HCV Research and News

December 8, 2017

The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: An ERCHIVES study

Hepatobiliary Malignancies

Darrick K. Li MD, PhD^1,6, Yanjie Ren MS², Daniel S. Fierer MD³, Stephanie Rutledge MD¹, Obaid S. Shaikh MD², Vincent Lo Re III MD, MSCE⁴, Tracey Simon MD^1,6, Abdul-Badi Abou-Samra MD, PhD^5,7, Raymond T. Chung MD^1,6,* and Adeel A. Butt MD, MS^2,5,7,*

DOI: 10.1002/hep.29707

Hepatology

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

Publication History

Accepted manuscript online: 2 DEC 2017 11:21AM EST
Manuscript Accepted: 20 NOV 2017
Manuscript Revised: 12 NOV 2017
Manuscript Received: 6 JUL 2017

Keywords: Cirrhosis; sustained virologic response; interferon; sofosbuvir; Veterans

Abstract

Recent studies have reported higher rates of hepatocellular carcinoma (HCC) in individuals treated with direct-acting antivirals (DAAs). However, making definitive conclusions has been challenging due to the heterogeneous populations and methodologies of these reports. We investigated whether DAA use is associated with higher rates of incident HCC compared to treatment with interferon-based regimens. We performed a retrospective population-based cohort study using the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database. In a cohort of 17,836 persons, SVR was achieved by 66.6% and 96.2% of the IFN and DAA groups, respectively. Among all treated persons, the risk of HCC was not higher in the DAA group compared to the IFN group (HR 1.07; [95% CI: 0.55, 2.08]). Among persons with cirrhosis who achieved SVR, neither the HCC incidence rate nor HCC-free survival were significantly different in the DAA group compared to the IFN group (21.2 vs. 22.8 per 1000 person years; p=0.78; and log-rank p=0.17, respectively). Untreated persons with cirrhosis had a significantly higher HCC incidence rate (45.3 per 1000 person years) compared to those treated with either IFN or DAAs (p=0.03). Both groups of treated persons had significantly lower probability of HCC development compared to untreated persons (log-rank p=0.0004).

Conclusions: DAA treatment is not associated with a higher risk of HCC in cirrhotics with chronic HCV infection in the short-term. Previously reported higher rates of HCC associated with DAA treatment may be explained by both the presence of relatively fewer baseline HCC risk factors in persons treated with IFN as well as selection bias, as DAA regimens were used to treat persons at higher risk for developing HCC. This article is protected by copyright. All rights reserved.

Source

Nonsurgical options for localized hepatocellular carcinoma

View issue TOC
Volume 10, Issue 4
October 2017
Pages 103–106

Review

John Ha M.D., Robert J. Wong M.D., M.S.

First published: 31 October 2017

First published: 31 October 2017 Full publication history

DOI: 10.1002/cld.662 View/save citation

Potential conflict of interest: Nothing to report.

Abstract

Watch a video presentation of this article

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the United States. With its current trend, HCC is projected to become the third leading cause of cancer-related deaths in the United States by 2030.[1] Currently, more than 55% of HCC cases are diagnosed beyond localized disease, and the majority do not receive definitive curative therapies, such as surgical resection or liver transplantation.[1, 2] Curative therapies are mainly reserved for patients with localized disease or those within Milan criteria. However, many nonsurgical treatment options are still available to patients with unresectable, advanced stage HCC (Table 1). Although there are many options for locoregional or systemic therapies in the management of unresectable HCC, this review will focus specifically on transarterial radioembolization (TARE), radiofrequency (RFA)/microwave ablation (MWA), stereotactic body radiation therapy (SBRT), systemic therapy, and hospice/supportive medicine. It is important to note that the approach for HCC treatment is variable and dependent on many factors, such as medical expertise, performance status, tumor stage and location, and degree of liver dysfunction. Therefore, utilizing multidisciplinary teams may provide the best option for developing a treatment plan.

Table 1. Curative Versus Noncurative Therapies for HCC

Continue reading full article here

Where I Have Been, and I Am back.

Everyone,

It has been a few years since I have been here to the blog. I went back to school to work on a second BS degree and finally get my MS degree. It did not all work out according to plan though, My health decided to interfere last year so I took some off from school. May 2016 I had my 11 year post PCR and still SVR. I also had a liver MRI done which showed 3 separate subcentimeter lesions. Let’s move ahead now to December 1st of this year, last Friday, 8 days ago …. I had a follow up MRI which showed early HCC. I have a 1.3cm mass and also a .9mm indeterminate mass. I am in the process of being referred to UNC Chapel Hill. My MRI results and other records are being reviewed there now and I am just waiting to find out who I will be seeing there and for my first appointment to be scheduled.

My plan is to start back posting research on the blog again. It is what I feel I need to get back to doing. All the research I have done over the years has helped me to become the best advocate I can be for myself and to help others.

Well, time to start researching and posting. It is good to be back.

Patricia Emory

April 25, 2015

AbbVie Presents Late-Breaking, Preliminary Phase 3b Data with VIEKIRAX® + EXVIERA® in Chronic Hepatitis C Patients with Renal Impairment at The International Liver Congress™ 2015

- RUBY-I evaluates treatment-naïve, non-cirrhotic, genotype 1 chronic hepatitis C patients with severe renal impairment
- In preliminary data from RUBY-I, patients receiving VIEKIRAX + EXVIERA with or without ribavirin who reached post-treatment week four (n=10 of 20 enrolled) achieved 100 percent sustained virologic response at four weeks post-treatment (SVR4)1
- AbbVie's Phase 3b studies explore VIEKIRAX + EXVIERA in additional patient populations seen in clinical practice and across multiple countries around the world

VIENNA, April 25, 2015 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced new, preliminary safety and efficacy data from the first cohort of its ongoing, Phase 3b RUBY-I study. RUBY-I is evaluating VIEKIRAX® (ombitasvir/paritaprevir/ritonavir tablets) + EXVIERA® (dasabuvir tablets) with or without ribavirin (RBV) in treatment-naïve, non-cirrhotic, genotype 1 (GT1) chronic hepatitis C patients with severe renal impairment (stage 4 or 5), including those on hemodialysis. The primary endpoint of the study is the percentage of patients achieving sustained virologic response at 12 weeks post-treatment (SVR₁₂). Patients who reached post-treatment week four to date (n=10 of 20 enrolled) achieved 100 percent SVR₄(n=10/10).¹ RUBY-I was presented as a late-breaker today at The International Liver Congress™ (ILC) 2015, the 50^th annual meeting of the European Association for the Study of the Liver (EASL) in Vienna, Austria.

"Treating hepatitis C patients with severe renal impairment may be a concern, particularly in those patients on hemodialysis," said Paul J. Pockros, M.D., director of Liver Disease Center Scripps Clinic and director of clinical research at Scripps Translational Science Institute in La Jolla, California. "With limited data currently available on the safety and efficacy of interferon-free treatments for patients with renal impairment, the preliminary results seen in RUBY-I show promising initial SVR rates with the VIEKIRAX + EXVIERA regimen in a dedicated study for this often difficult-to-treat patient population."

Additionally, RUBY-I data showed no virologic failures to date.¹ Preliminary safety analyses reported that patients experienced mainly mild or moderate adverse events when receiving VIEKIRAX + EXVIERA with or without RBV, most commonly (>20 percent) anemia, fatigue, diarrhea, nausea, dizziness and headache.¹ To date, eight of 13 genotype 1a (GT1a) patients had a RBV dose interruption.¹

"RUBY-I is part of AbbVie's broader Phase 3b program and demonstrates our continued focus on people living with hepatitis C that have specific needs," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "Studies in our Phase 3b program will help to further expand our knowledge of the utility of VIEKIRAX + EXVIERA in special populations encountered in clinical practice."

Additional Phase 3b studies from AbbVie presented at ILC 2015 included MALACHITE-I and MALACHITE-II data, and the TOPAZ-I and TOPAZ-II study design. The MALACHITE studies evaluate adult patients with GT1 chronic HCV infection without cirrhosis receiving VIEKIRAX + EXVIERA with or without RBV compared to treatment with telaprevir with pegylated-interferon and RBV, which remains the standard of care in many regions of the world.^2,3The TOPAZ studies will evaluate the effect of SVR₁₂ on long-term outcomes, five years following treatment with VIEKIRAX + EXVIERA with or without RBV in adults with GT1 chronic HCV infection.⁴

About RUBY-I Study
RUBY-I is an ongoing, multi-center, open-label Phase 3b study with two cohorts that evaluates the safety and efficacy of 12 or 24 weeks of treatment with VIEKIRAX® + EXVIERA® with or without ribavirin, based on sub-genotype in treatment-naïve, adult patients with genotype 1 (GT1) chronic hepatitis C virus infection who have severe renal impairment (pre-dialysis; stage 4 chronic kidney disease) or end-stage renal disease (on hemodialysis; stage 5 chronic kidney disease) with or without compensated cirrhosis.¹ Cohort 1 consists of 20 patients without cirrhosis and cohort 2 will evaluate approximately 20 patients with or without compensated cirrhosis. Ribavirin was started at 200mg once daily for all genotype 1a (GT1a)- infected patients and dosed four hours prior to the start of GT1a patients on hemodialysis. Additional study results, including cohort 2, will be disclosed at future scientific congresses.

About VIEKIRAX® + EXVIERA®
VIEKIRAX + EXVIERA is approved in the European Union for the treatment of genotype 1 (GT1) chronic hepatitis C virus (HCV) infection, including patients with compensated cirrhosis. VIEKIRAX is approved in the European Union for the treatment of genotype 4 (GT4) chronic HCV infection.

VIEKIRAX consists of the fixed-dose combination of paritaprevir 150mg (NS3/4A protease inhibitor) and ritonavir 100mg with ombitasvir 25mg (NS5A inhibitor), dosed once daily, and EXVIERA consists of dasabuvir 250mg (non-nucleoside NS5B polymerase inhibitor) dosed twice daily taken with or without ribavirin (RBV), dosed twice daily based on patient type. VIEKIRAX + EXVIERA is taken for 12 weeks with or without RBV, except in GT1a and GT4 patients with compensated cirrhosis, who should take it for 24 weeks with RBV.

Paritaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for hepatitis C protease inhibitors and regimens that include protease inhibitors. Paritaprevir has been developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of chronic hepatitis C.

Additional information about AbbVie's hepatitis C development program can be found on www.clinicaltrials.gov.

About AbbVie's HCV Clinical Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating interferon-free, all-oral treatments with or without ribavirin with the goal of achieving high sustained virologic response rates in as many patients as possible. AbbVie's global Phase 3b program plans to include more than 2,800 genotype 1 patients in over 200 study centers worldwide, including the U.S., Canada, Europe, Russia and Brazil. Data in patients with severe renal impairment, including patients on hemodialysis, will be presented at ILC. Additionally, AbbVie's Phase 3b HCV program includes studies in patients with decompensated and compensated cirrhosis. Data from these studies will be presented at future scientific congresses.

Additional information about AbbVie's hepatitis C development program can be found on www.clinicaltrials.gov.

VIEKIRAX® + EXVIERA® EU Indication
VIEKIRAX is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults. EXVIERA is indicated in combination with other medicinal products for the treatment of chronic hepatitis C (CHC) in adults.

Important EU Safety Information
Contraindications:
VIEKIRAX + EXVIERA are contraindicated in patients with severe hepatic impairment (Child-Pugh C). Patients taking ethinyl estradiol-containing medicinal products must discontinue them and switch to an alternative method of contraception prior to initiating VIEKIRAX + EXVIERA. Do not give VIEKIRAX with certain drugs that are sensitive CYP3A substrates or strong inhibitors of CYP3A. Do not give VIEKIRAX and EXVIERA with strong or moderate enzyme inducers. Do not give EXVIERA with certain drugs that are strong inhibitors of CYP2C8.

Special warnings and precautions for use:
VIEKIRAX and EXVIERA are not recommended as monotherapy and should be used in combination with other medicinal products for the treatment of hepatitis C infection.

Pregnancy and concomitant use with ribavirin
When VIEKIRAX + EXVIERA are used in combination with ribavirin, women of childbearing potential or their male partners must use an effective form of contraception during the treatment and 6 months after the treatment. Refer to the Summary of Product Characteristics for ribavirin for additional information.

ALT elevations
Transient elevations of ALT to >5x ULN without concomitant elevations of bilirubin occurred in clinical trials with VIEKIRAX + EXVIERA and were more frequent in a subgroup who were using ethinyl estradiol-containing contraceptives.

Use with concomitant medicinal products
Use caution when administering VIEKIRAX with fluticasone or other glucocorticoids that are metabolized by CYP3A4. A reduction in colchicine dosage or interruption in colchicine is recommended in patients with normal renal or hepatic function. VIEKIRAX with or without EXVIERA is expected to increase exposure of statins so certain statins need to be discontinued or dosages reduced. Low dose ritonavir, which is part of VIEKIRAX, may select for PI resistance in HIV co-infected patients without ongoing antiretroviral therapy. HIV co-infected patients without suppressive antiretroviral therapy should not be treated with VIEKIRAX.

Adverse Reactions
Most common (>20 percent) adverse reactions for VIEKIRAX + EXVIERA with RBV were fatigue and nausea.

Full summary of product characteristics is available at www.ema.europa.eu

Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs more than 26,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2014 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

References:
¹ Pockros P, et al. Safety Of Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir For Treating HCV GT1 Infection In Patients With Severe Renal Impairment Or End-stage Renal Disease: The RUBY-I Study. Presented at the 50th International Liver Congress (ILC); April 22-26; Vienna, Austria
² Conway B, et al. MALACHITE-I: Phase 3b Trial Of Ombitasvir/Paritaprevir/R And Dasabuvir +/-Ribavirin Or Telaprevir + Peginterferon/Ribavirin In Treatment-naïve Adults With HCV Genotype 1. Abstract presented at the 50th International Liver Congress (ILC); April 22-26; Vienna, Austria
³ Dore G, et al. MALACHITE-II: Phase 3b Trial Of Ombitasvir/Paritaprevir/R And Dasabuvir + Ribavirin Or Telaprevir + Peginterferon/Ribavirin In Peginterferon/Ribavirin Treatment-experienced Adults With HCV Genotype 1. Abstract presented at the 50th International Liver Congress (ILC); April 22-26; Vienna, Austria
⁴ Dumas E, et al. Phase 3b Studies To Assess Long-term Clinical Outcomes In HCV GT1-infected Patients Treated With Ombitasvir/Paritaprevir/Ritonavir And Dasabuvir With Or Without Ribavirin. Abstract presented at the 50th International Liver Congress (ILC); April 22-26; Vienna, Austria.

SOURCE AbbVie

Merck Announces Presentation of Phase 2 Clinical Trial Results of Investigational Chronic Hepatitis C Therapy Grazoprevir/Elbasvir at the International Liver Congress™ 2015

Results of C-SALVAGE Study Showed High Sustained Virologic Response Rates in Patients Who Failed Prior Combination Therapy with Certain Direct Acting Antiviral (DAA) Agents

Results of C-SWIFT Study Provide Proof-of-Concept for Shorter Than Twelve Weeks Duration of Treatment with Triple-DAA Regimen in Patients with Chronic Hepatitis C Virus (HCV) Genotypes 1 and 3 Infection

Saturday, April 25, 2015 9:00 am EDT

VIENNA – April 25, 2015 – Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of results from two Phase 2 clinical trials evaluating the safety and efficacy of the company’s investigational once-daily treatment regimen of grazoprevir (100mg) and elbasvir (50mg)[1] in adult patients with chronic hepatitis C virus (HCV) infection. Treatment with grazoprevir and elbasvir in combination with ribavirin (RBV) (C-SALVAGE trial) showed high rates of sustained virologic response 12 weeks after the completion of treatment (SVR12) in patients with chronic HCV genotype 1 (GT1) infection with or without liver cirrhosis who previously failed combination therapy with a DAA agent. In addition, final results from the C-SWIFT study evaluating grazoprevir/elbasvir in combination with sofosbuvir 400mg in treatment-naïve patients with or without liver cirrhosis chronically infected with HCV GT1 or GT3 were presented as proof-of-concept for potentially shortening HCV treatment duration below 12 weeks. Data from these studies were presented at The International Liver Congress^TM2015 – the 50^th annual congress of the European Association for the Study of the Liver.

“We continue to advance our Phase 3 clinical program for grazoprevir/elbasvir evaluating diverse patient populations with chronic HCV infection, including those widely considered among the most difficult to treat,” said Dr. Eliav Barr, vice president, infectious diseases, Merck Research Laboratories. “Findings from these Phase 2 studies formed part of the basis for our decision to rapidly advance our large and comprehensive clinical development program that incorporates studies dedicated to patient populations with specific unmet medical needs.”

C-SALVAGE Overview and Findings

C-SALVAGE (Abstract #O001) is a Phase 2, single arm, open label clinical trial conducted to evaluate the efficacy and safety of 12 weeks of treatment with grazoprevir and elbasvir plus RBV in patients with chronic HCV GT1 infection who have previously failed treatment with peginterferon and RBV combined with a DAA (boceprevir, simeprevir or telaprevir). Of the 79 patients who received one or more doses of grazoprevir and elbasvir, 43 percent had liver cirrhosis.

Following 12 weeks of treatment with a combination of grazoprevir and elbasvir plus RBV, 96 percent of the patients (76/79) with chronic HCV GT1 infection who had failed prior treatment with specified DAA-based regimens achieved SVR12. Ninety four percent (32/34) of patients with compensated cirrhosis achieved SVR12. Virologic failure was reported for three patients in the trial. All three patients had resistance associated variants at baseline and relapsed after completion of study treatment.

The most common adverse events included fatigue (28%), headache (19%), asthenia (15%) and nausea (12%). Five serious adverse events were reported, none of which were considered related to study drug. One patient discontinued treatment due to an adverse event that was not considered to be drug-related. Detailed findings of the study were recently posted online in the “Articles in Press” section of the Journal of Hepatology, the official journal of the European Association for the Study of the Liver.

C-SWIFT Overview and Findings

C-SWIFT (Abstract #O006) is a proof-of-concept Phase 2 open label clinical trial conducted to evaluate the efficacy and safety of grazoprevir/elbasvir plus sofosbuvir over shorter treatment durations. Specifically, treatment-naïve patients with or without liver cirrhosis chronically infected with HCV GT1 were treated for 4, 6 or 8 weeks and treatment-naïve patients with or without liver cirrhosis chronically infected with HCV GT3 were treated for 8 or 12 weeks. Interim findings were previously presented at the 65^th American Association for the Study of Liver Diseases in November 2014.

SVR12 results by treatment arm in the modified intent to treat population are shown above (table 1). Among GT1 patients, virologic relapse occurred in 20 non-cirrhotic patients receiving four weeks of treatment, in four non-cirrhotic and four cirrhotic patients receiving six weeks of treatment, and in one cirrhotic patient receiving eight weeks of treatment. Among GT3 patients, virologic relapse occurred in one non-cirrhotic patient receiving eight weeks of treatment, and in one cirrhotic patient receiving 12 weeks of treatment. There were no reported cases of virologic breakthrough.

No patients discontinued due to treatment-related adverse events. The most common adverse events reported across all treatment groups and genotypes were headache (4% overall, range 2-8% across treatment arms), fatigue (2% overall, range 0-8% across treatment arms) and nausea (2% overall, range 2-8% across treatment arms). Two serious adverse events – pyelonephritis and B-cell lymphoma – were reported but were not considered to be related to study medicine.

About Grazoprevir/Elbasvir

Grazoprevir/elbasvir is an investigational, once-daily single tablet regimen consisting of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A replication complex inhibitor). As part of Merck’s broad clinical trials program, grazoprevir/elbasvir is being studied in multiple HCV genotypes and in patients with difficult-to-treat conditions such as HIV/HCV co-infection, advanced chronic kidney disease, inherited blood disorders, liver cirrhosis and those on opiate substitution therapy.

Merck’s Commitment to HCV

For nearly 30 years, Merck has been at the forefront of the response to the HCV epidemic. Merck employees are dedicated to applying their scientific expertise, resources and global reach to deliver innovative health care solutions that support people living with HCV worldwide.

About Merck

Today’s Merck is a global health care leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise except as required by applicable law. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2014 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

[1] Grazoprevir is a HCV NS3/4A protease inhibitor and elbasvir is a HCV NS5A replication complex inhibitor

CONTACTS:

Merck Media: Doris Li (908) 246-5701

Sarra Herzog (201) 669-6570

Investor: Joe Romanelli (908) 740-1986

Justin Holko (908) 740-1879

Source

ALLY-1 Trial Results Show Investigational Daclatasvir-Based Regimen Cures 94% of Post-Liver Transplant Patients with Hepatitis C and Up to 94% of Hepatitis C Patients with Cirrhosis (Child-Pugh Class A or B)

97% of post-transplant patients with HCV genotype 1a achieved cure

91% of post-transplant patients with HCV genotype 3 achieved cure

No need seen to alter existing transplantation medication regimens

Saturday, April 25, 2015 10:00 am EDT

Dateline:

PRINCETON, N.J., APRIL 25, 2015

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(PRINCETON, N.J., APRIL 25, 2015) – Bristol-Myers Squibb Company (NYSE:BMY) today announced that primary endpoints were successfully met in ALLY-1, a Phase III clinical trial evaluating a 12-week regimen of daclatasvir and sofosbuvir once-daily with ribavirin for the treatment of patients with chronic hepatitis C virus (HCV) with either advanced cirrhosis or post-liver transplant recurrence of HCV. The data was presented as a late-breaker at The International Liver Congress™ 2015, the 50^th annual meeting of the European Association for the Study of the Liver (EASL) in Vienna, Austria from April 22-26.

“The results of the ALLY-1 trial point to the potential of this investigational daclatasvir-based regimen in a patient population with high unmet needs despite recent advances in hepatitis C treatment,” said Fred Poordad, M.D., ALLY-1 Lead Investigator and Clinical Professor of Medicine at The University of Texas Health Science Center at San Antonio. “Transplant patients take a variety of immunosuppressive medications to prevent organ rejection; that complicates the treatment of hepatitis C. In ALLY-1, we saw no drug-drug interactions between transplant and hepatitis C therapies and no need to make dose adjustments to patients’ transplant-related drugs while they received the daclatasvir-based regimen that resulted in high SVR12 rates.”

The study’s primary endpoints were reached, with 95% of post-transplant genotype 1 patients and 82% of genotype 1 patients with advanced cirrhosis achieving SVR12. Among all ALLY-1 patients, 94% of those with post-transplant HCV recurrence and 83% of all participants with advanced cirrhosis achieved cure (sustained virologic response 12 weeks after treatment; SVR12).

The Child-Pugh scoring system is commonly used to assess the severity and prognosis of chronic liver disease and cirrhosis, and uses an A through C classification (C being the most advanced) to categorize disease progression. Patients with class C cirrhosis are decompensated, often with later-stage conditions such as ascites (the build-up of fluid in the abdomen), hepatic encephalopathy (confusion or altered level of consciousness due to the liver’s inability to remove toxins from the blood), and abnormal liver function, which can complicate treatment. The ALLY-1 trial included 16 patients with decompensated cirrhosis Child-Pugh class C; nine (56%) achieved SVR12.

Over the course of the study, four advanced cirrhotic patients received a liver transplant during treatment; 3 of 4 extended treatment post-transplant (see study design below), and all 4 achieved SVR12.

In the study, there were no serious adverse events related to study medications throughout the treatment phase. The most common adverse events (≥10%) were headache (15%, 36%), fatigue (18%, 28%), anemia (20%, 19%), diarrhea (8%, 19%), nausea (17%, 6%), and arthralgia (2%, 13%) in the advanced cirrhotic and post-transplant cohorts, respectively. One patient discontinued therapy after 31 days due to headache, but still achieved SVR12. Nine patients in the cirrhosis cohort relapsed post-treatment, and one had detectable HCV RNA at the end of treatment; there were no on-treatment virologic breakthroughs. Three patients (genotypes 1a, 1b, 3) in the post-transplantation cohort relapsed. All 12 patients with relapse are being retreated with daclatasvir and sofosbuvir with ribavirin for 24 weeks.

HCV is the leading indication for liver transplantation worldwide. Without treatment, HCV infection of the new liver after transplant is inevitable, and is associated with rapid progression to cirrhosis and death in up to 30% of patients within 5 years. The ALLY-1 study is the third study to report out of the Phase III ALLY program, which evaluates daclatasvir in combination with sofosbuvir in multiple high-unmet need patient populations and is at the center of Bristol-Myers Squibb’s HCV research focus. The ALLY-2 and ALLY-3 studies have previously been presented at the 2015 Conference for Retroviral and Opportunistic Infections and the 2014 American Association for the Study of the Liver’s The Liver Meeting, respectively, and subanalyses from each study with the ribavirin-free regimen of daclatasvir and sofosbuvir were presented as posters during EASL 2015.

Additionally, EASL issued 2015 Hepatitis C treatment guidelines that include a regimen of daclatasvir+sofosbuvir as the first 12-week treatment for patients with genotype-3 virus. The EASL guidelines now list daclatasvir+sofosbuvir regimens as options for treating all HCV genotypes and for use with patients coinfected with HCV/HIV. (Guidelines available here.)

Other Bristol-Myers Squibb presentations at The International Liver Congress included data from compassionate use programs in the EU that add to the real-world clinical evidence informing the use of daclatasvir-based regimens to treat patients with HCV conditions posing high unmet medical needs.

“The ALLY-1 trial results build off the ALLY-2 and ALLY-3 studies by demonstrating the versatility of the daclatasvir-based regimen to provide HCV cure in multiple patient populations that have been historically hard to manage, such as HCV genotype 3 patients, HIV/HCV coinfected patients, and patients with decompensated cirrhosis,” said Douglas Manion, M.D., Head of Specialty Development, Bristol-Myers Squibb. “Post-liver transplant and cirrhotic patients represent a still-unmet need and continue to present challenges to currently available regimens.”

About ALLY-1: Study Design

This Phase III open-label clinical trial enrolled treatment-naïve and treatment-experienced patients with HCV infection of any genotype in 2 cohorts: advanced cirrhosis (n=60) and post-liver transplant with HCV recurrence (n=53). All patients received daclatasvir 60 mg plus sofosbuvir 400 mg once-daily with ribavirin initially dosed at 600 mg/d (with potential for adjustment based on hemoglobin levels and creatinine clearance) for 12 weeks. Patients receiving a variety of immunosuppressive agents were permitted. In the cirrhosis cohort, patients transplanted during treatment could receive 12 weeks of extended treatment immediately post-transplant, regardless of treatment duration before transplant. The primary endpoint was the SVR12 rate (defined as HCV RNA <LLOQ (25 IU/mL) at post-treatment week 12) among genotype 1 patients in each cohort.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. Approximately 170 million people worldwide are infected with hepatitis C. Up to 90 percent of those infected with hepatitis C will not spontaneously clear the virus and will become chronically infected. According to the World Health Organization, up to 20 percent of people with chronic hepatitis C will develop cirrhosis; of those, up to 20 percent may progress to liver cancer.

About Bristol-Myers Squibb’s HCV Portfolio

Bristol-Myers Squibb’s research efforts are focused on advancing late-stage compounds to deliver the most value to patients with hepatitis C. At the core of our pipeline is daclatasvir, a NS5A complex inhibitor which continues to be investigated in multiple treatment regimens and in patients with co-morbidities.

Daclatasvir was approved in Europe in August 2014 for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic hepatitis C virus (HCV) infection in adults. Beyond Europe, it is approved in Japan, as well as multiple countries in Latin and South America, the Middle East and Asia Pacific. Additionally, the U.S. FDA currently is reviewing a New Drug Application (NDA) for the use of daclatasvir and sofosbuvir to treat patients with HCV genotype 3.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that daclatasvir will receive regulatory approval in the United States, or if approved, that it will become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Contact:

Media:
Robert Perry, Office: 609-419-5378, Cell: 407-492-4616, rob.perry@bms.com

Investors:
Ranya Dajani, 609-252-5330, ranya.dajani@bms.com

Source

Gilead Announces Results From Studies Evaluating Sofosbuvir-Based Regimens in Chronic Hepatitis C Patients With Genotypes 2-5

-- High Cure Rates Observed Across a Range of Genotypes --

VIENNA, Austria--(BUSINESS WIRE)--Apr. 25, 2015-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from two studies evaluating the safety and efficacy of investigational uses of sofosbuvir-based regimens in chronic hepatitis C virus (HCV)-infected patients with genotypes 2, 3, 4 and 5. Results from the BOSON study of Sovaldi^® (sofosbuvir 400 mg) in combination with ribavirin (RBV) or with pegylated interferon (PEG)/RBV demonstrated high cure rates across all patients with genotypes 2 and 3. Separately, results from a Phase 2 study demonstrate the safety and efficacy of Harvoni^® (ledipasvir 90 mg/sofosbuvir 400 mg) in patients with genotypes 4 or 5 infection. Data from both studies will be presented in oral sessions at the 50th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress™ 2015) in Vienna, Austria.

Sovaldi and Harvoni are each approved in the United States for the treatment of chronic HCV infection. Sovaldi is used in combination with other agents and its efficacy has been established in patients with genotypes 1-4; Harvoni is indicated for patients with genotype 1.

BOSON (Study GS-US-334-0153, #LB05), a randomized Phase 3 study of 592 patients, evaluated the safety and efficacy of Sovaldi plus RBV for 16 or 24 weeks compared with Sovaldi plus PEG/RBV for 12 weeks among treatment-naïve or treatment-experienced genotype 3 patients with and without cirrhosis and treatment-experienced genotype 2 patients with cirrhosis. Thirty-seven percent of study participants had cirrhosis.

Among genotype 3 patients, rates of sustained virologic response 12 weeks after treatment (SVR12) were highest among those receiving Sovaldi plus PEG/RBV for 12 weeks (93 percent, n=168/181), compared to those receiving Sovaldi plus RBV for 24 weeks (84 percent, n=153/182) or for 16 weeks (71 percent, n=128/181). Treatment-experienced genotype 3 patients with cirrhosis receiving Sovaldi plus PEG/RBV demonstrated SVR12 rates of 86 percent (30/35).

Genotype 2 patients also demonstrated high SVR12 rates across all treatment arms. SVR12 rates among patients receiving Sovaldi plus PEG/RBV were 94 percent (15/16), and 100 percent (17/17) and 87 percent (13/15) for those receiving Sovaldi plus RBV for 24 and 16 weeks, respectively.

Sovaldi plus PEG/RBV and Sovaldi plus RBV were well tolerated. The most common adverse events in the study were fatigue, headache, insomnia and nausea. Overall, six patients (1 percent) discontinued treatment due to adverse events, one of whom was treated with Sovaldi plus PEG/RBV.

“It remains difficult to achieve a virological response in genotype 3, which is one of the most prevalent genotypes in the world, with higher prevalence in Europe and Asia,” said Graham R. Foster, FRCP, PhD, Professor of Hepatology, The Liver Unit, Queen Mary's University of London, Barts Health, London, United Kingdom. “These results are compelling because they represent the highest cure rates observed among treatment-experienced, cirrhotic genotype 3 patients in any Phase 3 clinical trial to date.”

In a separate open-label Phase 2 study of Harvoni conducted in France (Study GS-US-337-1119, O056), results demonstrated high SVR rates in both treatment-naïve and treatment-experienced patients with chronic HCV genotypes 4 or 5 infection, 50 percent of whom had cirrhosis.

Ninety-three percent of patients with genotype 4 (41/44) and 95 percent of patients with genotype 5 (39/41) achieved SVR12. Response rates were similar among both treatment-naïve and -experienced patients and regardless of cirrhosis.

The most common adverse events (affecting more than 10 percent of patients) were asthenia, headache and fatigue. Most adverse events were mild or moderate in severity and none resulted in treatment discontinuation. There were no grade 3 or 4 clinical laboratory abnormalities.

“HCV genotype 4 and 5 are less prevalent than other genotypes and therefore, have traditionally not been closely studied,” said Armand Abergel, MD, PhD, Department of Hepatology and Gastroenterology, Centre Hospitalier Universitaire-Estaing, Université d'Auvergne, Clermont-Ferrand, France. “These data provide important evidence that the all-oral, ribavirin-free Harvoni regimen is both safe and effective for many patients with genotype 4 or 5, regardless of prior treatment experience.”

The safety and efficacy of these investigational uses of Harvoni and Sovaldi have not been established.

Important Safety Information About Sovaldi

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

Serious Symptomatic Bradycardia When Coadministered with Amiodarone and Another HCV Direct Acting Antiviral (DAA): Amiodarone is not recommended for use with Sovaldi in combination with another DAA due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

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.

Important Safety Information About Harvoni

Warnings and Precautions

Risk of Serious Symptomatic Bradycardia When Coadministered with Amiodarone: Amiodarone is not recommended for use with Harvoni due to the risk of symptomatic bradycardia, particularly in patients also taking beta blockers or with underlying cardiac comorbidities and/or with advanced liver disease. In patients without alternative, viable treatment options, cardiac monitoring is recommended. Patients should seek immediate medical evaluation if they develop signs or symptoms of bradycardia.

Risk of Reduced Therapeutic Effect of Harvoni Due to P-gp Inducers: Rifampin and St. John’s wort are not recommended for use with Harvoni as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations.

Related Products Not Recommended: Harvoni is not recommended for use with other products containing sofosbuvir (Sovaldi).

Adverse Reactions

Most common (≥10 percent, all grades) adverse reactions were fatigue and headache.

Drug Interactions

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

Coadministration of Harvoni is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.

Consult the full Prescribing Information for Harvoni for more information on potentially significant drug interactions, including clinical comments.

About Gilead

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. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

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 risk that Gilead may observe unfavorable results from additional clinical trials involving Sovaldi and Harvoni for various patient populations, including those with genotype 2, 3, 4 and 5 HCV. 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, 2014, 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 and Harvoni is available at www.gilead.com.

Sovaldi and Harvoni are registered trademarks of Gilead Sciences, Inc., or its related companies.

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.
Sung Lee, +1 650-524-7792 (Investors)
Nathan Kaiser, +1 650-522-1853 (Media)
Michele Rest, +1 650-577-6935 (Media)

Source

Cancer rates among patients with hepatitis C are increased compared to those not infected

Public Release: 24-Apr-2015

Researchers suggest an extrahepatic manifestation of hepatitis C may be an increased risk of cancer

European Association for the Study of the Liver

April 24, 2015, Vienna , Austria: Results announced today at The International Liver CongressTM 2015 show that cancer rates in patients with the hepatitis C virus (HCV) were significantly increased compared to the non-HCV cohort. The researchers suggest an extrahepatic manifestation of HCV may be an increased risk of cancer.

The aim of the study was to describe the rates of all cancers in the cohort of HCV patients compared to the non-HCV population. Known cancer types associated with hepatitis C include non-Hodgkin's lymphoma, renal and prostate cancers, as well as liver cancer.

A retrospective study at Kaiser Permanente, Southern California, USA, was conducted. The study authors recorded all cancer diagnoses in patients over 18 years of age with or without HCV during 2008-2012. Within the timeframe of the study 145,210 patient years were included in the HCV cohort, and 13,948,826 patient years were included in the non-HCV cohort.

In the HCV cohort there were 2,213 cancer diagnoses (1,524/100,000) during the 5-year period and 1,654 cancer diagnoses when liver cancer was excluded (1,139/100,000). In the non-HCV cohort there were 84,419 cancer diagnoses (605/100,000) during the same 5-year period and 83,795 (601/100,000) when liver cancer was excluded. When all cancers are considered the rate is 2.5 times higher in the HCV cohort; when liver cancers are excluded, the rate is still almost 2 times higher.

Lisa Nyberg, MD, MPH, Kaiser Permanente, Southern California, senior author of the study, explains: "The results suggest that cancer rates are increased in the cohort of hepatitis C patients versus the non-hepatitis C patients, both including and excluding liver cancers. These findings certainly point to the suggestion that hepatitis C may be associated with an increased risk of cancer. However, the findings must be interpreted with caution, as the study also showed that confounding factors such as alcohol abuse, tobacco, obesity, and diabetes modified the results."

Dr Laurent Castera, Vice-Secretary, European Association for the Study of the Liver, commented: "This data adds to the evidence bank linking hepatitis C with an increased risk of cancer, and highlights that there is still a long way to go in order to fully understand this complex and devastating disease."

###

About The International Liver Congress™

This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Specialists share research studies and findings, and discuss the hottest topics related to liver disease. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. 2015 is a very special year for EASL and the hepatology community as they will celebrate the 50th annual meeting. The International Liver Congress™ takes place from April 22-26, 2015, Vienna, Austria.

About EASL

Since EASL's foundation in 1966, this not-for-profit organisation has grown to over 4,000 members from more than 100 countries around the world. EASL is the leading liver association in Europe, it attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

Contact

For more information, please contact the ILC Press Office at:

ilc.press@easloffice.eu or
+44 (0)20 3580 5444

INCREASED CANCER RATES IN PATIENTS WITH CHRONIC HEPATITIS C: AN ANALYSIS OF THE CANCER REGISTRY IN A LARGE U.S. HEALTH MAINTENANCE ORGANIZATION

Anders H. Nyberg* 1, Joanie W. Chung2, Jiaxiao M. Shi3, T. C. Cheetham3, Kevin M. Chiang4, Reina Haque5, Zobair M. Younossi6, Lisa M. Nyberg1

1Gastroenterology/Hepatology, Kaiser Permanente, San Diego, 2Kaiser Permanete, Research and Evaluation, 3Research and Evaluation, Kaiser Permanente, Pasadena, 4Pharmacy Analytical Services, Kaiser Permanente, Downey, 5Research and Evaluatuion, Kaiser Permanente, Pasadena, 6Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, United States

Background and Aims: Hepatitis C virus (HCV) is an oncogenic virus, and an increased risk of malignancy in HCV has previously been reported. Cancer types associated with HCV include non-Hodgkin's lymphoma, renal and prostate cancers; as well as liver cancer. The aim of this study was to describe cancer rates in our cohort of HCV patients compared to cancer rates in the non-HCV population.

Methods: This is a retrospective study at Kaiser Permanente Southern California (KPSC), a large health maintenance organization with 3.5-4 million members. The KPSC cancer registry is an accredited program maintaining a complete profile of all cancer diagnoses for all KP members. In this study, we recorded all cancer diagnoses in patients ?18 years of age with or without HCV during 2008-2012.

Results: From 2008 to 2012, 145,210 patient years were included in the HCV cohort, and 13,948,826 patient years were included in the non HCV cohort. Mean age at cancer diagnosis in the HCV cohort was 61.8 years, in the non-HCV cohort, 63.5 years. In the HCV cohort there were 2,213 cancer diagnoses (1524/100000) during the 5 year period and 1,654 cancer diagnoses when liver cancer was excluded (1139/100000). In the non HCV cohort there were 84,419 cancer diagnoses (605/100000) during the same 5 year period and 83,795 (601/100000) when liver cancer was excluded. The rate ratios between the HCV and non HCV cohorts for the total number of cancer cases including and excluding liver cancer are shown in Table 1.

Conclusions: In our cohort of Hepatitis C infected patients, cancer rates were significantly increased compared to the non-HCV cohort. This suggests that another extrahepatic manifestation of HCV may be an increased risk of cancer.

Source

April 24, 2015

EMA recommends avoidance of certain hepatitis C medicines and amiodarone together

Press Release

24/04/2015

Concomitant use may increase risk of slow heart rate and related problems

The European Medicines Agancy (EMA) has confirmed a risk of severe bradycardia (slow heart rate) or heart block (problems with conduction of electrical signals in the heart) when the hepatitis C medicines Harvoni (sofosbuvir with ledipasvir) or a combination of Sovaldi (sofosbuvir) and Daklinza (daclatasvir) are used in patients who are also taking the medicine amiodarone, which is an antiarrhythmic (a medicine used to treat irregular heartbeat).

To manage this risk the Agency recommends that amiodarone should only be used in patients taking these hepatitis C medicines if other antiarrhythmics cannot be given. If concomitant use with amiodarone cannot be avoided, patients should be closely monitored. Because amiodarone persists for a long time in the body, monitoring is also needed if patients start such hepatitis C treatments within a few months of stopping amiodarone.

The recommendations follow a review¹ of cases of severe bradycardia or heart block in patients taking amiodarone who started treatment with the hepatitis C combinations. It was considered that there was a likely relationship of these events to the medicines. The possible mechanism behind these effects is unknown and further investigation of other cases with Sovaldi and other hepatitis C medicines is ongoing.

Information for patients

A few cases of severe slow heart rate or interference with electrical signals in the heart have been reported in patients taking the medicines Harvoni or Sovaldi plus Daklinza (used to treat hepatitis C, a liver infection) at the same time as the heart medicine amiodarone.
Most of these cases occurred within 24 hours of starting the hepatitis C medicine but some occurred after up to 12 days. Two of the patients needed treatment with a pacemaker and one patient died.
Patients who need these hepatitis C combinations should not also be given amiodarone unless there is no other suitable alternative.
If there is no alternative to giving amiodarone at the same time as the hepatitis C medicine, patients’ heart function must be carefully monitored by the doctor. This may include monitoring in hospital for 48 hours after starting treatment.
Because amiodarone remains in the body for a long time, monitoring is also needed when the hepatitis C treatment is given to patients who stopped amiodarone treatment within the last few months.
Patients who are taking Harvoni or Sovaldi and Daklinza at the same time as amiodarone, with or without other heart medicines, and who experience symptoms such as slow heartbeat, dizziness, faintness, unusual tiredness, shortness of breath or chest pain during treatment should contact their doctor immediately.
Patients who have any concerns about their treatment should discuss them with their doctor or pharmacist.

Information for healthcare professionals

Severe bradycardia and heart block have been reported in patients taking amiodarone and Harvoni, or amiodarone and a combination of Sovaldi and Daklinza. Of 8 cases reviewed up to April 2015, one case resulted in fatal cardiac arrest and two required pacemaker intervention.
Onset of bradycardia was within 24 hours of initiating hepatitis C treatment in 6 cases and within 2 to 12 days in the other 2 cases. Rechallenge in the context of continued amiodarone treatment resulted in recurrence of symptomatic bradycardia in 2 cases. Recurrence was also seen on rechallenge with the antivirals 8 days after stopping amiodarone, but not 8 weeks after stopping.
Amiodarone should only be initiated in patients treated with Harvoni, or Sovaldi plus Daklinza, if other antiarrhythmics are contra-indicated or not tolerated.
If concomitant use with amiodarone is unavoidable, patients should be closely monitored, particularly during the first weeks of treatment. Those at high risk of bradyarrhythmia should be monitored in an appropriate clinical setting for 48 hours after starting concomitant treatment.
Due to its long half-life, patients who have discontinued amiodarone within the past few months should also be monitored when starting hepatitis C treatment with Harvoni or Sovaldi plus Daklinza.
Patients receiving these hepatitis C medicines with amiodarone, with or without other medicines that lower heart rate, should be warned of the symptoms of bradycardia and heart block and should be advised to seek urgent medical advice if they experience them.

The product information for Harvoni, Sovaldi and Daklinza will be updated appropriately. A letter will also be sent to healthcare professionals involved in hepatitis C treatment explaining these risks and the measures to manage them.

Because the number of patients taking amiodarone who have been exposed to Harvoni or Sovaldi in combination with Daklinza is unknown, it is not possible to estimate the incidence of occurrence of these events. The mechanism behind the findings has not been established.

More about the medicine

Harvoni, Sovaldi and Daklinza are among several novel hepatitis C treatments recently evaluated by EMA, which are available as tablets. They have simplified the management of the disease and allow the prospect of curing the infection. Sovaldi (sofosbuvir) was authorised in the EU in January 2014, Daklinza (dataclasvir) in August 2014 and Harvoni (sofosbuvir/ledipasvir) in November 2014.

The active substance sofosbuvir blocks the action of an enzyme called ‘NS5B RNA-dependent RNA polymerase’, while dataclasvir and ledipasvir target a protein called ‘NS5A’; by blocking these targets the medicines stop the hepatitis C virus from multiplying and infecting new cells.

¹The review was in the context of a “safety signal”. A safety signal is information on a new or incompletely documented adverse event that is potentially caused by a medicine and that warrants further investigation. The presence of a safety signal does not necessarily mean that a medicine has caused the reported adverse event.

Source

Merck’s Pivotal Phase 3 C-EDGE Program Evaluating Grazoprevir/Elbasvir Shows High Sustained Virologic Responses Across Broad Range of Patients with Chronic Hepatitis C Virus Infection

Data Sets Include Treatment-Naïve, Treatment-Experienced and HIV Co-Infected Patients with Chronic Hepatitis C Virus Genotypes 1, 4 or 6 Infection

Merck Remains on Track to Submit New Drug Application (NDA) to U.S. Food and Drug Administration (FDA) in First Half of 2015

Friday, April 24, 2015 1:00 am EDT

VIENNA--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the first presentations of data from the company’s ongoing C-EDGE pivotal Phase 3 clinical trial program evaluating the investigational once-daily tablet grazoprevir/elbasvir (100mg/50mg) in patients with or without cirrhosis who are infected with chronic hepatitis C virus (HCV) genotypes 1, 4 or 6 (GT1, 4 or 6).¹ Patients in both the HCV infected, treatment-naïve (C-EDGE TN), and HIV/HCV co-infected, treatment-naïve (C-EDGE CO-INFXN) trials treated for 12 weeks achieved rates of sustained virologic response 12 weeks after the completion of treatment (SVR12) of 95 percent (299/316 and 207/218, respectively). In addition, HCV infected, treatment-experienced patients (C-EDGE TE) treated with or without ribavirin (RBV) for 12 weeks achieved SVR12 rates of 94 percent (98/104) and 92 percent (97/105), respectively, and those treated for 16 weeks achieved SVR12 rates of 97 percent (103/106) and 92 percent (97/105), respectively. These data were presented at The International Liver Congress^TM2015 – the 50^th annual congress of the European Association for the Study of the Liver (Abstract #G07, E-Poster P0886 and E-Poster P0887). A paper detailing the findings of C-EDGE TN was published online in the Annals of Internal Medicine today.

“Patients with co-morbidities and varying treatment experiences represent important segments of the chronic hepatitis C population in need of additional innovative treatment options,” said Dr. Eric Lawitz, vice president, scientific and research development, The Texas Liver Institute and clinical professor of medicine, The University of Texas Health Science Center, San Antonio. “These findings are important because they demonstrate that a single pill of grazoprevir/elbasvir taken once-daily achieved consistently high rates of SVR12 in the patient populations studied.”

“At Merck, we continue to build upon our clinical experience using grazoprevir/elbasvir across diverse populations of patients infected with chronic hepatitis C virus,” said Dr. Eliav Barr, vice president, infectious diseases, Merck Research Laboratories. “We remain on track to submit a New Drug Application with the U.S. Food and Drug Administration in the first half of 2015.”

C-EDGE TN Overview and Additional Findings

C-EDGE TN is a randomized, blinded, placebo-controlled trial evaluating the efficacy and safety of grazoprevir/elbasvir in treatment-naïve patients with or without cirrhosis infected with chronic HCV GT1, 4 or 6 who received therapy for 12 weeks. Patients were randomized to an immediate treatment group that received grazoprevir/elbasvir for 12 weeks or to a deferred treatment group that received placebo for 12 weeks, were followed for an additional four weeks, and then received open label grazoprevir/elbasvir for the next 12 weeks. The primary efficacy analysis included those patients who received immediate treatment with grazoprevir/elbasvir or placebo. Of the 316 patients who received immediate treatment with grazoprevir/elbasvir, 50 percent were infected with GT1a, 42 percent with GT1b, six percent with GT4 and three percent with GT6. Overall, 22 percent of patients had liver cirrhosis.

In this study, virologic failure occurred in 13 patients (4%) in the immediate treatment group, including one virologic breakthrough and 12 virologic relapses. Serious adverse events occurred in nine (3%) and three (3%) patients in the immediate treatment and corresponding placebo arms, respectively; none were considered drug-related. The most common adverse events reported (greater than 5% incidence) in the immediate treatment and corresponding placebo groups, were headache (17%, 18%), fatigue (16%, 17%), nausea (9%, 8%) and arthralgia (6%, 6%), respectively.

C-EDGE CO-INFXN Overview and Additional Findings

C-EDGE CO-INFXN is an open label, single-arm study evaluating the efficacy and safety of grazoprevir/elbasvir in treatment-naïve patients with or without cirrhosis infected with chronic HCV GT1, 4 or 6 and HIV who received therapy for 12 weeks. Of the 218 patients enrolled in the trial, 66 percent were infected with HCV GT1a, 21 percent with GT1b or other GT1, 13 percent with GT4, and one percent with GT6. Overall, 16 percent of patients had liver cirrhosis.

In this study, virologic failure occurred in seven patients (3%), including six virologic relapses and one reinfection. There were no reported drug-related serious adverse events. The most common (greater than 5% incidence) adverse events reported were fatigue (13%), headache (12%) and nausea (9%).

C-EDGE TE Overview and Additional Findings

C-EDGE TE is a randomized study evaluating the efficacy and safety of once-daily grazoprevir/elbasvir with or without twice-daily RBV in treatment-experienced (prior null response, partial response or relapse with peg-interferon/RBV) patients with or without cirrhosis infected with chronic HCV GT1, 4 or 6 who received therapy for 12 weeks or 16 weeks.

12 week arms

Of the 209 patients randomized to the 12 week arms, 105 patients received grazoprevir/elbasvir only and 104 patients received grazoprevir/elbasvir plus RBV. Patients in the grazoprevir/elbasvir only arm comprised 58 percent GT1a, 33 percent GT1b or other GT1 and nine percent GT4. Overall, 35 percent had liver cirrhosis. Among the 104 patients receiving grazoprevir/elbasvir plus RBV, 58 percent were infected with chronic HCV GT1a, 28 percent GT1b or other GT1, and 14 percent GT4. Overall, 34 percent had liver cirrhosis.

In the grazoprevir/elbasvir only and grazoprevir/elbasvir plus RBV arms, six patients in each arm (6%) were reported to have virologic relapse. No patients were reported to have virologic breakthrough or rebound. Serious adverse events were reported in four patients in the grazoprevir/elbasvir only arm (4%) and three patients in the grazoprevir/elbasvir plus RBV arm (3%). The most common (greater than 10% incidence) adverse events reported in the grazoprevir/elbasvir and grazoprevir/elbasvir plus RBV arms, respectively, were fatigue (19%, 27%), headache (21%, 20%) and nausea (9%, 14%).

16 week arms

Of the 211 patients enrolled in the 16 week arms, 105 patients received grazoprevir/elbasvir only and 106 patients received grazoprevir/elbasvir plus RBV. In the grazoprevir/elbasvir only arm, 46 percent were infected with chronic HCV GT1a, 46 percent with GT1b or other GT1, five percent with GT4 and four percent with GT6. Overall, 36 percent of patients had liver cirrhosis. Among those in the grazoprevir/elbasvir plus RBV arm, 55 percent were infected with chronic HCV GT1a, 36 percent with GT1b or other GT1, eight percent with GT4, and two percent with GT6. Overall, 35 percent had liver cirrhosis.

Among the patients receiving grazoprevir/elbasvir only, three patients (3%) were reported to have virologic breakthrough or rebound and four patients (4%) were reported to have virologic relapse. No virologic failures occurred in patients receiving grazoprevir/elbasvir plus RBV. Serious adverse events were reported in three patients in the grazoprevir/elbasvir only arm (3%) and four patients in the grazoprevir/elbasvir plus RBV arm (4%). The most common (greater than 10% incidence) adverse events reported in the grazoprevir/elbasvir and grazoprevir/elbasvir plus RBV arms, respectively, were fatigue (16%, 30%), headache (19%, 19%) and nausea (4%,17%).

About the C-EDGE Program

C-EDGE is the Phase 3 clinical development program for Merck’s investigational HCV treatment grazoprevir/elbasvir comprising five studies with more than 1,700 patients across more than 25 countries. These studies are evaluating grazoprevir/elbasvir in multiple genotypes (GT1, 4 and 6) and diverse patient populations, including difficult-to-treat patients such as: treatment-experienced, patients with cirrhosis, HIV/HCV co-infection, advanced chronic kidney disease, inherited blood disorders, and those receiving opiate substitution therapies.

Merck’s Commitment to HCV

About Merck

Forward-Looking Statement

¹ Grazoprevir is an HCV NS3/4A protease inhibitor and elbasvir is an HCV NS5A replication complex inhibitor

Contact:

Merck
Media:
Doris Li , 908-246-5701
or
Sarra Herzog, 201-669-6570
or
Investors:
Joe Romanelli, 908-740-1986
or
Justin Holko, 908-740-1879

Source

Gilead uses Georgia as free-drug testbed for hepatitis C elimination

Provided by Reuters

Health | Wed Apr 22, 2015 11:58am EDT

Gregg Alton, Gilead's executive vice president, corporate and medical affairs, speaks with the media during a news conference in New Delhi September 15, 2014.

LONDON | By Ben Hirschler

LONDON (Reuters) - Gilead Sciences is seeking to convince governments and multilateral agencies worldwide that hepatitis C can be eliminated with a demonstration project in Georgia offering free drugs to all those who need them.

The unprecedented program will make the Caucasian country a testbed for uprooting the liver-destroying disease, using Gilead's highly effective but costly pill Sovaldi, plus its newer product Harvoni once approved.

Georgia has the world's third highest prevalence of hepatitis C, after Egypt and Mongolia, with nearly 7 percent of adults carrying the virus. It also has a wide range of viral variations and different types of patients.

What is more, the country is a manageable size, with a population of around 5 million, and has viral screening systems, making it ideal for scientific study, according to Gregg Alton, the U.S. drugmaker's head of corporate and medical affairs.

"It is a nice country for us to evaluate," he said in a telephone interview on Wednesday from the European Association for the Study of the Liver annual meeting in Vienna.

The scheme, which has the backing of the U.S. Centers for Disease Control and Prevention, will cover an initial 5,000 patients in 2015, with a second phase treating up to 20,000 a year.

Gilead's hepatitis C drugs, and rival products from the likes of AbbVie, can cure hepatitis C but are out of reach at Western prices to patients in poor countries, with a single Sovaldi pill costing $1,000 in the United States.

While Gilead has slashed the price for several low-income countries to $300 per bottle of 28 pills, it also wants to involve international donors in a broad eradication drive.

"We will take the Georgia data to other countries around the world to really make the case that investment can fundamentally change the disease over time," Alton said.

Alton admits the scheme may prompt other governments to ask for free drugs as well, but he said it was unrealistic to simply give away product globally. Instead, he wants to see international funding along the lines of the Global Fund to Fight AIDS, Tuberculosis and Malaria.

"Gilead cannot cure hepatitis C globally on our backs alone. There have to be other players that come in and make that investment," he said.

(Editing by William Hardy)

Source

U.S. FDA Grants Priority Review to AbbVie for Investigational, All-Oral, Interferon-Free Therapy for the Treatment of Genotype 4 Chronic Hepatitis C

- The New Drug Application (NDA) was accepted by the U.S. Food and Drug Administration (FDA) and is based on results from the PEARL-I study, which demonstrated up to 100 percent sustained virologic response rates at 12 weeks post-treatment with no discontinuations due to adverse events
- First all-oral, interferon-free therapy being evaluated by the FDA for patients with chronic genotype 4 (GT4) hepatitis C virus (HCV) infection
- AbbVie's investigational regimen has been previously designated as a breakthrough therapy and received priority review by the FDA

NORTH CHICAGO, Ill., April 24, 2015 /PRNewswire/ -- AbbVie (NYSE: ABBV) has announced that the U.S. Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) and granted priority review for the company's, all-oral, interferon-free, two direct-acting antiviral treatment of ombitasvir, paritaprevir, ritonavir (OBV/PTV/r), with ribavirin (RBV). The NDA is for the treatment of adults with chronic genotype 4 (GT4) hepatitis C virus (HCV) infection.

AbbVie's regimen is the first all-oral, interferon-free therapy being evaluated by the FDA for patients in the United States with chronic GT4 HCV infection. This submission affirms the company's commitment to seeking access to curative* therapy for patients living with chronic HCV infection (*curative is defined as when the virus is no longer detectable in the patient's blood 12 weeks after treatment ends; sustained virologic response [SVR₁₂]).

The FDA granted priority review to AbbVie for the regimen based in part on data from the PEARL-I study, which was recently published online in The Lancet. The FDA grants priority review designation to investigational therapies that treat a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. This designation shortens the regulatory review period for non-new chemical entity NDAs from the normal 10 months to six months. AbbVie's regimen was also granted a Breakthrough Therapy designation by the FDA on June 30, 2014, a status given to investigational treatments for serious or life-threatening conditions with preliminary clinical evidence that may demonstrate substantial improvement on at least one clinically significant endpoint compared to available therapy.¹

"We are pleased that the FDA has granted priority review for our all-oral, interferon-free treatment for patients with chronic GT4 HCV infection," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "Submission of this NDA further underscores AbbVie's commitment to developing therapies to treat a wide range of patients living with chronic HCV infection."

PEARL-I is an open-label, Phase 2b study that demonstrated 100 percent of GT4 patients without cirrhosis who were new to therapy (n=42/42) or who had failed previous treatment with pegylated interferon (pegIFN) and RBV (n=49/49) achieved SVR₁₂ after receiving OBV/PTV/r and RBV for 12 weeks. Additionally, 91 percent of patients who were new to therapy achieved SVR₁₂ (n=40/44) after taking the treatment without RBV.

The Centers for Disease Control and Prevention (CDC) estimates that in the United States, 3.2 million people are chronically infected with HCV.² While genotype 1 (GT1) is the most prevalent form of HCV in the U.S., accounting for approximately 73 percent of all cases, GT4 infection accounts for up to 6 percent of HCV infections.^3,4Hepatitis C is inflammation of the liver caused by an infection with HCV.⁵ It is transmitted when an infected person's blood enters the bloodstream of another person.⁶ There are six major HCV genotypes (GT1-6).⁷ Presently, there is no vaccine for HCV infection.²

About the PEARL-I Study

PEARL-I is an open-label, Phase 2b study designed to evaluate the safety and efficacy of 12 weeks of treatment with OBV/PTV/r with and without RBV in non-cirrhotic adult patients with chronic GT4 HCV infection who were new to therapy or had failed previous treatment with pegylated interferon and RBV. Treatment-naïve GT4 patients were randomized in a 1:1 ratio to receive OBV/PTV/r with or without RBV. All treatment-experienced GT4 patients received OBV/PTV/r with RBV. In the treatment-naïve group without RBV, on-treatment virologic breakthrough was reported in one patient (2 percent) and two patients (5 percent) experienced post-treatment relapse. There were no virologic failures in the other treatment arms. Patients with GT1b HCV infection were also studied but not included in the efficacy analysis for the NDA submission; the results in patients with GT4 HCV were reported in The Lancet.

There were no discontinuations due to adverse events in PEARL-I. The most commonly reported treatment-emergent adverse events (greater than 15 percent in any group) were headache (29-33 percent), asthenia (weakness) (24-33 percent), fatigue (7-18 percent), nausea (9-17 percent) and insomnia (5-16 percent). One patient had a grade 3 liver function test elevation (aspartate aminotransferase [AST] greater than five times the upper limit of normal), which was asymptomatic and resolved during continued dosing. Four patients with hemoglobin decreases (anemia) required RBV dose reductions; however, none of these patients required blood transfusions or medication to boost their red blood cell production.

About AbbVie's Two Direct-Acting Antiviral HCV Treatment
AbbVie's proposed all-oral antiviral treatment consists of the fixed-dose combination of paritaprevir/ritonavir (150/100mg) co-formulated with ombitasvir (25mg) dosed once daily, co-administered with weight-based ribavirin (1000mg or 1200mg in divided doses, twice daily). The combination of two direct-acting antivirals, each with distinct mechanisms of action, targets and inhibits specific HCV proteins in the viral replication process.

About AbbVie's HCV Clinical Development Program
AbbVie's HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating interferon-free, all-oral treatments with and without ribavirin with the goal of achieving high sustained virologic response rates in as many patients as possible. AbbVie's development programs combining two direct-acting antivirals are studying additional hepatitis C virus (HCV) genotypes.

Paritaprevir was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. Paritaprevir is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

Safety Information
Ombitasvir, paritaprevir, and ritonavir (OBV/PTV/r) and RBV are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.

There are special safety considerations when prescribing these drugs in approved populations.

OBV/PTV/r must not be used in patients with severe hepatic impairment or with certain medications, which may result in serious and/or life-threatening events or loss of therapeutic effect. OBV/PTV/r can cause increases in certain liver enzyme levels (ALT) and should be monitored during the first four weeks of treatment, and then as clinically indicated thereafter. Female patients should not take ethinyl estradiol-containing medications during treatment with OBV/PTV/r, as they are at greater risk for liver enzyme elevations when taking these medications.

Ritonavir must also not be used in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score ≥6.

See approved product labels for more information.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2014 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

¹ U.S. Food and Drug Administration Online. Fact Sheet: Breakthrough Therapies. http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/fdasia/ucm329491.htm. Accessed March 20, 2015.
² Centers for Disease Control and Prevention (CDC). Hepatitis C FAQs for health professionals. http://www.cdc.gov/hepatitis/hcv/hcvfaq.htm. Accessed March 10, 2015.
³ O'Leary JG, Davis GL. Hepatitis C. In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 9th ed, Vol 1. Philadelphia, PA: Saunders Elsevier. 2010:1313-1335.
⁴ Gower E, Estes C, Blach S, et al. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatology. 2014;61:S45-S57.
⁵ Mayo Clinic. Hepatitis C: Definition. http://www.mayoclinic.org/diseases-conditions/hepatitis-c/basics/definition/con-20030618. Accessed November 2013.
⁶ World Health Organization. Hepatitis C Fact Sheet 2014. http://www.who.int/mediacentre/factsheets/fs164/en/. Accessed April 2014.
⁷ AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed March 9, 2015.

SOURCE AbbVie

For further information: Media: Stefanie Prodouz, +1 (224) 637-0971, stefanie.prodouz@abbvie.com; David Freundel, +1 (847) 937-4522, david.freundel@abbvie.com; Investor Relations: Liz Shea, +1 (847) 935-2211, liz.shea@abbvie.com

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