HCV Research and News: Genotype 1

Showing posts with label Genotype 1. Show all posts

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.

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.

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

April 23, 2015

Janssen Announces SVR12 Rates with Twelve Weeks of Treatment with All-Oral, Once-Daily Regimen of Simeprevir Plus Sofosbuvir in Genotype 1 HCV Patients With and Without Cirrhosis

- Data from OPTIMIST-1 and OPTIMIST-2 Trials Showing SVR12 Rates of 97 Percent and 84 Percent to be Presented at The International Liver Congress™ 2015 of the European Association for the Study of the Liver -

CORK, Ireland, April 23, 2015 /PRNewswire/ -- Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson (Janssen), today announced results for its hepatitis C treatment simeprevir at The International Liver Congress™ 2015 of the European Association for the Study of the Liver (EASL) in Vienna. Late-breaking results from the Phase 3 OPTIMIST-1 and OPTIMIST-2 trials highlight the clinical outcomes of simeprevir in an all-oral combination regimen in a wide range of patients with hepatitis C virus (HCV) infection.

"The new data for simeprevir presented at The International Liver Congress™ confirms its efficacy when combined with sofosbuvir in an all-oral, ribavirin-free regimen for HCV patients, including those who are treatment-naive and treatment-experienced, both with and without cirrhosis," said Gaston Picchio, hepatitis disease area leader, Janssen. "These data further demonstrate the role of simeprevir within the HCV treatment landscape, as it provides patients with an important therapeutic option."

The results from the OPTIMIST-1 and OPTIMIST-2 trials are the first Phase 3 data to be presented on simeprevir in combination with sofosbuvir (SMV/SOF) in patients with genotype 1 chronic HCV infection, both with and without cirrhosis. Sofosbuvir is a nucleotide analog NS5B polymerase inhibitor developed by Gilead Sciences, Inc.

OPTIMIST-1¹

OPTIMIST-1 is a Phase 3, randomized, open-label trial to investigate the efficacy and safety of the all-oral regimen of SMV/SOF among treatment-naive and treatment-experienced genotype 1 chronic HCV-infected patients without cirrhosis. The primary objective was to show superior sustained virologic response (SVR) at 12 weeks after treatment (SVR12) with 12 and eight weeks of treatment with SMV/SOF versus a historical control (patients previously treated with approved regimens containing a direct-acting antiviral, pegylated interferon and ribavirin).
Ninety-seven (97) percent of patients treated with SMV/SOF for 12 weeks (n=150/155) achieved SVR12, which was superior to the SVR12 rate of 87 percent among the historical control.
- SVR12 rates of 100 percent were seen among patients with IL28B CC genotype (n=43/43) and those with baseline NS5A and NS3 Q80K polymorphisms (n=9/9).
Patients treated with eight weeks of SMV/SOF achieved an SVR12 rate of 83 percent (n=128/155), which was not superior to the SVR12 rate of 83 percent in the historical control.
- High SVR12 rates were seen among patients with baseline HCV RNA <4 million IU/mL (96 percent; n=46/48), IL28B CC genotype (93 percent; n=38/41), patients with genotype 1b HCV infection (92 percent; n=36/39) and patients without baseline NS5A and Q80K polymorphisms (89 percent; n=78/88).
The most frequently reported adverse events in the 12-week and eight-week treatment arms were headache (14 and 17 percent, respectively), fatigue (12 and 15 percent, respectively) and nausea (15 and 9 percent, respectively).

OPTIMIST-2²

OPTIMIST-2 is a Phase 3, open-label, single-arm trial to investigate the efficacy and safety of SMV/SOF in treatment-naive and treatment-experienced genotype 1 chronic HCV-infected patients with cirrhosis. The primary objective was to show superior SVR12 with 12 weeks of treatment with SMV/SOF versus a historical control.
Twelve (12) weeks of treatment with SMV/SOF resulted in SVR12 rates of 84 percent (n=86/103), which was superior to the SVR12 rate of 70 percent in the historical control.
Higher SVR12 rates were seen in patients with baseline NS5A polymorphisms with or without NS3 Q80K polymorphisms (100 percent, n=13/13), patients with albumin ≥4 g/dL (94 percent; n=47/50) and treatment-naïve patients (88 percent; n=44/50).
The most common adverse events were fatigue (20 percent), headache (20 percent) and nausea (11 percent).

"Chronic HCV infection is a leading cause of cirrhosis, and once it is developed, these patients can be very difficult to cure. The results of the OPTIMIST-2 study demonstrate the safety and efficacy of the all-oral regimen of simeprevir and sofosbuvir for genotype 1 chronic HCV patients with cirrhosis," said Eric Lawitz, M.D., Texas Liver Institute, principal investigator of the OPTIMIST-2 study.

About Hepatitis C
Hepatitis C, a blood-borne infectious disease of the liver and a leading cause of chronic liver disease, is a major global public health concern. Approximately 170 million people are infected with hepatitis C worldwide and 350,000 people per year die from the disease globally. When left untreated, hepatitis C can cause significant damage to the liver, including cirrhosis. Additionally, hepatitis C may increase the risk of developing complications from cirrhosis, which may include liver failure.

About Janssen's HCV Development Program
The goal of the Janssen hepatitis C virus (HCV) clinical development program is to provide physicians with multiple treatment options in order to offer patients the best possible chance at successful therapy.

Ongoing studies focus on the investigation of the NS3/4A protease inhibitor simeprevir in a number of different treatment combinations and HCV patient populations, including those who are difficult to cure.

Janssen's HCV pipeline also includes JNJ-56914845, an investigational NS5A replication complex inhibitor currently in Phase 2 studies, and following the acquisition of Alios BioPharma by Johnson & Johnson in November 2014, AL-335, a uridine-based nucleotide analog in Phase 1 development, and AL-516, a guanosine-based nucleotide analog NS5B polymerase inhibitor in pre-clinical development.

These compounds are being developed with the intent of targeting critical steps of the HCV replication cycle.

About Simeprevir (OLYSIO^®)
Simeprevir is an NS3/4A protease inhibitor which has been developed by Janssen Sciences Ireland UC in collaboration with Medivir AB.

In November 2013, simeprevir was initially approved by the U.S. Food and Drug Administration, and in May 2014, it was granted marketing authorization by the European Commission. Subsequent marketing authorizations have followed in several other countries around the world. Indications vary by market.

Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV.

About Janssen Pharmaceutical Companies of Johnson & Johnson
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.

INDICATIONS
OLYSIO^®is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection as a component of a combination antiviral treatment regimen.

Limitations of Use:

OLYSIO^® monotherapy is not recommended.
OLYSIO^® efficacy in combination with peginterferon alfa (Peg‑IFN‑alfa) and ribavirin (RBV) is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with hepatitis C virus (HCV) genotype 1a without the Q80K polymorphism. Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism.
OLYSIO^® is not recommended in patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C).
OLYSIO^® is not recommended in patients who have previously failed therapy with a treatment regimen that included OLYSIO^® or other HCV protease inhibitors.

IMPORTANT SAFETY INFORMATION

Contraindications:

There are no specific contraindications to OLYSIO^®. The contraindications to other antiviral drugs administered with OLYSIO^® for the treatment of CHC infection also apply to OLYSIO^® combination treatment. Prescribers should consult the complete prescribing information for these drugs for a description of contraindications.

Warnings and Precautions:

Serious Symptomatic Bradycardia When Co-administered with Sofosbuvir and Amiodarone: Postmarketing cases of symptomatic bradycardia and cases requiring pacemaker intervention have been reported when amiodarone is co-administered with sofosbuvir in combination with another HCV direct acting antiviral, including OLYSIO^®. A fatal cardiac arrest was reported in a patient receiving a sofosbuvir-containing regimen (ledipasvir/sofosbuvir). Bradycardia has generally occurred within hours to days, but cases have been observed up to 2 weeks after initiating HCV treatment. Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease may be at increased risk for symptomatic bradycardia with co-administration of amiodarone. Bradycardia generally resolved after discontinuation of HCV treatment. The mechanism for this bradycardia effect is unknown.
Co-administration of amiodarone with OLYSIO^® in combination with sofosbuvir is not recommended. For patients taking amiodarone who have no other alternative treatment options, and who will be co-administered OLYSIO and sofosbuvir:
         o    Counsel patients about the risk of serious symptomatic bradycardia
         o    Cardiac monitoring in an in-patient setting for the first 48 hours of
               co-administration is recommended, after which outpatient or self-monitoring
               of the heart rate should occur on a daily basis through at least the first 2
               weeks of treatment.
Patients who are taking sofosbuvir in combination with OLYSIO^® who need to start amiodarone therapy due to no other alternative treatment options should undergo similar cardiac monitoring as outlined above.
Due to amiodarone's long elimination half-life, patients discontinuing amiodarone just prior to starting sofosbuvir in combination with OLYSIO^® should also undergo similar cardiac monitoring as outlined above.
Patients who develop signs or symptoms of bradycardia should seek medical evaluation immediately. Symptoms may include near-fainting or fainting, dizziness or lightheadedness, malaise, weakness, excessive tiredness, shortness of breath, chest pain, confusion or memory problems.
Hepatic Decompensation and Hepatic Failure: Hepatic decompensation and hepatic failure, including fatal cases, have been reported postmarketing in patients treated with OLYSIO^® in combination with Peg‑IFN‑alfa and RBV or in combination with sofosbuvir. Most cases were reported in patients with advanced and/or decompensated cirrhosis who are at increased risk for hepatic decompensation or hepatic failure. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between treatment with OLYSIO^® and these events has not been established.
OLYSIO^® is not recommended for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C).
In clinical trials of OLYSIO^®, modest increases in bilirubin levels were observed without impacting hepatic function. Postmarketing cases of hepatic decompensation with markedly elevated bilirubin levels have been reported. Monitor liver chemistry tests before and as clinically indicated during OLYSIO^® combination therapy. Patients who experience an increase in total bilirubin to greater than 2.5 times the upper limit of normal should be closely monitored:
- Patients should be instructed to contact their healthcare provider if they have onset of fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discolored feces.
- Discontinue OLYSIO if elevation in bilirubin is accompanied by liver transaminase increases or clinical signs and symptoms of hepatic decompensation.
Risk of Serious Adverse Reactions Associated With Combination Treatment: OLYSIO^® should be used in combination with other antiviral drugs for the treatment of CHC infection. Therefore, consult the prescribing information for these drugs before starting therapy with OLYSIO^®.
Photosensitivity: Photosensitivity reactions have been observed with OLYSIO^® combination therapy. Serious photosensitivity reactions resulting in hospitalization have been observed with OLYSIO^® in combination with Peg‑IFN‑alfa and RBV. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema.
Use sun protective measures and limit sun exposure during treatment with OLYSIO^®. Avoid use of tanning devices during treatment with OLYSIO^®. Discontinuation of OLYSIO^® should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue OLYSIO^® in the setting of a photosensitivity reaction, expert consultation is advised.
Rash: Rash has been observed with OLYSIO^® combination therapy. Rash occurred most frequently in the first 4 weeks of treatment, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of OLYSIO^® have been reported in subjects receiving OLYSIO^® in combination with Peg‑IFN‑alfa and RBV. Most of the rash events in OLYSIO^®‑treated patients were of mild or moderate severity. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, OLYSIO^® should be discontinued. Patients should be monitored until the rash has resolved.
Sulfa Allergy: OLYSIO^® contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of OLYSIO^®.
Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions: Co‑administration of OLYSIO^® with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended as this may lead to significantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions.

Adverse Reactions

Use with Peg-IFN-alfa and RBV: Adverse reactions (all grades, at least 3% higher frequency) for OLYSIO^® with Peg-IFN-alfa and RBV vs. Peg-IFN-alfa and RBV alone in the first 12 weeks were rash (including photosensitivity) (28% vs. 20%), pruritus (22% vs. 15%), nausea (22% vs. 18%), myalgia (16% vs. 13%), and dyspnea (12% vs. 8%).

Use with sofosbuvir: The most common (> 10%) adverse reactions reported during 12 weeks treatment with OLYSIO^® in combination with sofosbuvir without RBV were fatigue (25%), headache (21%), nausea (21%), insomnia (14%) and pruritus (11%). Rash and photosensitivity were reported in 11% and 7% of subjects, respectively. During 24 weeks treatment with OLYSIO^® in combination with sofosbuvir, dizziness (16%), and diarrhea (16%) were also commonly reported.

Use in Specific Populations

Pregnancy Category C: Adequate and well-controlled trials with OLYSIO^® have not been conducted in pregnant women. OLYSIO^® should be used during pregnancy only if the potential benefit justifies the potential risk. Female patients of childbearing potential should use an effective contraceptive method.

Race: Patients of East Asian ancestry exhibit higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. There are insufficient safety data to recommend an appropriate dose for patients of East Asian ancestry. The potential risks and benefits of OLYSIO^® should be carefully considered prior to use in patients of East Asian ancestry.

Renal Impairment: No dose adjustment of OLYSIO^® is required in patients with mild, moderate or severe renal impairment. The safety and efficacy of OLYSIO^® have not been studied in HCV‑infected patients with severe renal impairment (creatinine clearance below 30 mL/min) or end‑stage renal disease, including patients requiring dialysis. Simeprevir is highly protein-bound; therefore, dialysis is unlikely to result in significant removal of simeprevir.

Hepatic Impairment: No dose adjustment of OLYSIO^® is required in patients with mild hepatic impairment (Child‑Pugh Class A). The safety and efficacy of OLYSIO^® have not been established in HCV‑infected patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C). OLYSIO^® is not recommended for patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C). There have been postmarketing reports of hepatic decompensation, hepatic failure, and death in patients with advanced or decompensated cirrhosis receiving OLYSIO^® combination therapy. Simeprevir exposures are increased in patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C). In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including increased bilirubin, rash and photosensitivity.

Other HCV Genotypes: The safety and efficacy of OLYSIO^® have not been established in patients infected with other HCV genotypes.

Liver Transplantation: The safety and efficacy of OLYSIO^® have not been studied in liver transplant patients.

Not a complete list of Uses in Specific Populations.

Consult the PI for Peg-IFN-alfa and RBV or sofosbuvir before starting therapy with OLYSIO^®. Safety information related to these drugs also applies to their use in OLYSIO^® combination treatment.

Please see full Prescribing Information and Patient Information for more details.

This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development. 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 known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen R&D Ireland and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in new product development, including the uncertainty of clinical success and of obtaining regulatory approvals; competition, including technological advances, new products and patents attained by competitors; challenges to patents; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 28, 2014, including in Exhibit 99 thereto, and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies or Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

References

¹A Phase 3, randomised, open-label study to evaluate the efficacy and safety of 12 and 8 weeks of treatment with simeprevir plus sofosbuvir in treatment-naive and -experienced patients with chronic HCV genotype 1 infection without cirrhosis: The OPTIMIST-1 study. Presented at The International Liver Congress™ 2015.

² A Phase 3, open-label, single-arm study to evaluate the efficacy and safety of 12 weeks of simeprevir plus sofosbuvir in treatment-naive or –experienced patients with chronic hepatitis c virus genotype 1 infection and cirrhosis: The OPTIMIST-2 study. Presented at The International Liver Congress™ 2015.

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SOURCE Janssen Sciences Ireland UC

Gilead’s Harvoni and Sovaldi Demonstrate Efficacy and Safety among Chronic Hepatitis C Patients with Advanced Liver Disease

-- High Cure Rates in More Than 600 Genotype 1 and 4 Patients With Limited or No Approved Treatment Options --

VIENNA, Austria--(BUSINESS WIRE)--Apr. 23, 2015-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from several Phase 2 clinical studies evaluating investigational uses of Harvoni^® (ledipasvir 90 mg/sofosbuvir 400 mg) and other Sovaldi^® (sofosbuvir 400 mg)-based regimens for the treatment of chronic hepatitis C virus (HCV) infection in patients with advanced liver disease, including patients with decompensated cirrhosis, patients with fibrosing cholestatic hepatitis C (a rare and severe form of the disease following liver transplantation) and patients with portal hypertension. These data will be presented this week at the 50th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress™ 2015) in Vienna, Austria.

“The patients included in these analyses are among the most difficult to both treat and cure and, until now, have had limited or no treatment options,” said Michael P. Manns, MD, Professor and Chairman, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. “These data demonstrate that, even among these difficult-to-treat patient groups, sofosbuvir-based oral therapy offers the potential of high cure rates, improves outcomes and is generally well tolerated with a favorable safety profile.”

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

Decompensated and Post-Liver Transplantation

In SOLAR-2 (Study GS-US-337-0124, Oral #G02), 328 genotype 1 or 4 HCV patients with decompensated liver disease before liver transplantation or recurrent HCV infection following liver transplantation were randomized to receive either 12 or 24 weeks of Harvoni plus ribavirin (RBV). Ten patients were excluded from the analysis because of transplantation (n=7) or because they were pre-transplantation, but not decompensated (n=3); an additional 27 of these patients have not yet reached post-treatment week 12. The number and proportion of genotype 1 patients with available data achieving sustained virologic response 12 weeks after treatment (SVR12) are summarized in the table below.

Of the 32 genotype 4 patients, 27 (84 percent) achieved SVR12. Additionally, among patients with compensated and decompensated cirrhosis before and after liver transplantation, virologic response was associated with improvements in Model for End-Stage Liver Disease (MELD) and CPT scores used to stage end-stage liver disease.

The most common adverse events were fatigue, anemia, nausea and headache. Overall, six patients discontinued treatment due to adverse events, five of whom had decompensated cirrhosis.

Further supporting the safety profile of Harvoni plus RBV among this patient population was data from a pooled safety analysis of 659 patients treated in the SOLAR-1 and SOLAR-2 studies (ePoster #P0774). Both studies evaluated Harvoni plus RBV for 12 or 24 weeks in genotype 1 or 4 HCV patients with decompensated liver disease or recurrent HCV infection following liver transplantation. SOLAR-1 was conducted in the United States, with data presented in November at The Liver Meeting2014 and SOLAR-2 was conducted in Australia, Canada, Europe and New Zealand. Overall, adverse events were similar to those seen in previous studies, including the Phase 3 ION studies. Fewer than three percent (n=19/659) of patients discontinued due to an adverse event, none of which were attributed to Harvoni treatment. There were a total of 20 deaths in these two studies, none of which was assessed by the investigator as related to study treatment.

Fibrosing Cholestatic Hepatitis C

A further subset of the SOLAR-1 and SOLAR-2 studies (ePoster #P0779) demonstrated 100 percent SVR12 rates among 11 patients who were confirmed to have fibrosing cholestatic hepatitis (FCH), following 12 or 24 weeks of Harvoni plus RBV. FCH is a rare and severe form of recurrent hepatitis that occurs after liver transplantation. It is associated with high morbidity and mortality rates and there are no currently approved treatment options.

Cirrhosis and Portal Hypertension

Study GS-US-334-0125 (ePoster LB #4283) evaluated 50 genotype 1-4 HCV-infected patients with cirrhosis and portal hypertension. Patients were randomized to receive either 48 weeks of Sovaldi plus RBV initially (n=25) or at the conclusion of a 24-week observation period (n=21). Four patients in the observation arm discontinued the study prior to receiving treatment. Of the patients who received treatment with Sovaldi plus RBV, 72 percent (n=33/46) achieved SVR12. A subset of 37 patients had paired hepatic venous pressure gradient (HVPG) measurements at baseline and end of treatment. Of these, 38 percent (14/37) of patients experienced a ≥10 percent reduction and 24 percent (9/37) of patients experienced a ≥20 percent decrease in HVPG from baseline to end of treatment. A baseline total bilirubin of <1.5 mg/dL was associated with a ≥20 percent decrease in HVPG (p=0.03). This study is the first to demonstrate the effect of direct acting antivirals like Sovaldi on HVPG, and additional assessments will be undertaken in these patients one-year post treatment.

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

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.

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.

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 that Gilead may observe unfavorable results from additional clinical trials involving Sovaldi and Harvoni for various difficult-to-treat patient groups, including patients with decompensated cirrhosis, fibrosing cholestatic hepatitis C and portal hypertension. 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)

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April 15, 2015

AbbVie's Investigational Chronic Hepatitis C Treatment Granted Priority Review in Japan

- AbbVie's investigational, interferon and ribavirin-free treatment in Japan consists of a 12-week, two direct-acting antiviral, fixed-dosed combination of paritaprevir/ritonavir with ombitasvir, dosed once daily
- New Drug Application, based on the Phase 3 GIFT-I study results in Japanese patients with genotype 1b hepatitis C virus (HCV) infection, was submitted in February 2015
- GIFT-I met its primary endpoint, achieving 95 percent sustained virologic response rate at 12 weeks post-treatment (SVR12); two patients (0.9 percent) discontinued treatment due to adverse events
- Approximately 1.5 to 2 million people are living with hepatitis C in Japan(1); genotype 1 is most common, accounting for 60 to 70 percent of all patients infected with HCV(2)

NORTH CHICAGO, Ill., April 15, 2015 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has granted priority review for its investigational, two direct-acting antiviral treatment of ombitasvir/paritaprevir/ritonavir. This all-oral treatment is interferon (IFN) and ribavirin (RBV)-free and will be dosed once daily. The MHLW grants priority review to certain medicines on the basis of clinical usefulness and severity of the disease, including diseases like hepatitis C, which affects approximately 1.5 to 2 million people in Japan.¹ AbbVie's investigational hepatitis C treatment was submitted for marketing approval in Japan in February 2015. The New Drug Application is for the treatment of patients with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection and is supported by the Phase 3 GIFT-I study in Japanese genotype 1b (GT1b) HCV patients.

"AbbVie is pleased that the Japanese MHLW has granted priority review for our interferon and ribavirin-free, 12-week, two direct-acting antiviral treatment regimen. This marks another important advancement in our HCV clinical development program as we aim to provide our HCV treatment to patients across the world," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "If approved, AbbVie's HCV treatment holds the potential to be a promising new treatment option for patients living with this chronic infection in Japan."

AbbVie studied a two direct-acting antiviral treatment regimen without RBV in Japan due to patient and viral characteristics specific to the Japanese population, including high prevalence of GT1b. In Japan, GT1 is the most common HCV genotype and accounts for 60 to 70 percent of all patients infected with HCV.² Of those patients, about 95 percent are infected with the GT1b sub-type.²

Additional information about AbbVie's GIFT-I study can be found on www.clinicaltrials.gov.

About AbbVie's Investigational Two Direct-Acting Antiviral HCV Treatment
For the treatment of genotype 1 chronic hepatitis C virus (HCV) infection in Japan, AbbVie's investigational, two direct-acting antiviral treatment consists of the fixed-dosed combination of paritaprevir/ritonavir (150/100 mg) with ombitasvir (25 mg), dosed once daily.

AbbVie's chronic HCV treatment combines two direct-acting antivirals, each with a distinct mechanism of action that targets and inhibits specific HCV proteins of the viral replication process.

About AbbVie's HCV Clinical Development Program in Japan
AbbVie's HCV clinical development program in Japan focuses on its investigational, two direct-acting antiviral treatment and is designed to achieve high SVR rates in chronic HCV infected patients, including additional genotypes and patients with compensated cirrhosis.

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 has been developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

Ombitasvir/paritaprevir/ritonavir is an investigational product and its safety and efficacy have not been established in Japan.

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 Kohnodai Hospital. National Center for Global Health and Medicine [cited 20 February 2013]. Available from:
http://www.ncgm.go.jp/center/forpatient_hcv.html

² Hajarizadeh B et al. Nat Rev Gastroenterol Hepatol 2013; 10: 553-562. http://www.nature.com/nrgastro/journal/v10/n9/fig_tab/nrgastro.2013.107_F1.html. Accessed December 2014

SOURCE AbbVie

April 11, 2015

Ombitasvir/Paritaprevir/r and Dasabuvir Plus Ribavirin in HCV Genotype 1-Infected Patients on Methadone or Buprenorphine

Journal of Hepatology

Articles in Press

Jacob Lalezari, J. Greg Sullivan, Peter Varunok, Edward Galen, Kris V. Kowdley, Vinod Rustgi, Humberto Aguilar, Franco Felizarta, Barbara McGovern, Martin King, Akshanth R. Polepally, Daniel E. Cohen

DOI: http://dx.doi.org/10.1016/j.jhep.2015.03.029
Open access funded by the Author(s)
Publication stage: In Press Accepted Manuscript

Publication History

Published Online: March 31, 2015
Accepted: March 25, 2015
Received in revised form: March 17, 2015
Received: September 19, 2014

Abstract

Background & Aims

HCV-infected patients with a history of injection drug use have low rates of initiation and completion of interferon-based therapies. This study evaluated efficacy, safety, and pharmacokinetics of a 12-week all-oral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir +ribavirin in HCV genotype 1-infected patients on stable opioid replacement therapy.

Methods

This was a phase 2, multicenter, open-label, single arm study in treatment-naïve or peginterferon/ribavirin-treatment experienced HCV genotype 1-infected patients on methadone or buprenorphine +/-naloxone. Patients received 12 weeks of co-formulated ombitasvir/paritaprevir/ritonavir(25mg/150mg/100mg once daily) and dasabuvir(250mg twice daily) +weight-based ribavirin. The primary efficacy endpoint was sustained virologic response 12 weeks post-treatment.

Results

Thirty-eight non-cirrhotic patients on chronic methadone(n=19) or buprenorphine(n=19) were enrolled. A total of 37 patients(97.4%) had a sustained virologic response 12 weeks post-treatment. No patient had a viral breakthrough or relapse. One patient discontinued due to serious adverse events unrelated to study drug (cerebrovascular accident and sarcoma). The most frequent adverse events were nausea, fatigue, and headache. Eight patients had on-treatment hemoglobin concentrations <10g/dL. Pharmacokinetic analyses indicated no clinically meaningful impact of methadone or buprenorphine on ombitasvir, paritaprevir, ritonavir, dasabuvir, or dasabuvir M1 metabolite exposures. No dose adjustments of methadone or buprenorphine were required

Conclusions

The interferon-free regimen of ombitasvir/paritaprevir/r and dasabuvir +ribavirin for 12 weeks was well-tolerated and achieved sustained virologic response in 97.4% of patients on opioid substitution therapy in this study. This all-oral regimen may provide an effective alternative to interferon-based therapies for HCV-infected patients with a history of injection drug use.

Continue reading full article here …..

Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 HCV previously treated in clinical trials of sofosbuvir regimens

Hepatology

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

Viral Hepatitis

David Wyles^1,*, Paul Pockros², Giuseppe Morelli³, Ziad Younes⁴, Evguenia Svarovskaia⁵, Jenny C. Yang⁵, Phillip S. Pang⁵, Yanni Zhu⁵, John G. McHutchison⁵, Steven Flamm⁶ and Eric Lawitz⁷

DOI: 10.1002/hep.27814

Publication History

Accepted manuscript online: 2 APR 2015 11:45AM EST
Manuscript Accepted: 26 MAR 2015
Manuscript Revised: 16 MAR 2015
Manuscript Received: 23 FEB 2015

Keywords: direct-acting antiviral agents; HCV NS5B polymerase inhibitor; retreatment

Abstract

Patients who fail to achieve sustained virologic response (SVR) after treatment with sofosbuvir plus ribavirin with or without peginterferon do not have established retreatment options. We conducted an open-label trial to assess the efficacy and safety of ledipasvir-sofosbuvir plus ribavirin in patients with genotype 1 HCV who did not achieve SVR after treatment in phase 2 and 3 trials of sofosbuvir regimens. We enrolled 51 patients at 24 sites in the United States. All patients received the fixed-dose combination tablet of ledipasvir-sofosbuvir once daily plus weight-based ribavirin (1000 or 1200 mg/day) for 12 weeks. The efficacy endpoint was the proportion of patients with SVR 12 weeks after discontinuation of therapy (SVR12). Of the 51 patients enrolled, 25 (49%) had previously received sofosbuvir plus peginterferon-ribavirin, 20 (39%) had received sofosbuvir-ribavirin, five (10%) had received sofosbuvir placebo plus peginterferon-ribavirin, and one (2%) received GS-0938 monotherapy. Fourteen (27%) had compensated cirrhosis at baseline, and 47 (92%) had non-CC IL28B genotypes. SVR12 was achieved by 50 of the 51 patients (98%) treated. Among the 45 patients who received sofosbuvir in prior treatment, 44 (98%) achieved SVR12. The only patient who did not achieve SVR12 was a patient with genotype 3a HCV who had been incorrectly genotyped as 1a in the previous study. Given the high rates of SVR12, no differences among patient subgroups were discernible. Of 51 patients, 41 (80%) experienced at least one adverse event, but most events were mild to moderate in severity. The most common adverse events were fatigue, headache, and diarrhea. One patient discontinued treatment due to an unrelated adverse event (bipolar disorder). Conclusion: Twelve weeks of ledipasvir-sofosbuvir plus ribavirin was an effective and safe treatment for patients who have not achieved SVR with prior regimens that included sofosbuvir. This article is protected by copyright. All rights reserved.

Source

April 10, 2015

Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial

Lancet. 2015 Mar 21;385(9973):1075-86. doi: 10.1016/S0140-6736(14)61795-5. Epub 2014 Nov 11.

Lawitz E¹, Gane E², Pearlman B³, Tam E⁴, Ghesquiere W⁵, Guyader D⁶, Alric L⁷, Bronowicki JP⁸, Lester L⁹, Sievert W¹⁰, Ghalib R¹¹, Balart L¹², Sund F¹³, Lagging M¹⁴, Dutko F¹⁵, Shaughnessy M¹⁵, Hwang P¹⁵, Howe AY¹⁵, Wahl J¹⁵, Robertson M¹⁵, Barr E¹⁵, Haber B¹⁵.

Erratum in Lancet. 2015 Mar 21;385(9973):1074.

Abstract

BACKGROUND: There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response.

METHODS: The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326.

FINDINGS: We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with ribavirin and 29 with no ribavirin) and 63 to the 18-week regimen (32 with ribavirin and 31 with no ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with ribavirin and 33 with no ribavirin) and 65 to the 18-week regimen (33 with ribavirin and 32 with no ribavirin. High SVR12 rates were achieved irrespective of the use of ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74-98; 28/31; cohort 1, 12 weeks, ribavirin-containing) to 100% (95% CI 89-100; 33/33; cohort 2, 18 weeks, ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without ribavirin, 97% (95% CI 82-100, 28/29) of patients in cohort 1 and 91% (76-98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21-32]), headache (58 patients, 23% [95% CI 18-29]), and asthenia (35 patients, 14% [95% CI 10-19]).

INTERPRETATION: Treatment with grazoprevir plus elbasvir, both with and without ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir.

FUNDING:

Merck & Co, Inc.

PMID: 25467591 [PubMed - indexed for MEDLINE]

Source

November 11, 2014

An Interferon-free Antiviral Regimen for HCV after Liver Transplantation

New England Journal of Medicine

Paul Y. Kwo, M.D., Parvez S. Mantry, M.D., Eoin Coakley, M.D., Helen S. Te, M.D., Hugo E. Vargas, M.D., Robert Brown, M.D., M.P.H., Fredric Gordon, M.D., Josh Levitsky, M.D., Norah A. Terrault, M.D., M.P.H., James R. Burton, M.D., Wangang Xie, Ph.D., Carolyn Setze, M.S., Prajakta Badri, Ph.D., Tami Pilot-Matias, Ph.D., Regis A. Vilchez, M.D., Ph.D., and Xavier Forns, M.D.

November 11, 2014DOI: 10.1056/NEJMoa1408921

Hepatitis C virus (HCV) presents a global health care challenge, with approximately 170 million people chronically infected.1 In 2012, approximately 24,000 liver transplantations were performed worldwide, with the largest proportion performed because of HCV-induced liver disease.2,3 In the United States, more than 40% of registrants on the liver-transplant waiting list are infected with HCV.3,4 After liver transplantation, recurrence of HCV infection is universal among recipients with viremia before transplantation.5,6 Fibrosis progression may be accelerated and HCV viral loads may be markedly increased in patients receiving post-transplantation immunosuppressive therapy as compared with patients not undergoing transplantation.7-9 Graft cirrhosis develops in 20 to 30% of HCV-infected persons within 5 years after transplantation.10,11 As a result of these complications, HCV infection has become the leading cause of death in liver-transplant recipients. Patient and graft survival rates are markedly lower among HCV-infected patients than among those who received a liver transplant owing to cholestatic or alcohol-related liver disease.3,12,13

Successful clearance of HCV after liver transplantation can reduce the risk of subsequent HCV-related complications such as progression to cirrhosis and graft loss.13-16 The standard of care in the treatment of recurrent HCV genotype 1 infection after liver transplantation has been 48 weeks of peginterferon with ribavirin, though the response rates of 13 to 43% are generally lower than the rates of 40 to 52% among patients not undergoing transplantation, in part because of treatment-limiting toxic effects.8,15,17-19 In addition, interferon-based therapies can induce alloimmune graft injury, reducing patient and graft survival.16,20

Calcineurin inhibitors, such as tacrolimus and cyclosporine, are key components of most current post-transplantation immunosuppressive regimens. Long-term exposure to calcineurin inhibitors can progressively impair renal function, reducing ribavirin clearance. Consequently, augmented ribavirin exposure may increase the frequency and severity of ribavirin-associated hemolytic anemia, commonly requiring the use of hematopoietic growth factors, blood transfusion, or both. HCV treatment with a first-generation protease inhibitor, boceprevir or telaprevir, in combination with peginterferon and ribavirin results in a 20 to 71% response rate among liver-transplant recipients; however, clinically significant side effects of these regimens, especially anemia and infections, were reported to limit their use.21-24 In addition, drug interactions between protease inhibitors and calcineurin inhibitors may require dose modification and monitoring.25,26

Phase 3 trials of an all-oral, interferon-free, direct-acting antiviral regimen of ombitasvir coformulated as a single tablet with ritonavir-boosted ABT-450 (ABT-50/r) plus dasabuvir and ribavirin have shown high rates of sustained virologic response among patients with HCV genotype 1 infection, irrespective of prior treatment with peginterferon–ribavirin or the presence of cirrhosis.27-31 Ombitasvir is a potent NS5A inhibitor32; ABT-450 is an NS3/4A protease inhibitor coadministered with ritonavir to increase peak, trough, and overall drug exposure, permitting once-daily dosing33; and dasabuvir is a nonnucleoside NS5B polymerase inhibitor. Next-generation interferon-free treatment regimens have not been extensively examined in transplant recipients with recurrent HCV genotype 1 infection. The CORAL-I trial assessed the safety and efficacy of ombitasvir–ABT-450/r and dasabuvir with ribavirin in this population of patients with an unmet need for safe and efficacious therapy.

Methods

Patients

Patients 18 to 70 years of age were eligible for the study if they had HCV genotype 1 infection (HCV RNA level >10,000 IU per milliliter) and had received a liver transplant at least 12 months before screening because of chronic HCV infection. Patients could have received interferon-based treatment for HCV infection before transplantation but not after transplantation. Eligible patients had no evidence of advanced fibrosis (Metavir score ≤F2) on liver biopsy performed not more than 6 months before screening. A stable tacrolimus-based or cyclosporine-based immunosuppressive regimen was required, and glucocorticoids were permitted at a dose of no more than 5 mg per day. Patients were excluded if they were coinfected with the human immunodeficiency virus or hepatitis B virus or had undergone multiple-organ transplantation or liver retransplantation. Patients were enrolled from 10 transplantation centers in the United States and Spain between May and August 2013. Detailed eligibility criteria are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Study Design and Oversight

Patients in this phase 2, open-label trial received ombitasvir–ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir) and dasabuvir (250 mg twice daily) for 24 weeks. Ribavirin dosing was at the investigator's discretion because of the known risk of ribavirin-related hematologic toxic effects in transplant recipients. Patients were followed for up to 48 weeks after the treatment period (Figure S1 in the Supplementary Appendix).

On the basis of simulations based on pharmacokinetic data from a phase 1 study that evaluated drug interaction between the study drugs and tacrolimus or cyclosporine, the following dosages of calcineurin inhibitors were recommended: for cyclosporine, one fifth of the pretreatment total daily dose, administered once daily; for tacrolimus, 0.5 mg once weekly or 0.2 mg, where available, every 3 days. Modifications in tacrolimus or cyclosporine dosing during treatment were guided by scheduled testing of trough levels of calcineurin inhibitors. Details of the dosing of ribavirin and calcineurin inhibitors are provided in the Supplementary Appendix.

The study was conducted in accordance with International Conference on Harmonisation Guidelines for Good Clinical Practice, applicable regulations, and guidelines governing clinical-study conduct that have their origin in the Declaration of Helsinki. All patients provided written informed consent. The study was designed by the sponsor (AbbVie); the investigators and the sponsor jointly conducted the study and gathered the data. The sponsor conducted the data analyses. All authors signed a confidentiality agreement with the sponsor. The first draft of the manuscript was written by a sponsor-employed medical writer, with input from all the authors. All the authors made the decision to submit the manuscript for publication and vouch for the completeness and accuracy of the data and analyses and for the fidelity of the study to the protocol, which is available at NEJM.org.

Efficacy and Safety Assessments

The primary efficacy end point was a sustained virologic response, defined as a plasma HCV RNA level of less than 25 IU per milliliter, 12 weeks after the end of treatment. Secondary assessments included the percentage of patients with a sustained virologic response at post-treatment week 24, virologic failure during treatment, and post-treatment relapse. A central laboratory used the COBAS TaqMan real-time reverse-transcriptase–polymerase-chain-reaction assay, version 2.0 (Roche), to test plasma samples for HCV RNA. Patients were monitored for clinical and laboratory evidence of adverse events at each study visit. Nonserious adverse events were recorded during the treatment period and until 30 days after the last dose. Serious adverse events were recorded from the time of informed consent until the end of the study. Details of plasma-sample collection, HCV RNA quantification, virologic-failure criteria, and resistance testing are provided in the Supplementary Appendix.

Statistical Analysis

Analyses of efficacy, safety, and baseline patient characteristics were performed on the intention-to-treat population, defined as all enrolled patients who received at least one dose of study drugs. The two-sided 95% confidence intervals for response rates were calculated with the use of the exact method based on the beta distribution. Patients with missing data at post-treatment week 12 or 24, including those who dropped out, were counted as having had virologic failure. Descriptive statistics are provided, such as the number of observations, mean, and standard deviation for continuous variables and counts and percentages for discrete variables. SAS software for the UNIX operating system (SAS Institute) was used for all analyses.

Results

Baseline Demographic and Clinical Characteristics

The CORAL-I study enrolled 34 patients, including 29 patients (85%) with HCV genotype 1a infection. The median time since liver transplantation was 3.3 years. Overall, 76% of patients had a non-CC IL28B genotype, 71% had previously been treated with peginterferon–ribavirin therapy, and 85% were receiving a tacrolimus-based immunosuppressive regimen (Table 1)

Treatment Efficacy

By week 4 of treatment, HCV RNA levels had decreased to less than 25 IU per milliliter in all 34 patients (Table 2); all the patients also had HCV RNA levels of less than 25 IU per milliliter at the end of treatment. With regard to the primary end point, 33 of 34 patients had a sustained virologic response at post-treatment week 12, for a rate of 97% (95% confidence interval [CI], 85 to 100). One patient did not have a sustained virologic response owing to a relapse on post-treatment day 3. No relapses occurred after post-treatment week 12; 33 of 34 patients (97%) had a sustained virologic response at post-treatment week 24. All 5 patients infected with genotype 1b (100%) and 28 of 29 patients infected with genotype 1a (97%) had a sustained virologic response. The remaining patient had resistance-associated variants R155K in NS3, M28T and Q30R in NS5A, and G554S in NS5B at the time of relapse, none of which were present at baseline. The NS3 variant Q80K was present in 11 of 29 patients (38%) with HCV genotype 1a infection at baseline, including the patient with a relapse, who had had a null response to prior peginterferon–ribavirin therapy. Variants at resistance-associated positions in NS3, NS5A, and NS5B were each observed in at least 1 patient at baseline (Table S1 in the Supplementary Appendix).

Safety

Adverse events were common, though the majority were mild or moderate in severity (Table 3). The most common adverse events were fatigue, headache, and cough. None of the patients had graft rejection and there were no deaths during the study. One patient discontinued the study drugs after week 18 owing to rash, memory impairment, and anxiety. These events were assessed as having a reasonable possibility of being related to the study drugs; they were moderate in severity. This patient had a sustained virologic response 12 weeks after ending treatment prematurely. Two patients (6%) had serious adverse events. Narratives on these two patients are provided in the Supplementary Appendix.

Grade 3 laboratory abnormalities were infrequent, and no grade 4 abnormalities were observed. Grade 3 elevations in the total bilirubin level were observed in two patients (6%), occurring within the first 8 days of treatment in both. No patient had jaundice or scleral icterus. Elevations in the total bilirubin level predominantly reflected elevated values for indirect bilirubin, a finding consistent with inhibition of the organic anion–transporting protein 1B1 by protease inhibitors. In one patient, total bilirubin levels were transiently elevated on day 92, to a value that was more than 2 times the upper limit of the normal range (predominantly accounted for by an elevated indirect bilirubin level), and alanine aminotransferase levels were transiently elevated on day 85, to a value that was more than 3 times the upper limit of the normal range. The values returned to the normal range on day 120 and on post-treatment day 4, respectively. Owing to persistent low-grade elevation of alanine aminotransferase levels during treatment, a liver biopsy was performed. The biopsy revealed markedly less necroinflammation than the prestudy biopsy, a finding consistent with a resolving HCV infection (Figure S2 in the Supplementary Appendix). This patient had a sustained virologic response at post-treatment week 12.

Grade 2 declines in hemoglobin levels (8 to <10 g per deciliter) occurred in nine patients (26%). One patient had a grade 3 decline in the hemoglobin level (6.5 to <8.0 g per deciliter) on day 15 and stopped ribavirin for 10 days. Erythropoietin was subsequently administered from day 26 to day 53; the hemoglobin level normalized by treatment day 42.

Ribavirin Dosing

The initial doses of ribavirin ranged from 400 to 1200 mg daily (Table 4.). The majority of patients received 600 or 800 mg daily at study initiation (19 of 34 [56%]) and also at the completion of treatment (23 of 34 [68%]). Overall, 19 patients (56%) had a modification in the ribavirin dose during treatment; 9 patients (26%) had modifications owing to declines in hemoglobin levels. Five patients (15%) received erythropoietin after detection of a nadir hemoglobin level of 7.6 to 9.1 g per deciliter. All 5 of these patients had initial ribavirin doses of 1000 to 1200 mg daily, and all 5 had a sustained virologic response at post-treatment week 12. No patient received a blood transfusion.

Dosing of Calcineurin Inhibitors

Modifications in the dose or dosing frequency of calcineurin inhibitors were made on the basis of blood levels of tacrolimus or cyclosporine. For most patients who received tacrolimus, 0.5-mg and 0.2-mg doses of tacrolimus were administered with a median dosing frequency of 10 days and 5 days, respectively. The geometric mean and range of trough blood concentrations of tacrolimus and cyclosporine during treatment were similar to those observed in the pretreatment period and were within the desired therapeutic range (Figure S3 in the Supplementary Appendix).

The mean creatinine clearance was 90.5 ml per minute at baseline and 85.9 ml per minute at week 24. No patient had a creatinine clearance of less than 50 ml per minute during treatment. Five of 29 patients (17%) had tacrolimus concentrations of more than 15.0 ng per milliliter during the treatment period, although dosing errors accounted for the elevations in 4 of the 5 patients. Only one adverse event (mild rash) was reported in a patient with an elevated tacrolimus level. Shortly after treatment completion, 8 patients (28%) had one or more tacrolimus measurements below the laboratory reference range; in all the patients, levels returned to the therapeutic range during subsequent follow-up, and no graft rejection occurred. The suggested adjustments in the cyclosporine dose maintained trough concentrations within the therapeutic range.

Neither tacrolimus nor cyclosporine substantially altered the trough concentrations of ombitasvir, ABT-450, dasabuvir, or ribavirin. The trough concentrations of the study drugs were within the range observed in phase 2 and 3 studies of this regimen.27-31,34

Discussion

Previous studies have shown that overall graft and patient survival rates are lower among liver-transplant recipients with HCV infection than among transplant recipients without HCV infection, owing to universal reinfection and accelerated disease progression. No existing therapeutic regimens are approved for HCV-infected liver-transplant recipients. In the phase 2 CORAL-I trial of a 24-week, interferon-free, all-oral antiviral regimen for HCV genotype 1 infection, a rate of sustained virologic response of 97% (95% CI, 85 to 100) at post-treatment weeks 12 and 24 was observed among liver-transplant recipients with no fibrosis or mild fibrosis. Sustained virologic responses of 96 to 100% have been reported in phase 3 studies of 12 weeks of treatment with ombitasvir–ABT-450/r and dasabuvir with ribavirin in nonimmunosuppressed patients not undergoing liver transplantation.27-30

Studies of a first-generation protease inhibitor (boceprevir or telaprevir) in combination with peginterferon and ribavirin have shown lower rates of sustained virologic response (20 to 71%) and high rates of toxic effects among immunosuppressed patients after transplantation, and some of these toxic effects can be life-threatening.21-24 In a phase 2 evaluation, treatment with the nucleotide polymerase inhibitor sofosbuvir and ribavirin for 24 weeks resulted in a sustained virologic response at post-treatment week 12 in 28 of 40 liver-transplant recipients (70%).35 The patients included in these studies generally had advanced fibrosis, which may be associated with a decreased response rate.

Treatment of liver-transplant recipients with telaprevir or boceprevir plus peginterferon and ribavirin is associated with high rates of treatment discontinuation owing to adverse events. Side effects of these regimens result in frequent use of erythropoietin (in 77 to 100% of patients), modifications in the ribavirin dose (in 70 to 100%), and blood transfusions (in 33 to 64%) to manage anemia.21-24 Grade 3 and grade 4 laboratory abnormalities were each observed in 28% of patients receiving treatment with sofosbuvir and ribavirin, including hemoglobin levels of less than 8.0 mg per deciliter in 20% of patients,35 although this study population included patients with cirrhosis, and such abnormalities may be observed more frequently in patients with cirrhosis than in those without cirrhosis.

In our study, doses of immunosuppressive calcineurin inhibitors were modified during the treatment period to maintain therapeutic levels. No deaths or episodes of graft rejection occurred in this population of difficult-to-cure transplant recipients with HCV infection. The rates of serious adverse events and study discontinuations due to adverse events observed in this small study were lower than the rates that have been observed with the interferon-based treatments that were the previous standard of care.36 Only one patient discontinued the study treatment owing to adverse events, and this patient had a sustained virologic response. In this immunosuppressed population, no new safety signals were identified, and events related to impairment of renal function and grade 3 laboratory abnormalities were similar to those observed in larger trials of this regimen involving patients not undergoing transplantation.27-31,34 However, this study was not large enough to accurately estimate rates of adverse events or to make comparisons with rates of adverse events in prior trials. No patient needed a blood transfusion; five patients (15%) required erythropoietin, all of whom had initially received ribavirin at a total daily dose of 1000 or 1200 mg. These five patients were among the first study participants to receive the study drugs, and this observation was communicated to the investigators with a suggestion to use a lower starting dose of ribavirin. Given the high response rate that was observed, regardless of the initial ribavirin dose, an initial dose of 600 to 800 mg may provide sufficient therapeutic benefit and minimize the risk of severe anemia.

This study has limitations. Patients were excluded if they had advanced fibrosis (Metavir score >F2) or had received interferon-based treatment after transplantation; thus, the study selected patients with cases of HCV infection that have historically been easier to treat than those characterized by advanced fibrosis. In addition, patients underwent transplantation at least 12 months before study initiation, so the study excluded those with early, aggressive forms of recurrent HCV infection (e.g., fibrosing cholestatic hepatitis) that can complicate treatment. Another limitation of the study was that immunosuppressive agents other than tacrolimus and cyclosporine were not evaluated; we assessed only these two agents because previous studies of interactions between drugs were restricted to these two agents.

In light of the worldwide organ shortage, a safe and effective antiviral regimen is needed for the treatment of HCV-infected liver-transplant recipients, who have lower survival rates than other liver-transplant recipients. Treatment of recurrent HCV infection after liver transplantation is associated with improved outcomes in patients who have a sustained virologic response,13-15 including improvements in graft and patient survival, changes that may potentially reduce the demand for retransplantation.8 We found that the multitargeted regimen of ombitasvir–ABT-450/r and dasabuvir with ribavirin resulted in a 97% response rate among immunosuppressed liver-transplant recipients with recurrent HCV genotype 1 infection. This all-oral, interferon-free regimen was efficacious in eradicating HCV infection in a patient population who are at high risk for severe illness and death and for whom treatment options are currently limited.

Supported by AbbVie.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on November 11, 2014, at NEJM.org.

We thank the trial participants, investigators, and coordinators who made this study possible; Anthony “Jake” Demetris, M.D., at the University of Pittsburgh and Christine Collins, Ph.D., Barbara McGovern, M.D., Rajeev Menon, Ph.D., Preethi Krishnan, Ph.D., Gretja Schnell, Ph.D., Rakesh L. Tripathi, M.S., Michelle Irvin, and Thomas Reisch, employees of AbbVie, for contributions to the study; and Douglas E. Dylla, Ph.D., of AbbVie for medical-writing support.

Source Information

From Indiana University, Indianapolis (P.Y.K.); the Liver Institute at Methodist Dallas, Dallas (P.S.M.); AbbVie, North Chicago, IL (E.C., W.X., C.S., P.B., T.P.-M., R.A.V.); University of Chicago Medical Center (H.S.T.) and Northwestern University Comprehensive Transplant Center (J.L.) — both in Chicago; Mayo Clinic, Phoenix, AZ (H.E.V.); Columbia University Medical Center, Center for Liver Disease and Transplantation, New York (R.B.); Lahey Hospital and Medical Center, Burlington, MA (F.G.); University of California, San Francisco, San Francisco (N.A.T.); University of Colorado Denver, Aurora (J.R.B.); and the Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona (X.F.).

Address reprint requests to Dr. Kwo at the Gastroenterology/Hepatology Division, Indiana University School of Medicine, 975 W. Walnut, IB 327, Indianapolis, IN 46202-5121, or at pkwo@iu.edu.

Source