Preclinical Characterization of GSK2336805, a Novel Inhibitor of Hepatitis C Virus Replication That Selects for Resistance in NS5A

Antimicrob Agents Chemother. 2014 Jan;58(1):38-47. doi: 10.1128/AAC.01363-13. Epub 2013 Oct 14.

Walker J, Crosby R, Wang A, Woldu E, Vamathevan J, Voitenleitner C, You S, Remlinger K, Duan M, Kazmierski W, Hamatake R.

Abstract

GSK2336805 is an inhibitor of hepatitis C virus (HCV) with picomolar activity on the standard genotype 1a, 1b, and 2a subgenomic replicons and exhibits a modest serum shift. GSK2336805 was not active on 22 RNA and DNA viruses that were profiled. We have identified changes in the N-terminal region of NS5A that cause a decrease in the activity of GSK2336805. These mutations in the genotype 1b replicon showed modest shifts in compound activity (<13-fold), while mutations identified in the genotype 1a replicon had a more dramatic impact on potency. GSK2336805 retained activity on chimeric replicons containing NS5A patient sequences from genotype 1 and patient and consensus sequences for genotypes 4 and 5 and part of genotype 6. Combination and cross-resistance studies demonstrated that GSK2336805 could be used as a component of a multidrug HCV regimen either with the current standard of care or in combination with compounds with different mechanisms of action that are still progressing through clinical development.

PMID: 24126581 [PubMed - in process]

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Janssen Acquires Investigational NS5A Inhibitor for the Treatment of Hepatitis C from GlaxoSmithKline

TITUSVILLE, N.J., Oct. 8, 2013 /PRNewswire/ -- Janssen Pharmaceuticals, Inc. (Janssen) announced today the acquisition of the investigational compound GSK2336805, an NS5a replication complex inhibitor in Phase 2 development for the treatment of chronic hepatitis C, from an affiliate of GlaxoSmithKline plc. Janssen has acquired all rights to develop and commercialize GSK2336805, including in combination with other drugs. Financial details of the agreement have not been disclosed.

Janssen plans to initiate Phase 2 studies to evaluate the use of GSK2336805 in interferon-free combinations with the investigational protease inhibitor simeprevir (TMC435) and TMC647055, Janssen's non-nucleoside polymerase inhibitor, for the treatment of chronic hepatitis C in adult patients with compensated liver disease.

"We're excited to add GSK2336805 to our existing portfolio of direct-acting antivirals (DAAs). This addition will broaden our clinical development program as we continue to look for new investigational interferon-free treatment combinations to combat the hepatitis C virus," said Gaston Picchio, Hepatitis Disease Area Leader, Janssen. "Janssen is dedicated to working with the hepatitis C community to investigate our portfolio of DAAs in a number of different treatment combinations and hepatitis C patient populations."  

About GSK2336805
GSK2336805 is an investigational once-daily NS5a replication complex inhibitor in Phase 2 development for the treatment of chronic hepatitis C in adult patients with compensated liver disease, including all stages of liver fibrosis.

About Simeprevir
Simeprevir is an investigational NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and Medivir AB for the treatment of genotype 1 and genotype 4 chronic hepatitis C in adult patients with compensated liver disease, including all stages of liver fibrosis. Simeprevir works by blocking the protease enzyme that enables the hepatitis C virus to replicate in host cells.

Janssen is responsible for the global clinical development of simeprevir and has acquired exclusive, worldwide marketing rights, except in the Nordic countries. Medivir will retain marketing rights for simeprevir in these countries. Simeprevir has been submitted for regulatory approval in the United States, Canada and Europe, and was approved in September 2013 in Japan. To date, more than 3,700 patients have been treated with simeprevir in clinical trials.

Additionally, simeprevir is being studied in combination with several DAAs with different mechanisms of action, with and without ribavirin, as part of interferon-free regimens. These include:

• The Phase 2 COSMOS study of simeprevir and Gilead's nucleotide inhibitor sofosbuvir (GS-7977) in treatment-naive and previous null-responder genotype 1 hepatitis C patients, including patients with cirrhosis; 
• A Phase 2 study of simeprevir and Bristol-Myers Squibb's NS5A replication complex inhibitor daclatasvir in treatment-naive and previous null-responder genotype 1 hepatitis C patients;  and
• The Phase 2 HELIX-1 study of simeprevir and Idenix's once-daily pan-genotypic NS5A inhibitor samatasvir (IDX719) in treatment-naive genotype 1b and genotype 4 hepatitis C patients.

For additional information about simeprevir, please visit www.clinicaltrials.gov.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease, is the focus of a rapidly evolving treatment landscape. Approximately 150 million people are infected with hepatitis C worldwide – including approximately 3.2 million people in the United States – and 350,000 people per year die from the disease globally. When left untreated, hepatitis C can cause significant damage to the liver including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which may include liver failure.

About Janssen
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in infectious diseases and vaccines, oncology, immunology, neuroscience, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen Pharmaceuticals, Inc. and Janssen R&D Ireland are part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Please visit http://www.janssenrnd.com for more information.

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995.  The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events.  If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Pharmaceuticals, Inc., any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson.  Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; challenges to patents; impact of business combinations; changes in behavior and spending patterns or financial distress of purchasers of health care products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; trends toward health care cost containment; and increased scrutiny of the health care industry by government agencies.  A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 30, 2012.  Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson.  None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.)

Media Contact: Daniel De Schryver 
Mobile: +49 173 76 89 149

Media Contact: Craig Stoltz 
Mobile: +1 (215) 325-3612

Investor Contact: Stan Panasewicz
Office: +1 (732) 524-2524

Investor Contact: Louise Mehrotra
Office: +1 (732) 524-6491

SOURCE Janssen Pharmaceuticals, Inc.

RELATED LINKS
http://www.janssenrnd.com

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Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of GSK2336805, an Inhibitor of Hepatitis C Virus (HCV) NS5A, in Healthy Subjects and Subjects Chronically Infected with HCV Genotype 1

Antimicrob Agents Chemother. 2013 Oct;57(10):5037-44. doi: 10.1128/AAC.00910-13. Epub 2013 Jul 29.

Wilfret DA, Walker J, Adkison KK, Jones LA, Lou Y, Gan J, Castellino S, Moseley CL, Horton J, de Serres M, Culp A, Goljer I, Spreen W.

GlaxoSmithKline, Research Triangle Park, North Carolina, USA.

Abstract

GSK2336805 is an orally bioavailable hepatitis C virus (HCV) inhibitor working through an NS5A-mediated mechanism. This first-time-in-human study was conducted to assess the safety, tolerability, pharmacokinetics, metabolism, and efficacy of GSK2336805 in healthy subjects and subjects infected with HCV genotype 1. We performed a three-part, randomized, double-blind, placebo-controlled study in 46 healthy subjects and 23 HCV-infected subjects. After an overnight fast, healthy subjects received GSK2336805 as 10 mg, 30 mg, 30 mg plus food, and 60 mg in a single dose and 10 mg (7 days), 30 mg (7 days), and 75 mg (14 days) in a once-daily multiple dose. Subjects with HCV received GSK2336805 as a 1- to 120-mg single dose. In subjects with HCV, reductions in HCV RNA were observed within 4 h and a single dose of GSK2336805 of ≥10 mg resulted in a statistically significant ≥2-log reduction in HCV RNA compared with placebo at 24 h postdose. GSK2336805 was readily absorbed in all subjects, and the half-life (t1/2) was suitable for once-daily dosing. Administration of GSK2336805 with food had no effect on plasma GSK2336805 exposure; however, absorption was delayed, with a median tmax (time to maximum concentration of drug in serum) of 4.5 versus 2.0 h. Twenty subjects who received GSK2336805 experienced mild to moderate adverse events; none were serious. GSK2336805 was well tolerated and exhibited rapid, significant antiviral activity after a single dose in HCV-infected subjects. These results support the conduct of further studies evaluating GSK2336805 administered once daily for longer durations in combination with peginterferon, ribavirin, and other direct-acting antivirals. (This study has been registered at ClinicalTrials.gov under registration no. NCT01277692.).

PMID: 23896477 [PubMed - in process]

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Also See: A Double-Blind, Randomized, Placebo-Controlled Study to Assess the Safety, Antiviral Activity, and Pharmacokinetics of GSK2336805 When Given as Monotherapy and in Combination With Peginterferon alfa-2a and Ribavirin in Hepatitis C Virus Genotype 1-infected Treatment-naive Subjects

A Double-Blind, Randomized, Placebo-Controlled Study to Assess the Safety, Antiviral Activity, and Pharmacokinetics of GSK2336805 When Given as Monotherapy and in Combination With Peginterferon alfa-2a and Ribavirin in Hepatitis C Virus Genotype 1-infected Treatment-naive Subjects

Liver International

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original Article

Stephen Gardner^1,*, Amy Cutrell¹, Cindy Elko-Simms², Kimberly Adkison¹, Robert Hamatake¹, Jill Walker¹, Maribel Rodriguez-Torres³, Zhi Hong¹

DOI: 10.1111/liv.12334

This article is protected by copyright. All rights reserved.

Publication History

Accepted manuscript online: 25 SEP 2013 06:46AM EST
Manuscript Accepted: 6 SEP 2013
Manuscript Revised: 22 AUG 2013
Manuscript Received: 10 JUN 2013

Keywords: GSK2336805; Peginterferon alfa-2a; Ribavirin; Hepatitis C; direct acting antiviral

Abstract

Background

GSK2336805 is a HCV NS5A inhibitor for chronic hepatitis C (CHC). In a prior Phase I study, GSK2336805 was well tolerated and had an antiviral and pharmacokinetic profile suitable for once daily administration.

Aims

The current 28-day, double-blind, randomized, placebo-controlled study evaluated once daily GSK2336805 60mg alone or in combination with peginterferon alfa-2a (180 μg per week) and ribavirin (1000-1200 mg daily) (PEG/RIBA) in treatment-naive genotype 1 CHC subjects.

Methods

5 centers enrolled 16 subjects in the USA and Puerto Rico who received GSK2336805 + PEG/RIBA or placebo + PEG/RIBA.

Results

Following a single monotherapy dose of GSK2336805 on Day 1, median reduction from Baseline in HCV RNA was -2.96 log10 (N=11) versus -0.13 log10 (N=4) for placebo. With the addition of PEG/RIBA on Day 2, subjects receiving GSK2336805 exhibited greater decreases in viral load over the 28-day treatment period as compared with placebo. At Day 28, median reduction from Baseline was -4.86 log10 (N=9) in the GSK2336805 + PEG/RIBA group as compared with -1.98 log10 (N=4) in the placebo + PEG/RIBA group. At Day 28, rapid virologic response (RVR) occurred in 8/11 (73%) of the GSK2336805 + PEG/RIBA subjects as compared with 1/4 (25%) of the placebo + PEG/RIBA subjects. Adverse events were consistent with those reported in clinical trials of peginterferon and ribavirin, and no unique adverse events appeared to be associated with GSK2336805.

Conclusions

GSK2336805 is a potent NS5A inhibitor that showed a substantial antiviral effect as a monotherapy and in combination with peginterferon and ribavirin.

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