 10:20 - KEYNOTE ADDRESS: New Treatment Paradigms with HIV Protease Inhibitor
Several highly potent HIV protease inhibitors have been identified and developed for clinical use. They have the distinct advantage of blocking HIV infection in both acutely and chronically infected cells, thus preventing the production of mature, infectious virions. Kaletra (lopinavir/r) is a highly potent HIV protease inhibitor now widely used both as a first line and for treatment-experienced patients based on its efficacy in suppressing viral replication. To date, the development of primary resistance to lopinavir
(LPV) have not been observed in antiretroviral naÔve patients treated for up to five years. Combination therapy with Kaletra, NNRTI and NRTIs was highly effective against mutant HIV strains with up to 10-fold reduction in LPV phenotypic susceptibility and up to 5 protease mutations associated with LPV resistance. Other protease inhibitors currently approved by FDA as well as currently under development will be discussed.

Akhter Molla, Ph.D.
Senior Project Leader, Antiviral Drug Discovery
ABBOTT LABORATORIES

10:20 - 11:00 - Networking, Refreshments & Exhibition



11:00 - 11:35 - KEYNOTE ADDRESS: Pyrophosphate Mimetics: A Mechanism Based Approach to Antiviral Drug Discovery
Daria Hazuda, M.D., Ph.D.
Executive Director of Biological Chemistry
MERCK & COMPANY

11:35 - 12:10 - KEYNOTE ADDRESS: Prospects for Better Therapy for Hepatitis B & C: Scientific and Practical Issues
Progress over the past 15 years illustrates that chronic hepatitis B and chronic hepatitis C, both globally common, are tractable to antiviral therapy. Responses which are durable post-treatment are associated with clearance of PCR-detectable HCV RNA in hepatitis C patients, or with partial viral suppression and poorly understood immunologic changes in hepatitis B patients. Prospects for advancing therapy for hepatitis B and C will be reviewed with consideration toward virus-specific and disease-specific scientific issues, as well as practical issues in pharmaceutic development.

Nathaniel A. Brown, M.D.
Senior Vice President, Hepatitis Clinical Research
IDENIX PHARMACEUTICALS

12:10 - 1:30 - Luncheon



1:30 - 2:00 - UK-427,857: A Novel CCR5 Inhibitor with Potent Anti-HIV Activity
Compounds that prevent the binding and fusion of HIV with its host cell are the latest new class of antiretroviral agents. UK-427,857, a CCR5 antagonist in clinical development for the treatment of HIV infection, has potent activity in vitro (IC90 = 2.03nM against primary HIV strains) which translates to efficacy in short-term clinical studies (mean viral load decrease of 1.42 log10 following 10-day monotherapy). We have shown that the inhibitor binds the receptor with a long half-life, blocking viral replication at the point of membrane fusion. UK-427,857 has good pharmacokinetic and safety credentials, and is an attractive candidate for further clinical development.

Manos Perros, Ph.D.
Head of Anti-Infectives Biology
PFIZER GLOBAL R&D SANDWICH LABORATORIES

2:00 - 2:30 - Fusion Inhibitors Treatment for HIV Infection
Over the past few years, HIV has developed extensive antiretroviral resistance against reverse transcriptase (RT) and protease inhibitors (PI). As a consequence, many patients are in need of antiretroviral agents against new targets. Fusion inhibitors constitute a new antiretroviral (ARV) class that preserves activity against viruses resistant to all RT and PI inhibitors. Enfuvirtide is the first approved agent of this class. Clinical studies have demonstrated that, in patients experienced to other classes of ARV, regimens containing enfuvirtide constitute the standard of care. Thus, fusion inhibitors represent a significant advancement in the treatment of HIV infection.

Diego Miralles, M.D.
Director of Clinical Trials
TRIMERIS INC.

2:30 - 3:00 - Searching for gp41-directed Antibodies that Neutralize Diverse HIV Isolates
Michael Miller, Ph.D.
Department of Biological Chemistry
MERCK RESEARCH LABORATORIES

3:00 - 3:45 - Refreshments, Networking & Exhibition



3:45 - 4:15 - Progress in the Clinical Development of ReversetTM, a Nucleoside Analog for the Treatment of HIV
ReversetTM (RVT), b-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, is a cytidine nucleoside analog that retains activity against many 3TC and AZTresistant viral variants in vitro. In a phase I clinical study in HIV-1 infected, treatment naÔve volunteers, RVT had excellent oral bioavailability with a dose dependent increase in the mean Cmax and AUC values. Over the range of doses tested (25 - 200 mg), mean plasma Cmax values ranged from approximately 1 to 8 µM, which are concentrations in excess of the in vitro
EC90 values for RVT against representative HIV isolates. Remarkably, viral loads dropped significantly after a single dose, with an average reduction of 0.4 ± 0.2 log10 for all dose levels. A 10-day monotherapy study in antiretroviral naÔve HIV-infected subjects is currently in progress. Results from this study as well as future plan will be discussed.

Michael J. Otto, Ph.D.
Chief Scientific Officer
PHARMASSET

4:15 - 4:45 - Maturation Inhibition: A New Class of Potent HIV Inhibitors That Disrupts Core Condensation by Targeting a Late Step in GAG Processing
Background: New targets for therapeutic intervention in HIV-1 replication are needed to counter the growing problem of resistance to currently used antiviral drugs. HIV-1 assembly/release and virus maturation represent largely undeveloped targets for antiviral therapy. PA-457, a betulinic acid derivative, potently inhibits HIV-1 replication with low nanomolar IC50 by interfering with capsid condensation. PA-457's potential for development was examined by analyzing in vitro activity, defining the compound's mechanism of action (MOA), and selecting for resistant virus isolates. Methods: We analyzed the activity of PA-457 against a panel of HIV-1 isolates resistant to NRTIs, NNRTIs, or PIs. MOA studies focused on events late in the virus life cycle including protease function and viral protein processing. PA-457-resistant isolates were generated by serial passage of virus in the presence of increasing concentrations of compound. Results: PA-457 retains low nM IC50 against all drug-resistant HIV-1 isolates tested.
MOA studies indicate that PA-457 inhibits virus replication by causing a defect in Gag processing, specifically the conversion of p25 to p24. Consistent with our MOA results, genotypic analysis of PA-457-resistant virus indicates that mutations that confer resistance map to residues flanking the p25 to p24 processing site. Conclusions: PA-457 potently inhibits HIV-1 replication by targeting a novel step late in the virus life cycle. The block to replication occurs at the level of virus maturation and involves disruption of Gag p25 to p24 processing. Analysis of resistant virus indicates that this cleavage site is a likely target for PA-457. PA-457's in vitro profile support further development of this compound as a novel antiretroviral drug candidate.

David E. Martin, PharmD, MBA
Vice President, Drug Development
PANACOS PHARMACEUTICALS

4:45 - 5:15 - mtDNA Levels in PBMC as Tool to Optimize Drug Administration During HIV Infection
Adverse effects of antiviral therapy can in part be explained by mitochondrial (mt) dysfunction caused by depletion of mtDNA. Monitoring mtDNA content in easily accessible cells like PBMC is helpful to assess toxic effects of drugs, both existing and in development. Hereto, a real-time, duplex assay was developed to measure mtDNA levels relative to nuclear DNA. Using this assay we have analyzed both the in vitro and in vivo effects of antiviral drugs on PBMCs. As HIV infection itself can cause mtDNA decline, the more toxic therapies will lead to a further decline of the mtDNA levels, possibly leading to severe adverse effects. The predictive value of mtDNA changes on the development of clinical adverse effects is currently being investigated in clinical trials.

Jos Rijntjes, Ph.D.
Chief Commercial Officer
PRIMAGEN

5:15 - 6:45 - Networking Reception



Tuesday, March 30, 2004

7:30 - 8:35 - Breakfast, Networking & Exhibits



8:35 - 8:45 - Chairpersons' Recap of Day One
Nathaniel A. Brown, M.D.
Senior Vice President, Hepatitis Clinical Research
IDENIX PHARMACEUTICALS

Akhter Molla, Ph.D.
Senior Project Leader, Antiviral Drug Discovery
ABBOTT LABORATORIES

8:45 - 9:15 - Peg-IFN Latest Clinical Studies in Combination with Ribavirin and Other Drugs
Pegylated interferon alfa-2a (PEGASYS(R)) plus Ribavirin (COPEGUS(R)) has become the standard of care in patients with chronic hepatitis C (CHC). A recently reported study has allowed for individualization of therapy according to viral genotype. Data from recently completed trials in patients with normal ALT activity, patients co-infected with HCV and HIV, and those with both e-antigenpositive and e-antigen-negative HBV infection continue to advance the field of viral hepatitis treatment.

Frank Duff, M.D.
Clinical Science Leader, Pegasys/Copegus
ROCHE GLOBAL RESEARCH & DEVELOPMENT

9:15 - 9:45 - VX-950: An Orally Bioavailable Inhibitor of the Hepatitis C NS3ï4A Protease & a Potential HCV Therapeutic
The poor tolerability and limited efficacy of the current standard of care treatment for HCV infection, pegylated interferon-???IFN-?)-ribavirin combination therapy, highlights the need for new HCV therapies. The NS3ï4A protease of the hepatitis C virus represents an attractive target amenable to modern structure-based drug design techniques. Vertex's lead HCV protease inhibitor, VX-950, has demonstrated potent activity in HCV replicon and viral clearance assays, as well as in a small animal model that measures activity of HCV protease expressed in the liver. VX-950 is a slow binding enzyme inhibitor with a multi-step binding process. VX-950 has a sustained antiviral response in HCV replicon cells that persists for 2 weeks or longer, which may result from the long half-life, approximately 1 hour, of the enzyme-inhibitor complex. VX-950 is orally bioavailable in several species with a favorable pharmacokinetic profile and a good pre-clinical safety profile. Clinical trials are expected to start in early 2004.

Steve Lyons, Ph.D.
Program Executive, HCV Protease Inhibitor Program
VERTEX PHARMACEUTICALS

9:45 - 10:15 - Clinical Development of Entecavir for the Treatment of Chronic Hepatitis B
Entecavir is a potent and selective inhibitor of hepatitis B virus (HBV) which is currently in Phase III development for the treatment of chronic HBV infection in adults. This talk will review the pre-clinical, phase I and phase II clinical development of entecavir, with an emphasis on safety and efficacy in a variety of patient subgroups, including HBeAg-positive and -negative, nucleoside-naÔve and lamivudine-refractory populations.

Bruce Kreter, M.D.
Global Project Leader
BRISTOL-MYERS SQUIBB

10:15 - 10:55 - Refreshments, Networking & Exhibition



10:55 - 11:25 - HCV Drug Development
Hepatitis C virus infection is a serious cause of chronic liver disease with more than 170 million infected individuals worldwide. Current interferon (IFN)-based therapies are suboptimal especially in patients infected with HCV genotype 1 and are poorly tolerated, highlighting the unmet medical need for novel therapeutics. Boehringer Ingelheim is currently studying the available pre-clinical data in order to decide on their impact on the clinical development of this substance.

Doug Mayers, M.D.
International Therapeutic Area Head
BOEHRINGER INGELHEIM PHARMACEUTICALS

11:25 - 11:55 - Mechanistic Studies of Resistance to HCV Polymerase Inhibitors
Several distinct structural classes of inhibitors of the HCV RNA polymerase have recently been identified through the use of in vitro enzyme and cellbased replicon assays. Kinetic and structural analyses have revealed divergent mechanisms of inhibition and distinct inhibitor binding sites. Resistance studies demonstrate that different single amino acid changes within the polymerase can lead to significant losses of potency for these inhibitor classes. The results suggest that combination therapies may prove advantageous in next-generation HCV therapies.

Steven Carroll, Ph.D.
Senior Research Fellow
MERCK RESEARCH LABORATORIES

11:55 - 12:25 - Safety and Efficacy of Hepavir B, a Liver-targeting Prodrug of PMEA, for Treatment of Chronic Hepatitis B
Hepavir B is designed to target the parent compound (PMEA) to the liver by using the HepDirectTM technology. Conversion of hepavir B by the liverspecific cytochrome P450 3A4 isozyme traps the active molecules in the hepatocytes and reduces systemic and renal exposure of PMEA. Preclinical as well as clinical studies in HBV-infected subjects support that hepavir B has the potential to improve both safety and efficacy profiles of Hepsera( for the treatment of hepatitis B.

Zhi Hong, Ph.D.
Vice President of Drug Discovery
ICN PHARMACEUTICALS

12:25 - 1:30 - Luncheon



1:30 - 2:00 - Highly Specific Antiviral Screens Using Related Viral Replicons
Parallel cell-based assay systems utilizing subgenomic replicons from HCV and related viruses, bovine viral diarrhea virus (BVDV) and GB virus B (GBV-B), have been established under similar cellular environment of Huh7 cells. Antiviral compounds with varying degrees of specificity can be evaluated using these systems and virus-specific inhibitors can be quickly identified for further development. In addition, virus-specific induction or inhibition of host gene functions can be characterized with the hope to identify new antiviral targets for development of future therapeutics.

Weidong Zhong, Ph.D.
Associate Director and Head of Virology
ICN PHARMACEUTICALS

2:00 - 2:30 - Developing the First Potent Oral Anti-Viral Product for the Treatment of RSV Infection
Respiratory Syncytial Virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide, and is increasingly recognised as representing a serious threat to patient groups with poorly functioning immune systems. Hospitalisations arising from this virus result in substantial costs. Arrow's goal is to develop the first potent oral anti-viral product for the treatment of RSV infection. A small molecule inhibitor of RSV replication is completing preclinical trials and will enter Phase I in early 2004.

Ken Powell
CEO
ARROW THERAPEUTICS

2:30 - 3:00 - AlphaHGA: A New Antiviral Substance Against HIV Affecting Capsid Assembly
We have previously shown that the tripeptide glycyl-prolyl-glycine-amide (GPG-amide) inhibits HIV-1 replication in vitro by affecting proper capsid assembly and the budding process of HIV-1. GPG-amide showed promising properties in that it was virtually atoxic in animals including pigs, had a new mode of action and thus was active against those viruses that had acquired resistance towards RT and protease inhibitors, and in that we for three consecutive years had not been able to provoke resistance to the substance. We now show that GPG-amide in itself does not exert the antiviral activity but is metabolized in two steps into the active compound alphaHGA by serum enzymes. The first step is cleavage of GPG-amide into glycine-amide (G-amide) by soluble CD26. The second step is an enzyme mediated oxidation of G-amide into alphaHGA. The latter is a small molecule. The conversion of G-amide into alphaHGA does not take place in human or mouse serum but in the serum from most species including fetal calf and pig serum. Hence, GPG-amide does not affect HIV-1 replication if the infected cells are cultured in the presence of human serum only. We have now synhesized alphaHGA and been able show that the synthesized substance inhibits HIV-1 replication in the presence of human serum only or with heat inactivated fetal calf serum. In the presence of alphaHGA in the culture medium progeny HIV-1 particles have deranged capsid structures and are non-infectious. The phenomenology earlier attributed to GPG-amide, i.e. mode of antiviral activity, favourable resistance profile and low toxicity most probably should apply to alphaHGA.

Anders Vahlne, M.D., Ph.D.
VP Head of Research & Professor in Clinical Virology
KAROLINSKA INSTITUTET

Michael A. Parniak, Ph.D.
Professor of Medicine, Molecular Genetics and Biochemistry
UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE

Daria Hazuda, M.D., Ph.D.
Executive Director of Biological Chemistry
MERCK & CO.