Gilead Announces Results from Study of Sovaldi® for Retreatment of Chronic Hepatitis C in Patients Not Cured with Prior Antiviral Therapy

-- Results Demonstrate Efficacy of Sovaldi-Based Regimen in GT1 Infected Patients Who Failed Prior Therapy with Other Direct Acting Antivirals--

-- Data Support Retreatment with Sovaldi-Based Regimen in GT2 or GT3 Infected Patients Who Failed Prior Treatment with Sovaldi --

LONDON--(BUSINESS WIRE)--Apr. 10, 2014-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from an open-label clinical trial (Study GS-US-334-0109) evaluating once-daily Sovaldi^® (sofosbuvir) 400 mg tablets for the retreatment of chronic hepatitis C virus (HCV) infection among patients who failed prior therapy. These data will be presented in two oral sessions at the 49th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress 2014) in London.

In Study GS-US-334-0109 (Oral #55), patients with genotype 1 HCV infection (n=80) received 12 weeks of treatment with once-daily Sovaldi plus weight-based ribavirin (RBV) twice-daily (1,000 or 1,200 mg/day) and pegylated interferon (peg-IFN; 180 μg/week). Patients in the study had failed prior regimens containing peg-IFN, RBV and an investigational NS3 protease inhibitor, with or without investigational direct-acting antivirals (DAAs) (NS5A and/or non-nucleoside NS5B inhibitors). Forty-five percent of patients (n=36) had received more than one course of prior therapy, and 90 percent (n=72) had at least one viral mutation associated with HCV NS3, NS5A or NS5B drug resistance.

Among the 50 patients for whom sustained virologic response data was available 12 weeks after the end of treatment (SVR12), 74 percent (n=37/50) achieved SVR12. Additionally, 80 percent (n=28/35) of patients with baseline resistance against two or more DAAs achieved SVR12.

“This study demonstrates that Sovaldi-based regimens can achieve high cure rates even among hepatitis C patients who previously failed therapy with baseline resistance to at least two DAAs,” said Stanislas Pol, MD, PhD, Professor of Hepatology and Gastroenterology, Paris Descartes University, Paris, France, and a principal investigator. “Importantly, Sovaldi has now demonstrated efficacy among genotype 1 HCV infected patients who failed prior treatment with three or four drug regimens and have developed viral resistance to some of the components of those regimens.”

In a separate presentation (Oral #8), retreatment with Sovaldi in genotype 2 (n=11) or genotype 3 (n=96) HCV infected patients who previously failed treatment with 12 or 16 weeks of Sovaldi plus RBV in the Phase 3 studies FISSION, FUSION and POSITRON was evaluated. Thirty-six percent of these patients (39/107) had cirrhosis. Patients were retreated either with a 12-week regimen of Sovaldi, RBV and peg-IFN, or a 24-week, interferon-free regimen of Sovaldi plus RBV. The choice of regimen was determined by study investigators.

Among patients with available SVR12 data, 63 percent (n=25/40) of those who received the 24-week all-oral regimen and 92 percent (n=24/26) of those who received the 12-week regimen of Sovaldi, RBV, and peg-IFN achieved SVR12.

“These data support initial findings from the Phase 3 trials, which demonstrate that Sovaldi is an effective treatment option and one that may also be particularly important for genotype 2 and 3 patients who failed a previous sofosbuvir-based regimen,” said Rafael Esteban, MD, Head of the Internal Medicine and Liver Unit, Hospital Universitari Vall d’Hebron and Professor of Medicine, Universitat Autónoma de Barcelona, Barcelona, Spain and a principal investigator for the study.

Sovaldi was well tolerated in Study GS-US-334-0109. The most common adverse events were consistent with the safety profiles of peg-IFN and/or RBV. Additional information about the study can be found at www.clinicaltrials.gov.

About Sovaldi

Sovaldi is an oral nucleotide analog inhibitor of the HCV NS5B polymerase enzyme, which plays an essential role in HCV replication. Sovaldi is a direct-acting agent, meaning that it interferes directly with the HCV life cycle by suppressing viral replication.

Sovaldi was approved in the United States on December 8, 2013 and in the European Union on January 17. In the United States, Sovaldi is approved for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen. Efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection. Treatment response varies based on baseline host and viral factors. Monotherapy is not recommended for treatment of chronic hepatitis C. Study GS-US-334-0109 evaluated investigational uses of Sovaldi, for which safety and efficacy have not yet been established.

IMPORTANT SAFETY INFORMATION

Contraindications

Sovaldi combination treatment with ribavirin or with peginterferon alfa plus ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risk for birth defects and fetal death associated with ribavirin. Contraindications to peginterferon alfa and ribavirin also apply to Sovaldi combination treatment. Refer to the prescribing information of peginterferon alfa and ribavirin for a list of their contraindications.

Warnings and Precautions

• Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners must use two forms of non-hormonal contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the prescribing information for ribavirin.

• Use with Potent P-gp Inducers: Rifampin and St. John’s wort should not be used with Sovaldi as they may significantly decrease sofosbuvir plasma concentration, reducing its therapeutic effect.

Adverse Reactions

Most common (≥20 percent, all grades) adverse reactions for:

• Sovaldi + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia, and anemia
• Sovaldi + ribavirin combination therapy were fatigue, and headache

Drug Interactions

In addition to rifampin and St. John’s wort, coadministration of Sovaldi is not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of sofosbuvir, reducing its therapeutic effect.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility of unfavorable longer-term results from clinical trials evaluating Sovaldi for the treatment or retreatment of HCV, and the risk that healthcare providers, payers or insurers may not recognize the benefits of Sovaldi. As Sovaldi is used over longer periods of time by treatment-experienced patients with underlying health problems taking numerous other medicines, Gilead may find new issues such as safety, resistance or drug interaction issues, which may require it to provide additional warnings or contraindications in the label, which could reduce the market acceptance of Sovaldi. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Sovaldi is available at www.gilead.com.

Sovaldi is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, +1 650-522-1936 (Investors)
Cara Miller, +1 650-522-1616 (Media (U.S.))
Arran Attridge, +44 208 587 2477 (Media (Europe))

Source

The Cost of Treatment Failure

Journal of Viral Hepatitis

Resource Use and Costs Incurred by Hepatitis C Virus Genotype 1-Infected Patients Who Do or Do Not Achieve Sustained Virological Response to Therapy

M. Backx, A. Lewszuk, J. R. White, J. Cole, A. Sreedharan, S. van Sanden, J. Diels, A. Lawson, K. R. Neal, M. J. Wiselka, T. Ito, W. L. Irving

J Viral Hepat. 2014;21(3):208-215

Abstract and Introduction

Abstract

Chronic hepatitis C virus (HCV) infection places a considerable economic burden on health services. Cost-effectiveness analyses of antiviral treatment for patients with chronic HCV infection are dependent on assumptions about cost reductions following sustained virological response (SVR) to therapy. This study quantified the medium-term difference in health resource usage and costs depending on treatment outcome. Retrospective chart review of patients with HCV genotype 1 infection who had received at least 2 months pegylated interferon and ribavirin therapy, with known treatment outcome was conducted. Disease status was categorized as chronic hepatitis, cirrhosis or decompensated liver disease. Health resource use was documented for each patient in each disease state. Unit costs were from the NHS 'Payment by Results' database and the British National Formulary. One hundred and ninety three patients (108 SVR, 85 non-SVR) with mean follow-up of 3.5 (SVR) and 4.9 (non-SVR) years were enrolled. No SVR patient progressed to a more severe liver disease state. Annual transition rates for non-SVR patients were 7.4% (chronic hepatitis to cirrhosis) and 4.9% (cirrhosis to decompensated liver disease). By extrapolation of modelled data over a 5-year post-treatment period, failure of patients with chronic hepatitis to achieve SVR was associated with a 13-fold increase (roughly £2300) in costs, whilst for patients who were retreated, the increase was 56-fold, equating to more than £10 000. Achievement of an SVR has significant effects on health service usage and costs. This work provides real-life data for future cost-effectiveness analyses related to the treatment for chronic HCV infection.

Introduction

An estimated 130–170 million people worldwide are chronically infected with hepatitis C virus (HCV), with around 216 000 living in the United Kingdom (UK).^[1] Chronic infection may result in progressive liver damage, leading to cirrhosis and its sequelae in at least 20–30% of individuals.^[2] Both hospital admissions and deaths related to chronic HCV infection are rising in the UK,^[1] and end-stage liver disease resulting from chronic HCV infection is now a leading indication for liver transplantation.^[3] It is estimated that by 2020, nearly 16 000 individuals will be living with HCV-related cirrhosis or hepatocellular carcinoma in England if left untreated.^[4] Estimates of direct medical expenses related to HCV infection in the USA predict a rise in total expenditure to over $10 billion in the next decade.^[5] The management of chronic HCV infection thus places a significant health and economic burden on national health services worldwide.

Until recently, the standard of care (SoC) for chronic HCV infection involved combination therapy with pegylated interferon and ribavirin. For genotype 1 disease, this resulted in a sustained viral response (SVR) in approximately 40–50% of patients,^[6] which in turn results in lower rates of liver-related morbidity and mortality.^[7] Recent advances in the understanding of HCV biology have led to the development of directly acting antiviral (DAA) agents. Two of these therapies, telaprevir and boceprevir, act on the viral NS3/4a protease and, in combination with pegylated interferon and ribavirin, have been shown to significantly improve SVR both in treatment-naïve and in treatment-experienced patients with genotype 1 disease. In the USA, triple therapy is now considered the new standard of care for patients with genotype 1 infection.^[8] In England and Wales, the National Institute for Health and Clinical Excellence (NICE) has recommended the use of telaprevir or boceprevir, each in combination with pegylated interferon and ribavirin, as treatment options for genotype 1 chronic HCV infection in adults with compensated liver disease for both treatment-naïve and treatment-experienced patients.^[9,10]

As treatment options for genotype 1 chronic HCV infection expand, it will be important to understand the cost reductions associated with achievement of an SVR, in addition to the obvious clinical benefits to an individual patient. Previous cost-effectiveness analyses of antiviral therapy have made assumptions that achieving an SVR reduces costs.^[11–13] Prior to this study, no previous paper has contrasted the resource use and costs of genotype 1 patients with and without SVR to assess the relative value of successful antiviral treatment in terms of offsetting morbidity costs.

This study aimed to compare disease progression, use of health services and costs to the UK National Health Service (NHS) between patients with genotype 1 infection who achieved an SVR following pegylated interferon and ribavirin therapy vs those who did not, using real-world data representative of routine NHS practice in the UK.

Continue reading full article here …..

Treatment failure may lead to accelerated fibrosis progression in patients with chronic HCV

J Viral Hepat. 2014 Feb;21(2):111-20. doi: 10.1111/jvh.12127. Epub 2013 Aug 27.

Baran B, Gulluoglu M, Soyer OM, Ormeci AC, Gokturk S, Evirgen S, Yesil S, Akyuz F, Karaca C, Demir K, Kaymakoglu S, Besisik F.

Abstract

Chronic hepatitis C (CHC) patients with treatment failure (TF) remain at risk of continuing fibrosis progression. However, it has not been investigated whether there is an increased risk of accelerated fibrosis progression after failed interferon-based therapy. We aimed to investigate long-term influence of TF on fibrosis progression compared with untreated patients with CHC. We studied 125 patients with CHC who underwent paired liver biopsies from 1994 to 2012. Patients with advanced fibrosis were excluded from the analysis. Sixty-three patients had TF, and 62 patients were treatment-naïve (TN). Annual fibrosis progression rate (FPR) was calculated, and significant fibrosis progression (SFP) was defined as ≥2 stage increase in fibrosis during follow-up. Multiple regression analyses were performed to find out independent predictors of FPR and SFP. Demographic characteristics and duration between paired liver biopsies were similar in TF and TN groups. Baseline alanine aminotransferase and gamma-glutamyl transferase (GGT) levels (71 ± 31 vs 47 ± 22, P < 0.001 and 49 ± 39 vs 36 ± 28, P = 0.027, respectively), baseline mean fibrosis stage (2.2 ± 0.7 vs 1.9 ± 0.7, P = 0.018) and histologic activity index (6.3 ± 1.9 vs 4.3 ± 1.6, P < 0.001) were higher in the TF group compared with the TN group. In regression analyses, the strongest independent predictor of fibrosis progression was the GGT level (OR: 1.03, 95%CI 1.01-1.5, P < 0.001). Treatment experience (OR: 5.97, 95%CI 1.81-19.7, P = 0.003) also appeared as an independent predictor of both FPR and SFP. Failed interferon-based CHC treatment may lead to accelerated FPR in the long-term compared with the natural course.

© 2013 John Wiley & Sons Ltd.

KEYWORDS: fibrosis progression, gamma-glutamyl transferase, hepatitis C, nonresponder, treatment failure

PMID: 24383924 [PubMed - in process]

Source

Simeprevir Administered Once Daily as Part of Combination Therapy Demonstrates Sustained Virologic Response in Treatment-Naive and Treatment-Experienced Genotype 1 Chronic Hepatitis C Adult Patients

WASHINGTON, Nov. 2, 2013 /PRNewswire/ -- Janssen R&D Ireland (Janssen) today announced the presentation of new data at The Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Washington, DC for the investigational protease inhibitor simeprevir (TMC435) in the treatment of genotype 1 chronic hepatitis C in treatment-naive and treatment-experienced adult patients with compensated liver disease. In analyses of the Phase 3 QUEST-1 and QUEST-2 studies in treatment-naive patients and the Phase 3 PROMISE study in prior relapse patients, the efficacy of simeprevir was observed in hepatitis C patients, including patients with the IL28B TT genotype and METAVIR scores of F4.

"Patients with certain baseline characteristics can be more likely to fail or relapse after prior treatment," said Ira Jacobson, M.D., simeprevir clinical trial investigator, chief of the Division of Gastroenterology and Hepatology, Vincent Astor Distinguished Professor of Medicine, Weill Cornell Medical College, and attending physician, New York-Presbyterian Hospital/Weill Cornell Medical Center. "The breadth of simeprevir data presented at AASLD reinforce its potential as a treatment option for patients and will offer important guidance to physicians once simeprevir is approved."   

On October 24, the U.S. Antiviral Drugs Advisory Committee of the FDA voted unanimously (19-0) to recommend approval of the new drug application filed by Janssen Research & Development, LLC for simeprevir administered once daily with pegylated interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C virus (HCV) in adult patients with compensated liver disease.

Pooled Analysis from QUEST-1 and QUEST-2 Confirms Clinical Benefit of Simeprevir in Sub-Populations of Patients (Abstract 1122)                                   
In a pooled analysis of the Phase 3 QUEST-1 and QUEST-2 studies, 80 percent of treatment-naive patients treated with simeprevir in combination with pegylated interferon and ribavirin achieved the primary endpoint of sustained virologic response 12 weeks after the end of treatment (SVR12) compared to 50 percent of patients treated with placebo plus pegylated interferon and ribavirin. The pooled analysis found that 61 percent of patients with the IL28B TT genotype, 60 percent of patients with a METAVIR score of F4 and 75 percent of patients with genotype 1a HCV treated with simeprevir combined with pegylated interferon and ribavirin achieved SVR12 compared to 21 percent, 34 percent and 47 percent of patients taking placebo plus pegylated interferon and ribavirin, respectively. Among patients with the genotype 1a Q80K polymorphism at baseline, 58 percent of patients treated with simeprevir combined with pegylated interferon and ribavirin achieved SVR12 compared to 52 percent of patients treated with placebo in combination with pegylated interferon and ribavirin, but the difference was not statistically significant.

Eight percent and 10 percent of patients treated with simeprevir combined with pegylated interferon and ribavirin experienced on-treatment failure and relapse, respectively, compared to 33 percent and 15 percent of patients taking placebo plus pegylated interferon and ribavirin, respectively. Three percent of patients treated with simeprevir discontinued treatment early due to an adverse event compared to two percent of patients treated with placebo.

Analysis from PROMISE Reinforces Efficacy of Simeprevir in Sub-Populations of Patients (Abstract 1092)                     
In the pivotal Phase 3 PROMISE study, 79 percent of treatment-experienced hepatitis C patients treated with simeprevir in combination with pegylated interferon and ribavirin who previously experienced a relapse after prior treatment with pegylated interferon-based therapy achieved the primary endpoint of SVR12 compared to 37 percent of patients treated with placebo plus pegylated interferon and ribavirin. In this sub-analysis, 65 percent of patients with the IL28B TT genotype, 74 percent of patients with a METAVIR score of F4 and 70 percent of patients with genotype 1a HCV treated with simeprevir combined with pegylated interferon and ribavirin achieved SVR12 compared to 19 percent, 26 percent and 28 percent of patients taking placebo plus pegylated interferon and ribavirin, respectively. Among patients with the genotype 1a Q80K polymorphism at baseline, 47 percent of patients treated with simeprevir combined with pegylated interferon and ribavirin achieved SVR12 compared to 30 percent of patients treated with placebo in combination with pegylated interferon and ribavirin.

The most common adverse events in patients treated with simeprevir combined with pegylated interferon and ribavirin in the first 12 weeks were fatigue, headache and influenza-like illness. Three percent and 18 percent of patients treated with simeprevir combined with pegylated interferon and ribavirin experienced on-treatment failure and relapse, respectively, compared to 27 percent and 34 percent of patients taking placebo plus pegylated interferon and ribavirin, respectively.

"We are very proud of the depth and breadth of our clinical trial program," said Gaston Picchio, Disease Area Leader Hepatitis, Janssen Research & Development. "Following last week's positive vote from the FDA's Antiviral Drugs Advisory Committee to recommend approval of simeprevir, we look forward to making simeprevir available to patients living with chronic HCV."

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 Simeprevir
Simeprevir (TMC435) is an investigational NS3/4A protease inhibitor jointly developed by Janssen R&D Ireland and its affiliated companies and Medivir AB for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including all stages of liver fibrosis. Simeprevir works by blocking the viral 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 for the Nordic countries. Medivir AB will retain marketing rights for simeprevir in these Nordic countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved on September 27, 2013 in Japan for the treatment of genotype 1 hepatitis C and a Marketing Authorisation Application was submitted to the European Medicines Agency (EMA) by Janssen-Cilag International NV seeking approval of simeprevir for the treatment of genotype 1 or genotype 4 chronic hepatitis C.

Simeprevir is also being studied in several interferon-free regimens using selected combinations of direct-acting antiviral agents with different mechanisms of action. To date, more than 3,700 patients have been treated with simeprevir in clinical trials.

In October, Janssen Pharmaceuticals, Inc. acquired the investigational compound GSK2336805, an NS5a replication complex inhibitor in Phase 2 development for the treatment of chronic HCV, from an affiliate of GlaxoSmithKline plc. Since being acquired, the compound has been renamed JNJ-56914845. Janssen Pharmaceuticals plans to initiate Phase 2 studies to evaluate the use of JNJ-56914845 in interferon-free combinations with simeprevir and TMC647055, the company's non-nucleoside polymerase inhibitor, for the treatment of chronic HCV in adult patients with compensated liver disease.

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

About Janssen R&D Ireland                  
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, 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 R&D Ireland is 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 R&D Ireland, 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 R&D Ireland

RELATED LINKS
http://www.janssenrnd.com

Source

Daclatasvir + Sofosbuvir Effective in Prior Telaprevir or Boceprevir Failures

Infectious Disease Week (IDWeek)
October 2-6, 2013
San Francisco, Ca

1357. Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) In Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) Or Boceprevir (BOC)

Session: Poster Abstract Session: Clinical Trials

Saturday, October 5, 2013

Room: The Moscone Center: Poster Hall C

Background: Daclatasvir (DCV) plus sofosbuvir (SOF) ±RBV achieved high rates of sustained virologic response in HCV GT1-3-infected previously untreated patients (arms A-H). Additional arms (I, J) evaluated the efficacy of DCV+SOF ±RBV in patients who failed TVR or BOC.

Methods: A total of 41 GT1 non-cirrhotic patients with previous breakthrough (n=15), relapse (n=13), or nonresponse (n=14) to pegIFN/RBV+TVR (n=33) or BOC (n=9) (1 patient received both) were randomized 1:1 to DCV+SOF with or without RBV for 24 weeks. Patients who discontinued TVR or BOC due to adverse events were excluded. DCV and SOF were dosed orally at 60mg QD and 400mg QD, respectively. RBV was dosed BID at 1000-1200 mg/d. The primary end point was HCV RNA<25 IU/mL at 12 weeks post-treatment (SVR₁₂).

Results: Most patients had HCV GT1a (83%), were IL28B non-CC (98%), and had estimated METAVIR stage ≥F2 (83%). Mean HCV RNA was ≥6 log IU/mL. HCV RNA <25 IU/mL was achieved in 40/41 patients by week 4 and in all patients by end of treatment. None had breakthrough or relapse and all patients with available data (40/41) achieved SVR₁₂ (Table). The most common adverse events (>30% total) were fatigue and headache. There were no grade 3-4 hematologic or hepatic laboratory abnormalities. 

Conclusion : The all-oral, once-daily combination of DCV+SOF with or without RBV for 24 weeks achieved SVR₁₂ in 98% of non-cirrhotic GT1 prior TVR/BOC treatment failures. These data provide proof-of-concept that the combination of two potent direct-acting antivirals with different viral targets is effective in patients who failed pegIFN/RBV + a protease inhibitor.

HCV RNA < 25 IU/mL, mITT	I DCV + SOF x 24 weeks (n = 21)	J DCV + SOF  + RBV x 24 weeks (n = 20)
Week 4	21 (100)	19 (95)a
End Of Treatment  (Week 24)	21 (100)	20 (100)
SVR4	21 (100)	20 (100)
SVR12	21 (100)	19 (95)b
a 1 missing; b 1 missing—patient had HCV RNA undetectable at post-treatment  week4 and post-treatment week 24 (preliminary)

Mark Sulkowski, MD¹, David Gardiner², Maribel Rodriguez-Torres, MD³, K. Rajender Reddy, MD⁴, Tarek Hassanein, MD⁵, Ira Jacobson, MD⁶, Eric Lawitz⁷, Anna S.F. Lok, MD, FRCP⁸, Federico Hinestrosa⁹, Paul J. Thuluvath¹⁰, Howard Schwartz¹¹, David Nelson¹², Gregory T. Everson¹³, Timothy Eley, PhD¹⁴, Megan Wind-Rotolo¹⁵, Shu-Pang Huang¹⁵, Min Gao¹⁶, Fiona Mcphee¹⁶, Dennis Hernandez¹⁶, Diane Sherman², Robert Hindes¹⁷, William Symonds, PharmD¹⁸, Claudio Pasquinelli¹⁴, Dennis Grasela, PharmD, PhD¹⁹ and AI444040 Study Group, (1)John Hopkins University School of Medicine, Baltimore, MD, (2)Bristol-Myers Squibb, Pennington, NJ, (3)Gastroenterology, Fundacion de Investigacion, Rio Piedras, PR, (4)Univ. of Pennsylvania, Philadelphia, PA, (5)230 Prospect Place, Suite 220, Southern California Liver Centers, Coronado, CA, (6)Weill Medical College of Cornell University, New York, NY, (7)Texas Liver Insititute, University of Texas Health Science Center, San Antonio, TX, (8)Internal Medicine, University of Michigan, Ann Arbor, MI, (9)Orlando Immunology Center, Orlando, FL, (10)Mercy Medical Center, Baltimore, MD, (11)Miami Research Associates, South Miami, FL, (12)University of Florida, Gainesville, FL, (13)University of Colorado Denver, Aurora, CO, (14)Bristol-Myers Squibb, Hopewell, NJ, (15)Bristol-Myers Squibb, Princeton, NJ, (16)Bristol-Myers Squibb, Wallingford, CT, (17)Consultant, Foster City, CA, (18)Gilead Sciences, Foster City, CA, (19)Bristol Myers-Squibb, Hopewell, NJ

Disclosures:

M. Sulkowski, AbbVie: Investigator and Scientific Advisor, Consulting fee and Research grant
BIPI: Investigator, Research Contractor and Scientific Advisor, Consulting fee and Research grant
BMS: Investigator and Scientific Advisor, Consulting fee and Research grant
Gilead : Investigator and Scientific Advisor, Consulting fee and Research grant
Janssen: Consultant, Investigator and Scientific Advisor, Consulting fee and Research grant
Merck : Investigator and Scientific Advisor, Research grant
Pfizer: Steering Committe, Consulting fee
Vertex: Investigator and Scientific Advisor, Consulting fee and Research grant

D. Gardiner, Bristol-Myers Squibb: Employee, Salary

M. Rodriguez-Torres, Bristol-Myers Squibb: Investigator, Research support

K. R. Reddy, Bristol-Myers Squibb: Investigator, Research support

T. Hassanein, Bristol-Myers Squibb: Investigator, Research support

I. Jacobson, Bristol-Myers Squibb: Investigator, Research support

E. Lawitz, Bristol-Myers Squibb: Investigator, Research support

A. S. F. Lok, Bristol-Myers Squibb: Investigator, Research support

F. Hinestrosa, Bristol-Myers Squibb: Investigator, Research support

P. J. Thuluvath, Bristol-Myers Squibb: Investigator, Research support

H. Schwartz, Bristol-Myers Squibb: Investigator, Research support

D. Nelson, Bristol-Myers Squibb: Investigator, Research support

G. T. Everson, Bristol-Myers Squibb: Investigator, Research support

T. Eley, Bristol-Myers Squibb: Employee, Salary

M. Wind-Rotolo, Bristol-Myers Squibb: Employee, Salary

S. P. Huang, Shu-Pang Huang: Employee, Salary

M. Gao, Bristol-Myers Squibb: Employee, Salary

F. Mcphee, Bristol-Myers Squibb: Employee, Salary

D. Hernandez, Bristol-Myers Squibb: Employee, Salary

D. Sherman, Bristol-Myers Squibb: Employee, Salary

R. Hindes, Bristol-Myers Squibb: Research Contractor, Research support

W. Symonds, Gilead Sciences: Employee, Salary

C. Pasquinelli, Bristol-Myers Squibb: Employee, Salary

D. Grasela, Bristol-Myers Squibb: Employee, Salary

Source

Treatment failure may lead to accelerated fibrosis progression in patients with chronic hepatitis C

Journal of Viral Hepatitis

Early View (Online Version of Record published before inclusion in an issue)

Original Article

B. Baran¹, M. Gulluoglu², O. M. Soyer¹, A. C. Ormeci¹, S. Gokturk¹, S. Evirgen¹, S. Yesil², F. Akyuz¹, C. Karaca¹, K. Demir¹, S. Kaymakoglu¹, F. Besisik^1,*

Article first published online: 27 AUG 2013

DOI: 10.1111/jvh.12127

© 2013 John Wiley & Sons Ltd

Abstract

Keywords: fibrosis progression; gamma-glutamyl transferase; hepatitis C; nonresponder; treatment failure

Summary

Chronic hepatitis C (CHC) patients with treatment failure (TF) remain at risk of continuing fibrosis progression. However, it has not been investigated whether there is an increased risk of accelerated fibrosis progression after failed interferon-based therapy. We aimed to investigate long-term influence of TF on fibrosis progression compared with untreated patients with CHC. We studied 125 patients with CHC who underwent paired liver biopsies from 1994 to 2012. Patients with advanced fibrosis were excluded from the analysis. Sixty-three patients had TF, and 62 patients were treatment-naïve (TN). Annual fibrosis progression rate (FPR) was calculated, and significant fibrosis progression (SFP) was defined as ≥2 stage increase in fibrosis during follow-up. Multiple regression analyses were performed to find out independent predictors of FPR and SFP. Demographic characteristics and duration between paired liver biopsies were similar in TF and TN groups. Baseline alanine aminotransferase and gamma-glutamyl transferase (GGT) levels (71 ± 31 vs 47 ± 22, P < 0.001 and 49 ± 39 vs 36 ± 28, P = 0.027, respectively), baseline mean fibrosis stage (2.2 ± 0.7 vs 1.9 ± 0.7, P = 0.018) and histologic activity index (6.3 ± 1.9 vs 4.3 ± 1.6, P < 0.001) were higher in the TF group compared with the TN group. In regression analyses, the strongest independent predictor of fibrosis progression was the GGT level (OR: 1.03, 95%CI 1.01–1.5, P < 0.001). Treatment experience (OR: 5.97, 95%CI 1.81–19.7, P = 0.003) also appeared as an independent predictor of both FPR and SFP. Failed interferon-based CHC treatment may lead to accelerated FPR in the long-term compared with the natural course.

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