Sunday, October 3, 2010

(BMS-790052) With Peginterferon/Ribavirin Trials

Biological Activity of BMS-790052:

BMS-790052 is a first-in-class, highly-selective oral HCV NS5A inhibitor. NS5A is an essential component for hepatitis C virus (HCV) replication complex. BMS-790052 has broad genotype coverage and exhibits picomolar in vitro potency against genotypes 1a (EC50 50pm) and 1b (EC50 9pm).
BMS-790052 produces a robust decline in HCV RNA (-3.6 logs after 48 hours from a single 100 mg) dosefollowing a single dose in patients chronically infected with HCV genotype 1.

BMS-790052
NS5A Inhibitor
Bristol-Myers Squibb
Phase II
Comments: The results from a study of 48 HCV genotype 1 treatment-naïve patients who received doses of BMS-790052 (3, 10, & 60 mg once a day) combined with pegylated interferon/ribavirin (or just pegylated interferon plus ribavirin – control arm) were released.
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In the 10 mg & 60 mg groups the rapid virological response (undetectable at week 4) was 83 to 92% and the complete early virological response (undetectable at week 12) was ~83%. There were no safety concerns noted. (July 14, 2010)
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Trials
Recruiting
Study of the Anti-HCV Drug (BMS-790052) Combined With Peginterferon and Ribavirin in Patients Who Failed Prior Treatment
Last Updated: September 13, 2010
Condition(s): Hepatitis C Virus

Recruiting
Study of BMS-790052 Add-On to Standard of Care in Treatment Naive Subjects
Last Updated: September 13, 2010
Condition(s): Hepatitis C Virus


Active, not recruiting
Safety and Efficacy of BMS-790052 Plus Standard of Care in Japanese Patients (Pegylated-interferon Alpha-2b and Ribavirin)
Last Updated: September 13, 2010
Condition(s): Hepatitis C Infection

Recruiting
Safety and Efficacy of BMS-790052 Plus Standard of Care in Japanese Patients (Pegylated-interferon Alpha-2a and Ribavirin)
Last Updated: September 13, 2010
Condition(s): Hepatitis C Infection


Active, not recruiting
A Multiple Ascending Dose Study of BMS-790052 in Hepatitis C Virus (HCV) Infected Subjects
Last Updated: August 30, 2010
Condition(s): Chronic Hepatitis C


Recruiting
An Anti-viral Combination Study With Japanese Hepatitis C Infection (HCV) Subject
Last Updated: August 30, 2010
Condition(s): Hepatitis C Infection
Recruiting
Study to Determine the Effectiveness of Antiviral Combination Therapy to Treat Hepatitis C Virus (HCV) Infected Patients Who Have Previously Failed Standard of Care
Last Updated: September 13, 2010
Condition(s): Chronic Hepatitis C


Clinical Trials Authorship and Review
Clinical Trials content is provided directly by the U.S. National Institutes of Health via ClinicalTrials.gov and is not reviewed separately by ClinicalTrialsFeeds.org. Every page of specific clinical trials information contains a unique identifier which can be used to find further details directly from the National Institutes of Health.
http://clinicaltrialsfeeds.org/clinical-trials/results/term=Drug%3A+BMS-790052
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New Data on Multiple Bristol-Myers Squibb Compounds to be Presented at AASLD 2010
PRINCETON, N.J.--(BUSINESS WIRE)--
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New data on multiple Bristol-Myers Squibb Company (NYSE:BMY) compounds will be presented at the 61st annual meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston from October 29 to November 2.
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Data will be presented on BARACLUDE® (entecavir) in patients with chronic hepatitis B, and on compounds in clinical development for the treatment of hepatitis C, using multiple scientific approaches to target the hepatitis C virus (HCV). Key hepatitis C presentations include data on novel combinations of investigational agents, including BMS-790052, a NS5A inhibitor, and BMS-650032, an NS3 inhibitor. Additionally, 12-week Phase 2a data on PEG-Interferon lambda, a novel type 3 interferon with enhanced specificity for hepatocyte binding, will be presented.
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The Company will also present outcomes research data in both hepatitis C and hepatocellular carcinoma.
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“Bristol-Myers Squibb is focused on developing innovative medicines to treat liver disease,” said Elliott Sigal, M.D., Ph.D., executive vice president, chief scientific officer and president, Research and Development, Bristol-Myers Squibb. “Building on our established expertise in viral hepatitis and oncology, the data at this year’s Liver Meeting demonstrates the breadth and strength of our hepatitis C portfolio.
We are pursuing multiple targets with the potential to be used in combination regimens to advance the treatment of this serious disease.”
BARACLUDE, BMS-790052, and BMS-650032 were discovered by Bristol-Myers Squibb Research and Development.
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PEG-Interferon lambda was discovered by ZymoGenetics, Inc. Bristol-Myers Squibb and ZymoGenetics announced a global collaboration for PEG-Interferon lambda and its related development program in 2009. In September 2010, Bristol-Myers Squibb announced its intent to acquire ZymoGenetics.
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Full prescribing information for BARACLUDE is available at http://www.bms.com/.
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Resistance Analysis of the Hepatitis C Virus NS5A Inhibitor BMS-790052 in an In Vitro Replicon System
Robert A. Fridell,* Dike Qiu, Chunfu Wang, Lourdes Valera, and Min Gao
Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut

Received 23 April 2010/
Returned for modification 27 May 2010/ Accepted 23 June 2010
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BMS-790052 is the most potent hepatitis C virus (HCV) inhibitor reported to date, with 50% effective concentrations (EC50s) of 50 pM against genotype 1 replicons. This exceptional potency translated to rapid viral load declines in a phase I clinical study.
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By targeting NS5A, BMS-790052 is distinct from most HCV inhibitors in clinical evaluation. As an initial step toward correlating in vitro and in vivo resistances, multiple cell lines and selective pressures were used to identify BMS-790052-resistant variants in genotype 1 replicons. Similarities and differences were observed between genotypes 1a and 1b.
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For genotype 1b, L31F/V, P32L, and Y93H/N were identified as primary resistance mutations. L23F, R30Q, and P58S acted as secondary resistance substitutions, enhancing the resistance of primary mutations but themselves not conferring resistance. For genotype 1a, more sites of resistance were identified, and substitutions at these sites (M28T, Q30E/H/R, L31M/V, P32L, and Y93C/H/N) conferred higher levels of resistance.
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For both subtypes, combining two resistance mutations markedly decreased inhibitor susceptibility. Selection studies with a 1b/1a hybrid replicon highlighted the importance of the NS5A N-terminal region in determining genotype-specific inhibitor responses. As single mutations, Q30E and Y93N in genotype 1a conferred the highest levels of resistance. For genotype 1b, BMS-790052 retained subnanomolar potency against all variants with single amino acid substitutions, suggesting that multiple mutations will likely be required for significant in vivo resistance in this genetic background. Importantly, BMS-790052-resistant variants remained fully sensitive to alpha interferon and small-molecule inhibitors of HCV protease and polymerase.
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* Corresponding author. Mailing address: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492. Phone: (203) 677-7034. Fax: (203) 677-6088. E-mail: robert.fridell@bms.com

Published ahead of print on 28 June 2010.
Present address: Discovery Biology, Bristol-Myers Squibb Research and Development, Hopewell, NJ.
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