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EASL 45th Annual Meeting
(European Association for the Study of the Liver)
April 14-18, 2010
Vienna, Austria
* New HCV Drugs EASL 2010 - (04/15/10)
* From Ash To Cure - EASL April 14-18 2010 - (04/21/10)
* Resistance Profile Of ABT-333 And Relationship To Viral Load Decrease In Patients Treated In Combination With Peg-interferon And Ribavirin For 28 Days. - (04/28/10)
* Pharmacokinetics of the HCV Polymerase Inhibitor ABT-333 in US and Japanese Healthy Volunteers - (04/28/10)
* Exposure-Viral Response Analyses of the Non-nucleoside Polymerase Inhibitor ABT-333, Following Monotherapy and ABT-333 Plus Pegylated Interferon and Ribavirin Therapy - (04/28/10)
* Pharmacokinetics of the HCV Polymerase Inhibitor ABT-072 Following Single and Multiple Dosing in Healthy Adult Volunteers - (04/28/10)
* Virologic Response Rates Following 4 Weeks of Filibuvir in Combination with Pegylated Interferon Alfa-2a and Ribavirin in Chronically-Infected HCV Genotype-1 Patients - (04/27/10)
* Genotypic Characterisation of Filibuvir Resistance in Patients Receiving Four Weeks Co-administration of Filibuvir with pegIFN/RBV(12 Week Analysis) - (04/27/10)
* Exposure-response Relationship of Filibuvir in HCV-infected Patients: Application to Dose Selection for Combination Therapy - (04/27/10)
* Impact of Sustained Virological Response After Antiviral Treatment in Chronic Hepatitis C Patients on Life Expectancy and Quality-adjusted Life-years - (04/27/10)
* Locteron, controlled-release interferon alpha 2b, 3 studies at EASL 2010 Vienna - 3 company press releases - (04/26/10)
* PHASE IIB STUDY OF BALAPIRAVIR (RG1626; NUCLEOSIDE ANALOGUE INHIBITOR OF HCV POLYMERASE) PLUS PEGINTERFERON ALFA-2A (40KD) AND RIBAVIRIN FOR CHRONIC HEPATITIS C GENOTYPE 1: FINAL RESULTS - (04/26/10)
* RANDOMIZED, OPEN-LABEL, 12-WEEK COMPARISON OF CONTROLLED-RELEASE INTERFERON ALPHA2B + RIBAVRIN VS. PEGYLATED-INTERFERON ALPHA2B + RIBAVRIN IN TREATMENT-NAïVE GENOTYPE1 HEPATITIS C: 4 WEEK RESULTS FROM 480STUDY (PANEL A) - (04/23/10)
* Slow Responders Benefit From 72 Weeks Peg/Rbv - Predicting Treatment Outcome Among Slow Responders: A Retrospective Analysis of the SUCCESS Study - (04/23/10)
* Q2week Controlled Release Interferon Alpha2b + Ribavrin Reduces Flu-like Symptoms >50% And Provides Equivalent Efficacy In Comparison To Weekly Pegylated Interferon Alpha2b + Ribavirin In Treatment-naïve Genotype-1 Chronic Hepatitis C: Results From EMPOWER, A Randomized Open-label 12-week Comparison In 133 Patients - (04/23/10)
* Early Viral Response Of Controlled-release Interferon Alpha2b And Ribavirin Vs. Pegylated-interferon Alpha2b And Ribavirin In Treatment-naïve Genotype-1 Hepatitis C: 12 Week Results (SELECT-2 Trial) - (04/23/10)
* IMPACT OF LOW-DOSE RITONAVIR BOOSTING ON THE PHARMACOKINETICS OF DANOPREVIR (RG7227; ITMN-191), A HIGHLY POTENT AND SELECTIVE INHIBITOR OF THE HCV NS3/4A PROTEASE - (04/23/10)
* High Dose Pegasys/rbv can improve SVR: Impact of higher doses of peginterferon alfa-2a and ribavirin on RVR, cEVR and SVR in HCV G1 patients with viral loads ≥400 000 IU/mL weighing ≥85 kg - (04/23/10)
* Predictors of relapse among patients treated with standard- or induction-dose peginterferon alfa-2a (40KD) combined with standard- or higher-dose ribavirin in difficult-to-cure patients - (04/23/10)
* Pegasys vs Pegintron, Baseline characteristics and on-treatment predictors of responses from real-world patient cohorts: interim results of the multinational PROPHESYS cohorts - (04/23/10)
* Metabolic Syndrome (MS) [glucose/diabetes] Is a Negative Predictor of Treatment Outcome in Patients With Chronic Hepatitis C: Results From the IDEAL Study - (04/23/10)
* Improved Inflammatory Activity With Low-Dose PegIntron (PEG) Maintenance Therapy in Prior Nonresponders With METAVIR Fibrosis Scores (MFS) of F2/F3: Final Results From the EPIC3 Program - (04/23/10)
* Characterization of resistant mutants selected in vitro by the HCV NS3/4A protease inhibitor BI 201335 - (04/22/10)
* Preclinical characterization of non-covalent HCV NS3/4A protease inhibitor BI 201335 - (04/22/10)
* HBsAg Kinetics of Decay and Baseline Characteristics of HBeAg-Positive Patients with Chronic Hepatitis B Following 3 Years of Tenofovir Disoproxil Fumarate (TDF) Treatment - (04/22/10)
* Evaluation of Potential Virologic Resistance in HBV Polymerase Among Subjects with Persistent Viremia Following up to 144 Weeks of Therapy with Tenofovir DF - (04/22/10)
* Efficacy of Tenofovir DF Treatment in Patients with a Suboptimal Response to Adefovir Dipivoxil - (04/21/10)
* Risk and Predictors of Mortality or Hepatocellular Carcinoma among Entecavir- or Adefovir-Treated Chronic Hepatitis B Patients with Evidence of Hepatic Decompensation - (04/21/10)
* Low Rates of Nucleos(t)ide-associated Adverse Events in the Long-term Experience with Entecavir - (04/21/10)
* MK-5172, the 1st HCV Protease Inibitor with Potent Acyivity Against Resistance Mutations In Vitro - (04/21/10)
* TMC435 & Drug Interactions: Evaluation of metabolic interactions for TMC435 via cytochrome P450 (CYP) enzymes in healthy volunteers - (04/21/10)
* EARLY ON-TREATMENT RESPONSES DURING PEGYLATED INTERFERON PLUS RIBAVIRIN ARE INCREASED FOLLOWING 13 DAYS OF COMBINATION NUCLEOSIDE POLYMERASE (RG7128) AND PROTEASE (RG7227) INHIBITOR THERAPY (INFORM-1) - (04/21/10)
* Combination of TMC435 with two novel NS5B inhibitors increases anti-HCV activity and results in a higher genetic barrier in vitro - (04/21/10)
* 4 week therapy with the non-nucleosidic polymerase inhibitor BI 207127 in combination with peginterferon alfa2A and ribavirin in treatment naïve and treatment experienced chronic HCV GT1 patients - (04/21/10)
* Pharmacokinetic-pharmacodynamic (PK-PD) analyses of TMC435 in treatment-naïve hepatitis C (HCV)-infected patients in the OPERA-1 study - (04/20/10)
* Once-daily NS5A Inhibitor (BMS-790052) Plus Peginterferon-alpha-2a And Ribavirin Produces High Rates Of Extended Rapid Virologic Response In Treatment-naïve HCV-genotype 1 Subjects: Phase 2a Trial - Bristol-Myers Squibb Study AI444014 - (04/20/10)
* SILEN-C2: Early antiviral activity and safety of BI 201335 combined with peginterferon alfa-2a and ribavirin (PegIFN/RBV) in chronic HCV genotype 1 patients with non-response to PegIFN/RBV - (04/20/10)
* Phase 2 Randomized, Double-Blind Placebo-Controlled Study of Nitazoxanide with Peginterferon Alfa-2a and Ribavirin in Nonresponders with Chronic Hepatitis C Genotype 1: Final Report - (04/20/10)
* Nitazoxanide + Peg/Rbv in Nonresponders - (04/20/10)
* Combination of two complementary nucleotide analogues, PSI-7977 and PSI-938, effectively clears wild type and NS5b: S282T HCV replicons - Comparison with combinations of other antiviral compounds - (04/20/10)
* Sustained Virologic Response following RG7128 1500 mg BID PEG-IFN/RBV for 28 days in HCV Genotype 2/3 prior non-responders - (04/20/10)
* Vitamin D Supplement improve SVR in Chronic Hepatitis C (Genotype 1) Naïve Patients treated with Peg Interferon and Ribavirin - (04/20/10)
* Idenix Pharmaceuticals Reports Favorable Pharmacokinetic Data for IDX320, a Potent, Multi-Genotypic Protease Inhibitor for the Treatment of Hepatitis C - (04/20/10)
* Idenix Pharmaceuticals Reports Positive Results With IDX184 nucleoside polymerase From Interim Analysis of Phase IIa Hepatitis C Study - (04/19/10)
* Triple Combinations of Direct-Acting Antiviral Agents Demonstrate Robust Anti-HCV Activity In Vitro - (04/19/10)
* Antiviral Activity, Pharmacokinetics & Safety of IDX184 in Combination with Peg/Rbv in Treatment Naïve Genotype 1 - (04/19/10)
* In Vitro Antiviral Activity of IDX320, a Novel and Potent Macrocyclic HCV Protease Inhibitor - (04/19/10)
* ANA598 HCV Polymerase Inhititor Safety & Activity + Peg/Rbv in Genotype 1 - (04/19/10)
* 72% OF PATIENTS RECEIVING ANA598 IN PHASE II COMBINATION STUDY WITH INTERFERON AND RIBAVIRIN ACHIEVE UNDETECTABLE LEVELS OF VIRUS AT WEEK EIGHT - (04/19/10)
* Idenix Pharmaceuticals Reports Favorable Pharmacokinetic Data for IDX320, a Potent, Multi-Genotypic Protease Inhibitor for the Treatment of Hepatitis C - (04/19/10)
* Discrepancies Between Definitions of Null Response to Treatment with Peginterferon Alfa-2a and Ribavirin: Implications for New HCV Drug Development - (04/18/10)
* On-Treatment Response-Guided Therapy with Telaprevir q8h or q12h Combined with Peginterferon Alfa-2a or Alfa-2b and Ribavirin in Treatment-Naïve Genotype 1 Hepatitis C (Study C208) - (04/18/10)
* Activity of Telaprevir Alone or in Combination with Peginterferon Alfa-2a and Ribavirin in Treatment-naïve, Genotype 2 and 3, Hepatitis C Patients: Final Results of Study C209 - (04/18/10)
* On-Treatment Response-Guided Therapy with Telaprevir q8h or q12h Combined with Peginterferon Alfa-2a or Alfa-2b and Ribavirin in Treatment-Naïve Genotype 1 Hepatitis C (Study C208) - (04/18/10)
* Idenix Pharmaceuticals Reports Positive Results With IDX184 From Interim Analysis of Phase IIa Hepatitis C Study - (04/18/10)
* Silibinin as Rescue Therapy for Suboptimal Response to Peg/Rbv - (04/18/10)
* Vitamin D Improves SVR in Naïve Genotype 1 with Peg/Rbv - (04/16/10)
* InterMune Reports Virologic Response of Ritonavir-Boosted Danoprevir (RG7227/ITMN-191) in Patients with Chronic Hepatitis C - (04/16/10)
* Identification and Characterization of PPI-461, a Potent and Selective HCV NS5A Inhibitor with Activity Against all HCV Genotypes - (04/16/10)
* Dose-Ranging, Three-Day Monotherapy Study of the HCV NS3 Protease Inhibitor GS-9256 - (04/16/10)
* Long-term Outcomes Following Combination Treatment with Boceprevir plus PegIntron/Ribavirin (P/R) in Patients with Chronic Hepatitis C, Genotype 1 (CHC-G1) - (04/16/10)
* Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of Nitazoxanide Plus Peginterferon and Ribavirin in HCV Genotype 1 Naïve Patients: Week 12 Sustained Virologic Response Rate - (04/16/10)
* GlobeImmune GI-5005 HCV Product Candidate Improves Sustained Virologic Response by 10 Percent, Demonstrating Potential to Be First Therapeutic Vaccine for HCV - (04/16/10)
* Ritonavir boosting of low-dose danoprevir (RG7227; ITMN-191), HCV NS3/4A protease inhibitor, results in robust reduction in HCV RNA at lower exposures than provided by unboosted regimens - (04/15/10)
* Telaprevir in Null-Responders & Non-Responders - (04/15/10)
* VX-222 Vertex NNRTI Polymerase Inhibitor 3 Days Monotherapy - (04/15/10)
* Merck HCV Protease Inhibitor For Resistance - (04/15/10)
Sunday, May 2, 2010
BMS NS5A HCV Inhibitor - chemical genetics discovery process in Nature
BMS NS5A HCV Inhibitor - chemical genetics
discovery process in Nature jnl - pdf attached
Download the PDF Here
"Individuals infected with HCV are at considerable risk of developing liver cirrhosis, end-stage liver disease and hepatocellular carcinoma.....We designed a mechanistically unbiased approach based on chemical genetics to identify chemical starting points for interfering with HCV replication.....we screened over one million compounds from the Bristol-Myers Squibb proprietary collection in high throughput mode.....The results with BMS-790052 provide clinical validation for the first in a new class of HCV inhibitors that target a viral protein with no known enzymatic function and an as yet poorly understood role in viral replication16, 22. The strategy used to identify a lead HCV NS5A inhibitor and to optimize this molecule into a clinical candidate offers a contemporary demonstration of the effectiveness of an approach to drug discovery based on chemical genetics......In a randomized, double-blind, placebo-controlled, single ascending-dose study, BMS-790052 was administered to subjects with genotype 1 chronic HCV at doses of 1, 10 and 100mg as an oral solution. All subjects were infected with HCV genotype 1a except for two subjects at 10mg and three subjects at 100mg who were infected with genotype 1b. BMS-790052 was safe and well tolerated in HCV-infected subjects after single oral doses up to 100mg.....BMS-790052 had a mean plasma elimination half-life ranging from 10 to 14h, and plasma drug levels were similar to those in non-HCV-infected subjects. After single oral doses of 10-100mg BMS-790052, all subjects had 24-h plasma concentrations above the tenfold protein binding-adjusted EC90 for HCV genotypes 1a and 1b, suggesting the possibility for once daily administration.....A single milligram dose of BMS-790052 produced a mean 1.8log10 reduction (range 0.2-3.0log10) in HCV viral load measured 24h after drug administration. Both the 10 and 100mg doses produced a greater antiviral effect, with mean plasma viral RNA falling by 3.2 log10 (range 2.9-4.0log10) and 3.3log10 (range 2.7-3.6log10), respectively, at 24h post-dose. Moreover, the 100mg dose resulted in a mean maximal HCV RNA decline of 3.6 log10 (range 3.0-4.1log10) and a prolonged antiviral response was observed in two subjects infected with genotype 1b virus, with an HCV RNA measurement that reached the lower limit of quantification (less than 25IUml-1) in one subject"
BMS - Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect - pdf of full article attached
Letters to Nature
Nature , | doi:10.1038/nature08960; Received 29 October 2009; Accepted 26 February 2010; Published online 21 April 2010
Min Gao1, Richard E. Nettles2, Makonen Belema3, Lawrence B. Snyder3, Van N. Nguyen3, Robert A. Fridell1, Michael H. Serrano-Wu3, David R. Langley4, Jin-Hua Sun1, Donald R. O'Boyle II1, Julie A. Lemm1, Chunfu Wang1, Jay O. Knipe5, Caly Chien2, Richard J. Colonno1, Dennis M. Grasela2, Nicholas A. Meanwell3 & Lawrence G. Hamann3
1. Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA
2. Department of Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA
3. Department of Discovery Chemistry,
4. Department of Computer-Aided Drug Design,
5. Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA
Correspondence to: Nicholas A. Meanwell3 Correspondence and requests for materials should be addressed to N.A.M. (Email: Nicholas.Meanwell@bms.com).
Abstract
The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200million people1. Current therapy relies upon a combination of pegylated interferon-α and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus2, 3. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B4. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC50) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3log10 reduction in mean viral load measured 24h post-dose that was sustained for an additional 120h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.
We designed a mechanistically unbiased approach based on chemical genetics to identify chemical starting points for interfering with HCV replication. Our differentiating strategy centred on the identification of compounds functionally distinct from those acting on the traditional targets of antiviral research in this field, the NS3 protease and the NS5B RNA-dependent RNA polymerase5, 6, 7. Using a Con-1 genotype 1b replicon replicating in Huh-7 liver cells8, we screened over one million compounds from the Bristol-Myers Squibb proprietary collection in high throughput mode. We used a dual assay format that simultaneously evaluated replication of the related flavivirus bovine viral diarrhoea virus (BVDV) and host cell cytotoxicity as an efficient means of preliminarily eliminating compounds without specificity for HCV9. Active inhibitors were further triaged by evaluation in biochemical assays for NS3 protease, NS3 helicase and NS5B polymerase in addition to screening against a panel of unrelated viruses. The iminothiazolidinone BMS-858 (Fig. 1) emerged as a weak but, more importantly, specific inhibitor of HCV RNA replication (EC50 = 0.57µM, half-maximum cytotoxic concentration (CC50) = >50µM) for which resistance was mapped to a tyrosine to histidine substitution at residue 93 in the NS5A protein (Y93H or Y2065H in the HCV polyprotein)10. BMS-858 formed the basis of an extensive series of chemical refinements that focused on improving antiviral potency, broadening inhibitory activity to encompass the HCV 1a genotype, and optimizing for oral bioavailability and sustained pharmacokinetic properties. After defining symmetry as an important contributor to antiviral activity10, a discovery that preceded the disclosure of structural information (see below), we subsequently identified BMS-790052 (Fig. 1) as a development candidate for advancement into clinical trials11. (The studies leading to the identification of BMS-790052 and its preclinical profiling will be the subject of a series of separate publications.) This compound is the most potent HCV replication inhibitor reported so far, with mean EC50 values of 50 and 9pM against genotype 1a and 1b replicons, respectively (data summarized in Table 1). BMS-790052 displays a therapeutic index (CC50/EC50) of at least 100,000 in vitro and is inactive towards a panel of 10 RNA and DNA viruses, with EC50 values greater than 10µM, which confirms specificity for HCV (Supplementary Tables 1 and 2).
Upon further analysis, we determined that the inhibitory activity of BMS-790052 maps to the first 100 amino acids of HCV NS5A (see below). The antiviral activity of the compound towards additional genotypes was assessed by using replication-competent 1a12 or 1b replicons to construct hybrids in which the entire NS5A coding region or the first 100 amino acids of NS5A from genotypes 2a, 3a, 4a and 5a replaced the corresponding sequence of the parent replicon13. This approach has been validated using genotype-specific inhibitors of HCV NS5A10. As summarized in Table 1, BMS-790052 demonstrates potent inhibitory activity towards all genotypes tested, with EC50 values ranging from 9 to 146pM. In combination studies, BMS-790052 displayed additive-to-synergistic effects with interferon-α/ribavirin, an inhibitor of NS3 protease (ITMN-191), and both nucleoside and allosteric inhibitors of NS5B polymerase, which is indicative of the potential of this molecule as a candidate for combination therapy with other HCV therapeutic agents (data summarized in Table 2) (Supplementary Tables 3-7). More significantly, BMS-790052 is a potent inhibitor of the JFH-1 genotype 2a infectious virus that replicates in cell culture (EC50 = 28pM), an assay considered to be a more biologically relevant in vitro cell culture system14. In addition, BMS-790052 displayed similar potency in Huh-7, HeLa and HEK293T cells (Supplementary Table 8), demonstrating that the function(s) of NS5A inhibited by BMS-790052 is (are) highly conserved in different cellular environments.
To confirm that NS5A inhibitors bind to the viral protein, we prepared the biotin-tagged derivative 1, with the natural (S)-configuration at both proline stereocentres, and its diastereomer 2 (Fig. 1). Compound 1 inhibited subgenomic viral RNA replication in the Con-1 genotype 1b replicon with an EC50 of 33nM but was inactive towards a Y93H replicon (EC50>10µM) whereas the diastereomer 2, used as a control, was inactive in vitro (EC50>10µM). After exposure to active inhibitor 1, the replicon lysate was passed over streptavidin agarose beads, separated by SDS-polyacrylamide gel electrophoresis and probed with an antibody specific for HCV NS5A, with a parallel experiment using the inactive diastereomer 2 serving as a control. NS5A could only be pulled down efficiently with active inhibitor 1 but not by the inactive compound 2 (Fig. 2); NS3 and NS5B were not detected in pull-down experiments with 1, suggesting selective binding to NS5A. In a similar experiment conducted with replicons expressing BVDV RNA, compound 1 failed to bind to BVDV NS5A.
Table 3: Resistance profile of genotype 1a and 1b replicons exposed to BMS-790052
HCV NS5A is a 447 amino-acid, zinc-binding phosphoprotein that plays a critically important but enigmatic role in the virus life cycle16. The substitutions conferring resistance to BMS-790052 map to domain I of the protein, which incorporates an amphipathic amino (N)-terminal α-helix (residues 5-25) thought to anchor the protein to the membrane16. The solid-state structure of fragments of domain I (residues 36-198 and 33-191) of HCV NS5A reveal dimeric complexes with patterns of interfacial recognition that anticipate an oligomeric form of the protein17, 18, postulated to sequester RNA within the replication complex19. The unique palindromic topology of BMS-790052 complements the dimeric structure of the NS5A protein. The location of the resistant substitutions suggests that the compound binds across the dimer interface, proximal to the N terminus of domain I between the protein and the membrane, and on the face opposite that of the putative RNA binding domain. We speculate that BMS-790052 may interfere with the precision of dimer association, effecting subtle structural distortions that directly or allosterically interfere with protein function. Under these circumstances, the exquisite inhibitory potency exhibited by BMS-790052 in vitro may be related to the disruption of the function of a limited number of NS5A dimers that compromise the activity of an oligomeric complex. However, although this hypothesis allows for an amplification of inhibitory effect, an alternative explanation relies on the inhibition of two or more activities of NS5A that interact synergistically. Further studies with BMS-790052 will be required to define its exact mode of action more fully and, conversely, the compound is a useful tool with which to study aspects of HCV NS5A function in viral replication. These investigations may be aided by compounds with an in vitro profile similar to 1, which is restricted to genotype 1b inhibition10.
BMS-790052 exhibited no significant effects in an extensive battery of in vitro receptor binding and enzymatic assays designed to assess promiscuity. Despite a molecular mass of over 700daltons, the compound is orally bioavailable in four preclinical species, with plasma levels readily achieved that surpass the in vitro EC50, and it distributes effectively to the liver.
In a randomized, double-blind, placebo-controlled, single ascending-dose study, BMS-790052 was administered at six dose levels to healthy, non-HCV-infected subjects over a range of 1 to 200mg as an oral solution. The compound was safe and well tolerated up to 200mg with no clinically relevant adverse effects. After oral administration, BMS-790052 was readily absorbed, with dose-proportional exposures over the studied dose range, and all subjects had drug concentrations greater than the protein-binding-adjusted EC90 for genotypes 1a and 1b, as measured in the replicon assay, at and beyond 24h post-dose (Fig. 3). (The protein binding-adjusted EC90 figures were derived from an analysis of the effect of the addition of human serum on antiviral activity in replicons. In the presence of 40% human serum, the EC90 for BMS-790052 is 383pM (0.28ngml-1) for the genotype 1a replicon and 49pM (0.04ngml-1) for the genotyope 1b replicon.)
In a randomized, double-blind, placebo-controlled, single ascending-dose study, BMS-790052 was administered to subjects with genotype 1 chronic HCV at doses of 1, 10 and 100mg as an oral solution. All subjects were infected with HCV genotype 1a except for two subjects at 10mg and three subjects at 100mg who were infected with genotype 1b. BMS-790052 was safe and well tolerated in HCV-infected subjects after single oral doses up to 100mg. Specifically, there were no deaths, serious adverse events, discontinuations due to adverse events or clinically relevant adverse effects. Headache was the most frequent adverse event, reported by four subjects after administration of BMS-790052. In HCV-infected subjects, BMS-790052 had a mean plasma elimination half-life ranging from 10 to 14h, and plasma drug levels were similar to those in non-HCV-infected subjects. After single oral doses of 10-100mg BMS-790052, all subjects had 24-h plasma concentrations above the tenfold protein binding-adjusted EC90 for HCV genotypes 1a and 1b, suggesting the possibility for once daily administration. The plasma HCV RNA levels were measured for up to 6days after administration; the mean decline from the time of administration to 144h post-dose is shown in Fig. 4. A single milligram dose of BMS-790052 produced a mean 1.8log10 reduction (range 0.2-3.0log10) in HCV viral load measured 24h after drug administration. Both the 10 and 100mg doses produced a greater antiviral effect, with mean plasma viral RNA falling by 3.2 log10 (range 2.9-4.0log10) and 3.3log10 (range 2.7-3.6log10), respectively, at 24h post-dose. Moreover, the 100mg dose resulted in a mean maximal HCV RNA decline of 3.6 log10 (range 3.0-4.1log10) and a prolonged antiviral response was observed in two subjects infected with genotype 1b virus, with an HCV RNA measurement that reached the lower limit of quantification (less than 25IUml-1) in one subject and 35IUml-1 in the other measured at hour 144. Genotypic analysis of samples taken at baseline (T0), 24 (T24) and 144 (T144) hours post-dose revealed that, in general, a marked reduction in viral load was required to detect major HCV variants. Substitutions were observed at amino-acid positions identified using the in vitro replicon system (Supplementary Tables 12-14): M28T, Q30H/R and L31M for genotype 1a, and Y93H for genotype 1b, results that suggest the usefulness of the replicon system for assessing resistance in response to inhibitor pressure in vivo. Follow-up samples were available for only one of these subjects, which revealed that HCV RNA had returned to near baseline; however, genotype analysis was not performed on this sample. As would be anticipated based on the in vitro replicon potency of BMS-790052, a greater and more sustained decline in HCV RNA was observed for subjects infected with genotype 1b (mean 3.6log10 reduction (range 3.1-4.0log10) and mean 3.1log10 reduction (range 2.7-3.4log10) in HCV viral load measured 24h after a 10 and 100mg dose, respectively) than for subjects infected with genotype 1a (mean 1.8log10 reduction (range 0.2-3.0log10), mean 2.9log10 reduction (range 2.9-3.0log10) and mean 3.6log10 reduction (range 3.5-3.6log10) in HCV viral load measured 24h after a 1, 10 and 100mg dose, respectively). The mean rates of decline for subjects who received 10 and 100mg doses of BMS-790052 were similar up to 36h after dosing, after which the mean decline was greater and more sustained in the subjects who received 100mg. Subjects who received 1mg of BMS-790052 had a lower mean decline in HCV RNA than subjects treated with 10 and 100mg (Fig. 4). However, multiple-dose studies are needed to define the optimal dose range for maximal antiviral effect beyond the first phase of viral decline. The relationships between maximum decline from baseline in HCV RNA and drug pharmacokinetics exposures were explored using Pearson's correlation coefficients. All estimated Pearson's correlation coefficients were above 0.65, suggesting that the maximum declines in log10 HCV RNA and log pharmacokinetics exposures (BMS-790052 Cmax, AUC(0-T), AUC(INF), C12 and C24) were positively correlated; that is, that the maximum declines in log10 HCV RNA increase with the exposure to BMS-790052.
Individuals infected with HCV are at considerable risk of developing liver cirrhosis, end-stage liver disease and hepatocellular carcinoma20. The current standard of care for the treatment of HCV infection is a combination of weekly subcutaneous injections of pegylated interferon-α in conjunction with ribavirin, administered orally twice a day, for periods ranging from 24 to 72 weeks, depending on genotype2, 3. However, the side effects associated with this therapeutic regimen impose a significant physiological and psychological burden on the patient. Moreover, sustained virological response rates in those infected with genotype 1 are typically less than 50% (refs 2, 3). The direct-acting HCV antiviral drug candidates currently reported to be in late-stage clinical development are inhibitors of NS3 protease and NS5B polymerase, more traditional antiviral targets. Although these compounds are currently being developed as an add-on therapy to the standard of care, there is considerable anticipation for combinations of direct-acting agents, which will require at least two mechanistically distinct inhibitors to suppress the emergence of resistant virus4, 21. The preliminary in vitro and clinical profile of NS5A inhibitors described in this paper makes them a potentially valuable component of any interferon-free treatment regimen.
The results with BMS-790052 provide clinical validation for the first in a new class of HCV inhibitors that target a viral protein with no known enzymatic function and an as yet poorly understood role in viral replication16, 22. The strategy used to identify a lead HCV NS5A inhibitor and to optimize this molecule into a clinical candidate offers a contemporary demonstration of the effectiveness of an approach to drug discovery based on chemical genetics6. Indeed, this methodology is uniquely applicable to targets similar to HCV NS5A for which precise function is enigmatic and the development of biochemical assays could neither be anticipated nor are feasible. As a specific inhibitor of HCV, BMS-790052 exhibits a spectrum of genotype inhibition, in vitro potency, and efficacy and potency after single oral doses to chronically HCV-infected subjects that is collectively and individually unprecedented. Achieving high potency and selectivity against a non-mammalian target, the traditional goal of antiviral medicinal chemistry, has in the past translated into a wider therapeutic index in the clinic. Although preliminary, these data indicate that inhibitors of HCV NS5A offer considerable promise for the treatment of HCV infection. The in vitro data demonstrating additive to synergistic interactions with known HCV inhibitors suggest that combinations of BMS-790052, with either current standard of care or, ultimately, emerging inhibitors of HCV NS3 and NS5B as part of a cocktail of direct-acting antiviral agents, may lead to therapeutic regimens with better tolerability and improved clinical outcomes21.
discovery process in Nature jnl - pdf attached
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"Individuals infected with HCV are at considerable risk of developing liver cirrhosis, end-stage liver disease and hepatocellular carcinoma.....We designed a mechanistically unbiased approach based on chemical genetics to identify chemical starting points for interfering with HCV replication.....we screened over one million compounds from the Bristol-Myers Squibb proprietary collection in high throughput mode.....The results with BMS-790052 provide clinical validation for the first in a new class of HCV inhibitors that target a viral protein with no known enzymatic function and an as yet poorly understood role in viral replication16, 22. The strategy used to identify a lead HCV NS5A inhibitor and to optimize this molecule into a clinical candidate offers a contemporary demonstration of the effectiveness of an approach to drug discovery based on chemical genetics......In a randomized, double-blind, placebo-controlled, single ascending-dose study, BMS-790052 was administered to subjects with genotype 1 chronic HCV at doses of 1, 10 and 100mg as an oral solution. All subjects were infected with HCV genotype 1a except for two subjects at 10mg and three subjects at 100mg who were infected with genotype 1b. BMS-790052 was safe and well tolerated in HCV-infected subjects after single oral doses up to 100mg.....BMS-790052 had a mean plasma elimination half-life ranging from 10 to 14h, and plasma drug levels were similar to those in non-HCV-infected subjects. After single oral doses of 10-100mg BMS-790052, all subjects had 24-h plasma concentrations above the tenfold protein binding-adjusted EC90 for HCV genotypes 1a and 1b, suggesting the possibility for once daily administration.....A single milligram dose of BMS-790052 produced a mean 1.8log10 reduction (range 0.2-3.0log10) in HCV viral load measured 24h after drug administration. Both the 10 and 100mg doses produced a greater antiviral effect, with mean plasma viral RNA falling by 3.2 log10 (range 2.9-4.0log10) and 3.3log10 (range 2.7-3.6log10), respectively, at 24h post-dose. Moreover, the 100mg dose resulted in a mean maximal HCV RNA decline of 3.6 log10 (range 3.0-4.1log10) and a prolonged antiviral response was observed in two subjects infected with genotype 1b virus, with an HCV RNA measurement that reached the lower limit of quantification (less than 25IUml-1) in one subject"
BMS - Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect - pdf of full article attached
Letters to Nature
Nature , | doi:10.1038/nature08960; Received 29 October 2009; Accepted 26 February 2010; Published online 21 April 2010
Min Gao1, Richard E. Nettles2, Makonen Belema3, Lawrence B. Snyder3, Van N. Nguyen3, Robert A. Fridell1, Michael H. Serrano-Wu3, David R. Langley4, Jin-Hua Sun1, Donald R. O'Boyle II1, Julie A. Lemm1, Chunfu Wang1, Jay O. Knipe5, Caly Chien2, Richard J. Colonno1, Dennis M. Grasela2, Nicholas A. Meanwell3 & Lawrence G. Hamann3
1. Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA
2. Department of Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA
3. Department of Discovery Chemistry,
4. Department of Computer-Aided Drug Design,
5. Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA
Correspondence to: Nicholas A. Meanwell3 Correspondence and requests for materials should be addressed to N.A.M. (Email: Nicholas.Meanwell@bms.com).
Abstract
The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200million people1. Current therapy relies upon a combination of pegylated interferon-α and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus2, 3. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B4. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC50) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3log10 reduction in mean viral load measured 24h post-dose that was sustained for an additional 120h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.
We designed a mechanistically unbiased approach based on chemical genetics to identify chemical starting points for interfering with HCV replication. Our differentiating strategy centred on the identification of compounds functionally distinct from those acting on the traditional targets of antiviral research in this field, the NS3 protease and the NS5B RNA-dependent RNA polymerase5, 6, 7. Using a Con-1 genotype 1b replicon replicating in Huh-7 liver cells8, we screened over one million compounds from the Bristol-Myers Squibb proprietary collection in high throughput mode. We used a dual assay format that simultaneously evaluated replication of the related flavivirus bovine viral diarrhoea virus (BVDV) and host cell cytotoxicity as an efficient means of preliminarily eliminating compounds without specificity for HCV9. Active inhibitors were further triaged by evaluation in biochemical assays for NS3 protease, NS3 helicase and NS5B polymerase in addition to screening against a panel of unrelated viruses. The iminothiazolidinone BMS-858 (Fig. 1) emerged as a weak but, more importantly, specific inhibitor of HCV RNA replication (EC50 = 0.57µM, half-maximum cytotoxic concentration (CC50) = >50µM) for which resistance was mapped to a tyrosine to histidine substitution at residue 93 in the NS5A protein (Y93H or Y2065H in the HCV polyprotein)10. BMS-858 formed the basis of an extensive series of chemical refinements that focused on improving antiviral potency, broadening inhibitory activity to encompass the HCV 1a genotype, and optimizing for oral bioavailability and sustained pharmacokinetic properties. After defining symmetry as an important contributor to antiviral activity10, a discovery that preceded the disclosure of structural information (see below), we subsequently identified BMS-790052 (Fig. 1) as a development candidate for advancement into clinical trials11. (The studies leading to the identification of BMS-790052 and its preclinical profiling will be the subject of a series of separate publications.) This compound is the most potent HCV replication inhibitor reported so far, with mean EC50 values of 50 and 9pM against genotype 1a and 1b replicons, respectively (data summarized in Table 1). BMS-790052 displays a therapeutic index (CC50/EC50) of at least 100,000 in vitro and is inactive towards a panel of 10 RNA and DNA viruses, with EC50 values greater than 10µM, which confirms specificity for HCV (Supplementary Tables 1 and 2).
Upon further analysis, we determined that the inhibitory activity of BMS-790052 maps to the first 100 amino acids of HCV NS5A (see below). The antiviral activity of the compound towards additional genotypes was assessed by using replication-competent 1a12 or 1b replicons to construct hybrids in which the entire NS5A coding region or the first 100 amino acids of NS5A from genotypes 2a, 3a, 4a and 5a replaced the corresponding sequence of the parent replicon13. This approach has been validated using genotype-specific inhibitors of HCV NS5A10. As summarized in Table 1, BMS-790052 demonstrates potent inhibitory activity towards all genotypes tested, with EC50 values ranging from 9 to 146pM. In combination studies, BMS-790052 displayed additive-to-synergistic effects with interferon-α/ribavirin, an inhibitor of NS3 protease (ITMN-191), and both nucleoside and allosteric inhibitors of NS5B polymerase, which is indicative of the potential of this molecule as a candidate for combination therapy with other HCV therapeutic agents (data summarized in Table 2) (Supplementary Tables 3-7). More significantly, BMS-790052 is a potent inhibitor of the JFH-1 genotype 2a infectious virus that replicates in cell culture (EC50 = 28pM), an assay considered to be a more biologically relevant in vitro cell culture system14. In addition, BMS-790052 displayed similar potency in Huh-7, HeLa and HEK293T cells (Supplementary Table 8), demonstrating that the function(s) of NS5A inhibited by BMS-790052 is (are) highly conserved in different cellular environments.
To confirm that NS5A inhibitors bind to the viral protein, we prepared the biotin-tagged derivative 1, with the natural (S)-configuration at both proline stereocentres, and its diastereomer 2 (Fig. 1). Compound 1 inhibited subgenomic viral RNA replication in the Con-1 genotype 1b replicon with an EC50 of 33nM but was inactive towards a Y93H replicon (EC50>10µM) whereas the diastereomer 2, used as a control, was inactive in vitro (EC50>10µM). After exposure to active inhibitor 1, the replicon lysate was passed over streptavidin agarose beads, separated by SDS-polyacrylamide gel electrophoresis and probed with an antibody specific for HCV NS5A, with a parallel experiment using the inactive diastereomer 2 serving as a control. NS5A could only be pulled down efficiently with active inhibitor 1 but not by the inactive compound 2 (Fig. 2); NS3 and NS5B were not detected in pull-down experiments with 1, suggesting selective binding to NS5A. In a similar experiment conducted with replicons expressing BVDV RNA, compound 1 failed to bind to BVDV NS5A.
Table 3: Resistance profile of genotype 1a and 1b replicons exposed to BMS-790052
HCV NS5A is a 447 amino-acid, zinc-binding phosphoprotein that plays a critically important but enigmatic role in the virus life cycle16. The substitutions conferring resistance to BMS-790052 map to domain I of the protein, which incorporates an amphipathic amino (N)-terminal α-helix (residues 5-25) thought to anchor the protein to the membrane16. The solid-state structure of fragments of domain I (residues 36-198 and 33-191) of HCV NS5A reveal dimeric complexes with patterns of interfacial recognition that anticipate an oligomeric form of the protein17, 18, postulated to sequester RNA within the replication complex19. The unique palindromic topology of BMS-790052 complements the dimeric structure of the NS5A protein. The location of the resistant substitutions suggests that the compound binds across the dimer interface, proximal to the N terminus of domain I between the protein and the membrane, and on the face opposite that of the putative RNA binding domain. We speculate that BMS-790052 may interfere with the precision of dimer association, effecting subtle structural distortions that directly or allosterically interfere with protein function. Under these circumstances, the exquisite inhibitory potency exhibited by BMS-790052 in vitro may be related to the disruption of the function of a limited number of NS5A dimers that compromise the activity of an oligomeric complex. However, although this hypothesis allows for an amplification of inhibitory effect, an alternative explanation relies on the inhibition of two or more activities of NS5A that interact synergistically. Further studies with BMS-790052 will be required to define its exact mode of action more fully and, conversely, the compound is a useful tool with which to study aspects of HCV NS5A function in viral replication. These investigations may be aided by compounds with an in vitro profile similar to 1, which is restricted to genotype 1b inhibition10.
BMS-790052 exhibited no significant effects in an extensive battery of in vitro receptor binding and enzymatic assays designed to assess promiscuity. Despite a molecular mass of over 700daltons, the compound is orally bioavailable in four preclinical species, with plasma levels readily achieved that surpass the in vitro EC50, and it distributes effectively to the liver.
In a randomized, double-blind, placebo-controlled, single ascending-dose study, BMS-790052 was administered at six dose levels to healthy, non-HCV-infected subjects over a range of 1 to 200mg as an oral solution. The compound was safe and well tolerated up to 200mg with no clinically relevant adverse effects. After oral administration, BMS-790052 was readily absorbed, with dose-proportional exposures over the studied dose range, and all subjects had drug concentrations greater than the protein-binding-adjusted EC90 for genotypes 1a and 1b, as measured in the replicon assay, at and beyond 24h post-dose (Fig. 3). (The protein binding-adjusted EC90 figures were derived from an analysis of the effect of the addition of human serum on antiviral activity in replicons. In the presence of 40% human serum, the EC90 for BMS-790052 is 383pM (0.28ngml-1) for the genotype 1a replicon and 49pM (0.04ngml-1) for the genotyope 1b replicon.)
In a randomized, double-blind, placebo-controlled, single ascending-dose study, BMS-790052 was administered to subjects with genotype 1 chronic HCV at doses of 1, 10 and 100mg as an oral solution. All subjects were infected with HCV genotype 1a except for two subjects at 10mg and three subjects at 100mg who were infected with genotype 1b. BMS-790052 was safe and well tolerated in HCV-infected subjects after single oral doses up to 100mg. Specifically, there were no deaths, serious adverse events, discontinuations due to adverse events or clinically relevant adverse effects. Headache was the most frequent adverse event, reported by four subjects after administration of BMS-790052. In HCV-infected subjects, BMS-790052 had a mean plasma elimination half-life ranging from 10 to 14h, and plasma drug levels were similar to those in non-HCV-infected subjects. After single oral doses of 10-100mg BMS-790052, all subjects had 24-h plasma concentrations above the tenfold protein binding-adjusted EC90 for HCV genotypes 1a and 1b, suggesting the possibility for once daily administration. The plasma HCV RNA levels were measured for up to 6days after administration; the mean decline from the time of administration to 144h post-dose is shown in Fig. 4. A single milligram dose of BMS-790052 produced a mean 1.8log10 reduction (range 0.2-3.0log10) in HCV viral load measured 24h after drug administration. Both the 10 and 100mg doses produced a greater antiviral effect, with mean plasma viral RNA falling by 3.2 log10 (range 2.9-4.0log10) and 3.3log10 (range 2.7-3.6log10), respectively, at 24h post-dose. Moreover, the 100mg dose resulted in a mean maximal HCV RNA decline of 3.6 log10 (range 3.0-4.1log10) and a prolonged antiviral response was observed in two subjects infected with genotype 1b virus, with an HCV RNA measurement that reached the lower limit of quantification (less than 25IUml-1) in one subject and 35IUml-1 in the other measured at hour 144. Genotypic analysis of samples taken at baseline (T0), 24 (T24) and 144 (T144) hours post-dose revealed that, in general, a marked reduction in viral load was required to detect major HCV variants. Substitutions were observed at amino-acid positions identified using the in vitro replicon system (Supplementary Tables 12-14): M28T, Q30H/R and L31M for genotype 1a, and Y93H for genotype 1b, results that suggest the usefulness of the replicon system for assessing resistance in response to inhibitor pressure in vivo. Follow-up samples were available for only one of these subjects, which revealed that HCV RNA had returned to near baseline; however, genotype analysis was not performed on this sample. As would be anticipated based on the in vitro replicon potency of BMS-790052, a greater and more sustained decline in HCV RNA was observed for subjects infected with genotype 1b (mean 3.6log10 reduction (range 3.1-4.0log10) and mean 3.1log10 reduction (range 2.7-3.4log10) in HCV viral load measured 24h after a 10 and 100mg dose, respectively) than for subjects infected with genotype 1a (mean 1.8log10 reduction (range 0.2-3.0log10), mean 2.9log10 reduction (range 2.9-3.0log10) and mean 3.6log10 reduction (range 3.5-3.6log10) in HCV viral load measured 24h after a 1, 10 and 100mg dose, respectively). The mean rates of decline for subjects who received 10 and 100mg doses of BMS-790052 were similar up to 36h after dosing, after which the mean decline was greater and more sustained in the subjects who received 100mg. Subjects who received 1mg of BMS-790052 had a lower mean decline in HCV RNA than subjects treated with 10 and 100mg (Fig. 4). However, multiple-dose studies are needed to define the optimal dose range for maximal antiviral effect beyond the first phase of viral decline. The relationships between maximum decline from baseline in HCV RNA and drug pharmacokinetics exposures were explored using Pearson's correlation coefficients. All estimated Pearson's correlation coefficients were above 0.65, suggesting that the maximum declines in log10 HCV RNA and log pharmacokinetics exposures (BMS-790052 Cmax, AUC(0-T), AUC(INF), C12 and C24) were positively correlated; that is, that the maximum declines in log10 HCV RNA increase with the exposure to BMS-790052.
Individuals infected with HCV are at considerable risk of developing liver cirrhosis, end-stage liver disease and hepatocellular carcinoma20. The current standard of care for the treatment of HCV infection is a combination of weekly subcutaneous injections of pegylated interferon-α in conjunction with ribavirin, administered orally twice a day, for periods ranging from 24 to 72 weeks, depending on genotype2, 3. However, the side effects associated with this therapeutic regimen impose a significant physiological and psychological burden on the patient. Moreover, sustained virological response rates in those infected with genotype 1 are typically less than 50% (refs 2, 3). The direct-acting HCV antiviral drug candidates currently reported to be in late-stage clinical development are inhibitors of NS3 protease and NS5B polymerase, more traditional antiviral targets. Although these compounds are currently being developed as an add-on therapy to the standard of care, there is considerable anticipation for combinations of direct-acting agents, which will require at least two mechanistically distinct inhibitors to suppress the emergence of resistant virus4, 21. The preliminary in vitro and clinical profile of NS5A inhibitors described in this paper makes them a potentially valuable component of any interferon-free treatment regimen.
The results with BMS-790052 provide clinical validation for the first in a new class of HCV inhibitors that target a viral protein with no known enzymatic function and an as yet poorly understood role in viral replication16, 22. The strategy used to identify a lead HCV NS5A inhibitor and to optimize this molecule into a clinical candidate offers a contemporary demonstration of the effectiveness of an approach to drug discovery based on chemical genetics6. Indeed, this methodology is uniquely applicable to targets similar to HCV NS5A for which precise function is enigmatic and the development of biochemical assays could neither be anticipated nor are feasible. As a specific inhibitor of HCV, BMS-790052 exhibits a spectrum of genotype inhibition, in vitro potency, and efficacy and potency after single oral doses to chronically HCV-infected subjects that is collectively and individually unprecedented. Achieving high potency and selectivity against a non-mammalian target, the traditional goal of antiviral medicinal chemistry, has in the past translated into a wider therapeutic index in the clinic. Although preliminary, these data indicate that inhibitors of HCV NS5A offer considerable promise for the treatment of HCV infection. The in vitro data demonstrating additive to synergistic interactions with known HCV inhibitors suggest that combinations of BMS-790052, with either current standard of care or, ultimately, emerging inhibitors of HCV NS3 and NS5B as part of a cocktail of direct-acting antiviral agents, may lead to therapeutic regimens with better tolerability and improved clinical outcomes21.
BMS' NS5A Experimental compound potent against hepatitis C - "at least 3 drugs required to prevent resistance"
BMS' NS5A Experimental compound potent against hepatitis C - "at least 3 drugs required to prevent resistance"
(Reuters) - An experimental Bristol-Myers Squibb compound called BMS-790052 is proving to be the most potent yet at treating hepatitis C, an infection poorly treated with existing drugs, company researchers said on Wednesday.
An early, phase I safety study of the compound found it was highly effective at blocking the protein NS5A, a new target that might provide one more weapon against a virus that can quickly develop re sistance.
"A lot like HIV, it is anticipated that a combination of at least three drugs will be required to prevent the emergence of resistance," said Bristol-Myers Squibb's Nicholas Meanwell, who worked on the study published in the journal Nature.
"We are targeting a different protein. This will provide a unique resistance profile," Meanwell said in a telephone interview.
Hepatitis damages the liver, causing chronic liver problems, liver cancer, cirrhosis and death.
It is the leading cause of liver disease worldwide, affecting an estimated 3.2 million people in the United States alone and 170 million worldwide.
Typical treatment involves 52 weeks of interferon plus the antiviral drug ribavirin. The combination works in only about half of all patients, and some develop such taxing side effects that they have to stop.
The Bristol-Myers compound works differently than a new class of drugs called protease inhibitors being developed by Merck's Schering-Plough division and Vertex Pharmaceuticals Inc .
SUPPRESSING VIRAL LOAD
Meanwell said BMS-790052 helps inhibit the hepatitis C virus from replicating. Infected patients who got a single 100 milligram dose of the compound saw their viral load -- a measurement of the virus in their blood -- drop more than 99.9 percent.
Early results of a phase II study presented last week at the European Association for the Study of the Liver in Vienna were also promising. Seven out of eight patients who got the highest dose of the drug had undetectable levels of the virus. The eighth patient had stopped taking the drug for a while. "It's got potency and effectiveness in a single dose that is unmatched by anything else," Meanwell said.
He said the findings are very early, but the hope is that the compound could be used in a cocktail of drugs to keep the virus from developing resistance long enough for patients to clear the disease.
"The data we've seen so far is extremely encouraging," he said. New treatments for hepatitis C infection have drawn much attention on Wall Street.
Vertex Pharmaceuticals' experimental hepatitis C treatment telaprevir, which is expected to have phase III results in the third quarter of this year, is projected to have peak U.S. sales of $3.9 billion in 2013, if it wins U.S. approval as expected in the first half of 2011.
(Reuters) - An experimental Bristol-Myers Squibb compound called BMS-790052 is proving to be the most potent yet at treating hepatitis C, an infection poorly treated with existing drugs, company researchers said on Wednesday.
An early, phase I safety study of the compound found it was highly effective at blocking the protein NS5A, a new target that might provide one more weapon against a virus that can quickly develop re sistance.
"A lot like HIV, it is anticipated that a combination of at least three drugs will be required to prevent the emergence of resistance," said Bristol-Myers Squibb's Nicholas Meanwell, who worked on the study published in the journal Nature.
"We are targeting a different protein. This will provide a unique resistance profile," Meanwell said in a telephone interview.
Hepatitis damages the liver, causing chronic liver problems, liver cancer, cirrhosis and death.
It is the leading cause of liver disease worldwide, affecting an estimated 3.2 million people in the United States alone and 170 million worldwide.
Typical treatment involves 52 weeks of interferon plus the antiviral drug ribavirin. The combination works in only about half of all patients, and some develop such taxing side effects that they have to stop.
The Bristol-Myers compound works differently than a new class of drugs called protease inhibitors being developed by Merck's Schering-Plough division and Vertex Pharmaceuticals Inc .
SUPPRESSING VIRAL LOAD
Meanwell said BMS-790052 helps inhibit the hepatitis C virus from replicating. Infected patients who got a single 100 milligram dose of the compound saw their viral load -- a measurement of the virus in their blood -- drop more than 99.9 percent.
Early results of a phase II study presented last week at the European Association for the Study of the Liver in Vienna were also promising. Seven out of eight patients who got the highest dose of the drug had undetectable levels of the virus. The eighth patient had stopped taking the drug for a while. "It's got potency and effectiveness in a single dose that is unmatched by anything else," Meanwell said.
He said the findings are very early, but the hope is that the compound could be used in a cocktail of drugs to keep the virus from developing resistance long enough for patients to clear the disease.
"The data we've seen so far is extremely encouraging," he said. New treatments for hepatitis C infection have drawn much attention on Wall Street.
Vertex Pharmaceuticals' experimental hepatitis C treatment telaprevir, which is expected to have phase III results in the third quarter of this year, is projected to have peak U.S. sales of $3.9 billion in 2013, if it wins U.S. approval as expected in the first half of 2011.
IMPACT OF LOW-DOSE RITONAVIR BOOSTING ON THE PHARMACOKINETICS OF DANOPREVIR
IMPACT OF LOW-DOSE RITONAVIR BOOSTING ON THE PHARMACOKINETICS OF DANOPREVIR (RG7227; ITMN-191), A HIGHLY POTENT AND SELECTIVE INHIBITOR OF THE HCV NS3/4A PROTEASE - see attached full poster report
Reported by Jules Levin, EASL Apr 14-18 2010 Vienna Austria
Joshua Haznedar,1 Jennifer Fretland,2 Gilbert Leong,2 Steven Blotner,3 Todd Hill,4 Patrick Smith,1 and Jonathan Tran1. 1Roche, Clinical Pharmacology, South San Francisco, CA, USA; 2Roche Palo Alto LLC, Department of Drug Metabolism and Pharmacokinetics, Palo Alto, CA, USA; 3Hoffmann-La Roche Inc., Pharma Development Innovation Biomathematics, Nutley, NJ, USA; 4Hoffmann-La Roche Inc., Clinical Research and Exploratory Development Operations, Nutley, NJ, USA
Author Discussion
- CYP3A-mediated inhibition by low-dose RTV has been successfully utilised in the HIV treatment paradigm to simplify HIV protease inhibitor regimens.
- The main objective of this pilot PK study in healthy volunteers was to determine if low-dose RTV could ‘boost’ the PK of danoprevir. Low-dose RTV significantly enhances danoprevir C12h (representative of Cmin for a q12h dosing regimen), which appears to be the key parameter driving efficacy and prevention of resistance. Less of an effect was observed on AUC and Cmax, which are key parameters often attributed to safety.
- The effect of multiple doses of RTV 100 mg q12h x 10 days on danoprevir C12h is about 2-fold less than the effect of a single dose of RTV 100 mg. This is likely due to the mixed inhibition and induction effects of RTV on CYP enzymes.[4]
- Based on the PK results, a phase Ib study of RTV-boosted danoprevir in combination with standard of care in HCV-infected patients was conducted.[5] Low doses and dosing frequency of danoprevir (100 mg and 200 mg; q12h and q24h) were chosen for co-administration with RTV 100 mg to achieve lower danoprevir Cmax and AUC than unboosted high doses of danoprevir while maintaining optimal Cmin for efficacy.
Author Conclusions
- PK boosting of danoprevir by low-dose RTV appears feasible. Danoprevir dose and dosing frequency may be reduced when co-administered with low-dose RTV.
- The co-administration of danoprevir single dose and low-dose RTV was safe and well tolerated in healthy volunteers.
Picture 41.png
Picture 42.png
Reported by Jules Levin, EASL Apr 14-18 2010 Vienna Austria
Joshua Haznedar,1 Jennifer Fretland,2 Gilbert Leong,2 Steven Blotner,3 Todd Hill,4 Patrick Smith,1 and Jonathan Tran1. 1Roche, Clinical Pharmacology, South San Francisco, CA, USA; 2Roche Palo Alto LLC, Department of Drug Metabolism and Pharmacokinetics, Palo Alto, CA, USA; 3Hoffmann-La Roche Inc., Pharma Development Innovation Biomathematics, Nutley, NJ, USA; 4Hoffmann-La Roche Inc., Clinical Research and Exploratory Development Operations, Nutley, NJ, USA
Author Discussion
- CYP3A-mediated inhibition by low-dose RTV has been successfully utilised in the HIV treatment paradigm to simplify HIV protease inhibitor regimens.
- The main objective of this pilot PK study in healthy volunteers was to determine if low-dose RTV could ‘boost’ the PK of danoprevir. Low-dose RTV significantly enhances danoprevir C12h (representative of Cmin for a q12h dosing regimen), which appears to be the key parameter driving efficacy and prevention of resistance. Less of an effect was observed on AUC and Cmax, which are key parameters often attributed to safety.
- The effect of multiple doses of RTV 100 mg q12h x 10 days on danoprevir C12h is about 2-fold less than the effect of a single dose of RTV 100 mg. This is likely due to the mixed inhibition and induction effects of RTV on CYP enzymes.[4]
- Based on the PK results, a phase Ib study of RTV-boosted danoprevir in combination with standard of care in HCV-infected patients was conducted.[5] Low doses and dosing frequency of danoprevir (100 mg and 200 mg; q12h and q24h) were chosen for co-administration with RTV 100 mg to achieve lower danoprevir Cmax and AUC than unboosted high doses of danoprevir while maintaining optimal Cmin for efficacy.
Author Conclusions
- PK boosting of danoprevir by low-dose RTV appears feasible. Danoprevir dose and dosing frequency may be reduced when co-administered with low-dose RTV.
- The co-administration of danoprevir single dose and low-dose RTV was safe and well tolerated in healthy volunteers.
Picture 41.png
Picture 42.png
Metabolic Syndrome (MS) [glucose/diabetes] Is a Negative Predictor of Treatment Outcome in Patients With Chronic Hepatitis C
Metabolic Syndrome (MS) [glucose/diabetes] Is a Negative Predictor of Treatment Outcome in Patients With Chronic Hepatitis C: Results From the IDEAL Study - see attached full poster report for this interesting analysis
Reported by Jules Levin, EASL Apr 14-18 2010 Vienna Austria
M. S. Sulkowski et al.
“Patients with elevated glucose and HDL-C (18%; 557/3070) had a very low probability of SVR (OR = 1.97)”
Author Summary
• Baseline MS, particularly elevated glucose level (glucose intolerance), is a negative predictor of SVR in patients with chronic hepatitis C genotype 1 infection receiving PEG-IFN alfa plus RBV therapy
• Low HDL-C was associated with improved SVR rate
Author Conclusions
• While MS is a predictor of response to PEG-IFN/RBV therapy in patients with chronic hepatitis C genotype 1 infection, the current definition of MS may not present the ideal framework to investigate HCV treatment response because 3 components are strong independent “negative” predictors of SVR (elevated fasting glucose, hypertension, elevated triglycerides), whereas 1 component of MS (low HDL) is a strong “positive” predictor of SVR
Reported by Jules Levin, EASL Apr 14-18 2010 Vienna Austria
M. S. Sulkowski et al.
“Patients with elevated glucose and HDL-C (18%; 557/3070) had a very low probability of SVR (OR = 1.97)”
Author Summary
• Baseline MS, particularly elevated glucose level (glucose intolerance), is a negative predictor of SVR in patients with chronic hepatitis C genotype 1 infection receiving PEG-IFN alfa plus RBV therapy
• Low HDL-C was associated with improved SVR rate
Author Conclusions
• While MS is a predictor of response to PEG-IFN/RBV therapy in patients with chronic hepatitis C genotype 1 infection, the current definition of MS may not present the ideal framework to investigate HCV treatment response because 3 components are strong independent “negative” predictors of SVR (elevated fasting glucose, hypertension, elevated triglycerides), whereas 1 component of MS (low HDL) is a strong “positive” predictor of SVR
Improved Inflammatory Activity With Low-Dose PegIntron
Improved Inflammatory Activity With Low-Dose PegIntron (PEG) Maintenance Therapy in Prior Nonresponders With METAVIR Fibrosis Scores (MFS) of F2/F3: Final Results From the EPIC3 Program - see attached fulk poster report
Reported by Jules Levin,
EASL Apr 14-18 2010 Vienna Austria
T. Poynard,1 J. Bruix,2 E. Schiff,3 M. Diago,4 T. Berg,5 R. Moreno-Otero,6 L. G. Lyra,7 F. Carrilho,8 L. H. Griffel,9 N. Boparai,10 M. Burroughs,10 C. A. Brass,10 and J. K. Albrecht10
1Service d’Hepato-Gastroenterologie, APHP-UPMC Liver Center, Paris, France; 2Centro de Investigación Biomédica en Red de Enfermedades Hepaticas y Digestivas, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain; 3University of Miami School of Medicine, Miami, Florida, U.S.A.; 4Hospital General Universitario de Valencia, Valencia, Spain; 5Klinik und Poliklinik für Gastroenterologie & Rheumatologie, Sektion Hepatologie, Universitätsklinikum Leipzig, Leipzig, Germany; 6Hospital Universitario de la Princesa and Centro de Investigación Biomédica en Red de Enfermedades Hepaticas y Digestivas (Instituto de Salud Carlos III), Madrid, Spain; 7Hospital Sao Rafael, Salvador, Brazil; 8Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil; 9Former employee of Schering-Plough Corporation, now Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A.; 10Schering-Plough Corporation, now Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A.
AUTHOR SUMMARY
• In the primary analysis, low-dose PEG-IFN alfa-2b did not significantly improve fibrosis response among patients with METAVIR F2 and F3 compared with the Observed group
• Significantly more patients receiving PEG-IFN alfa-2b had improvement in METAVIR activity score compared with patients in the Observed group
• In the subgroup of patients treated for >2.5 years, both METAVIR fibrosis and activity scores trended toward improvement
— 21% of PEG-IFN alfa-2b recipients and 14% of Observed patients had ≥1-unit improvement in METAVIR fibrosis score
— 26% of PEG-IFN alfa-2b recipients and 10% of Observed patients had ≥1-unit improvement in METAVIR activity score
• The possibility that carry-over effects from full-dose PEG-IFN alfa-2b plus weight-based ribavirin may have obscured maintenance therapy treatment effects cannot be excluded
Author Conclusion
• These data suggest that PEG-IFN alfa-2b decreases hepatic inflammation, but impact on METAVIR fibrosis score could not be demonstrated in the 3 years of maintenance therapy that followed ~18 weeks of full-dose PEG-IFN alfa-2b therapy plus weight-based ribavirin. For those patients with HCV with significant hepatic fibrosis who are unable to clear virus, therapies to slow or reverse
the march toward cirrhosis are still needed. It remains undefined whether longer periods of low-dose PEG-IFN alfa-2b therapy would extend the trend toward improvement in fibrosis observed in patients treated for >2.5 years
Reported by Jules Levin,
EASL Apr 14-18 2010 Vienna Austria
T. Poynard,1 J. Bruix,2 E. Schiff,3 M. Diago,4 T. Berg,5 R. Moreno-Otero,6 L. G. Lyra,7 F. Carrilho,8 L. H. Griffel,9 N. Boparai,10 M. Burroughs,10 C. A. Brass,10 and J. K. Albrecht10
1Service d’Hepato-Gastroenterologie, APHP-UPMC Liver Center, Paris, France; 2Centro de Investigación Biomédica en Red de Enfermedades Hepaticas y Digestivas, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain; 3University of Miami School of Medicine, Miami, Florida, U.S.A.; 4Hospital General Universitario de Valencia, Valencia, Spain; 5Klinik und Poliklinik für Gastroenterologie & Rheumatologie, Sektion Hepatologie, Universitätsklinikum Leipzig, Leipzig, Germany; 6Hospital Universitario de la Princesa and Centro de Investigación Biomédica en Red de Enfermedades Hepaticas y Digestivas (Instituto de Salud Carlos III), Madrid, Spain; 7Hospital Sao Rafael, Salvador, Brazil; 8Gastroenterology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil; 9Former employee of Schering-Plough Corporation, now Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A.; 10Schering-Plough Corporation, now Merck & Co., Inc., Whitehouse Station, New Jersey, U.S.A.
AUTHOR SUMMARY
• In the primary analysis, low-dose PEG-IFN alfa-2b did not significantly improve fibrosis response among patients with METAVIR F2 and F3 compared with the Observed group
• Significantly more patients receiving PEG-IFN alfa-2b had improvement in METAVIR activity score compared with patients in the Observed group
• In the subgroup of patients treated for >2.5 years, both METAVIR fibrosis and activity scores trended toward improvement
— 21% of PEG-IFN alfa-2b recipients and 14% of Observed patients had ≥1-unit improvement in METAVIR fibrosis score
— 26% of PEG-IFN alfa-2b recipients and 10% of Observed patients had ≥1-unit improvement in METAVIR activity score
• The possibility that carry-over effects from full-dose PEG-IFN alfa-2b plus weight-based ribavirin may have obscured maintenance therapy treatment effects cannot be excluded
Author Conclusion
• These data suggest that PEG-IFN alfa-2b decreases hepatic inflammation, but impact on METAVIR fibrosis score could not be demonstrated in the 3 years of maintenance therapy that followed ~18 weeks of full-dose PEG-IFN alfa-2b therapy plus weight-based ribavirin. For those patients with HCV with significant hepatic fibrosis who are unable to clear virus, therapies to slow or reverse
the march toward cirrhosis are still needed. It remains undefined whether longer periods of low-dose PEG-IFN alfa-2b therapy would extend the trend toward improvement in fibrosis observed in patients treated for >2.5 years
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