Showing posts with label 2014-EASL. Show all posts
Showing posts with label 2014-EASL. Show all posts

Friday, April 11, 2014

EASL - Gilead's Sovaldi® Demonstrates Efficacy/Safety Among Chronic Hepatitis C Patients with Advanced Liver Disease

Elsewhere - New data reveals positive outcomes for hepatitis C transplant patients
New research announced at the International Liver CongressTM 2014 today provides new hope for the notoriously difficult-to-treat population of liver transplant patients with recurring hepatitis C (HCV). As part of a compassionate use program, 104 post-liver transplant patients with recurring HCV who had exhausted all treatment options and had poor clinical prognoses, received sofosbuvir (SOF) and ribavirin (RBV) with pegylated interferon (PEG) included at the physicians' discretion for up to 48 weeks. Among patients whose clinical outcomes have been reported, 62% achieved SVR12. Additionally, 62% of patients had improvements in clinical conditions associated with hepatic decompensation (e.g., ascites and encephalopathy) and/or improvement in liver function tests. SOF+RBV±PEG was well-tolerated and led to high rates of virologic suppression.

Press Release

Gilead's Sovaldi® Demonstrates Efficacy and Safety Among Chronic Hepatitis C Patients with Advanced Liver Disease

-- Benefit in Patients with Decompensated Cirrhosis and Recurrent HCV Infection Following Liver Transplantation --

LONDON--(BUSINESS WIRE)--Apr. 11, 2014-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced data from two Phase 2 studies and a compassionate access study in which a regimen containing once-daily Sovaldi® (sofosbuvir) 400 mg was administered for the treatment of chronic hepatitis C virus (HCV) infection in patients with advanced liver disease. These data are being presented this week at the 49th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress 2014) in London.

The first study, Study GS-US-334-0125 (Oral #068), is an ongoing open-label Phase 2 clinical trial evaluating HCV patients with cirrhosis and portal hypertension, with or without decompensation, who were randomized 1:1 to an immediate treatment arm in which Sovaldi and ribavirin (RBV) was administered for 48 weeks (n=25) or to a deferred treatment arm in which this regimen was initiated after a 24-week observation period (n=25). Eighty percent of participants were treatment-experienced.

Of the 22 patients who completed 24 weeks of therapy, 95 percent (n=21/22) achieved virologic suppression on treatment. Additionally, patients taking Sovaldi-based therapy experienced trends in clinical and laboratory parameter improvements compared to patients in the observation arm. Sovaldi-based therapy was well tolerated in the study, and only one patient discontinued treatment due to an adverse event. The most common adverse events occurring in more than 25 percent of patients included nausea and pruritis. Patients in both arms of the study will be followed to determine their 12-week sustained virologic response rates (SVR12) after 48 weeks of Sovaldi-based therapy.

Study GS-US-334-0126 (Poster #1232), was a single-arm open-label Phase 2 trial in which patients with established recurrent HCV infection following liver transplantation received up to 24 weeks of therapy with Sovaldi plus RBV (escalating doses starting at 400 mg/day). The majority of patients had genotype 1-HCV infection (n=33/40) and 88 percent (n=35/40) were treatment-experienced.

Seventy percent (n=28/40) of patients in this study achieved SVR12. The most common adverse events occurring in more than 20 percent of patients were fatigue, headache, arthralgia (joint pain) and diarrhea. There were no deaths, graft losses or episodes of organ rejection among post-liver transplantation patients, and no drug-drug interactions were reported between Sovaldi and immunosuppressive agents.

A third, compassionate access study (Oral #62), evaluated Sovaldi therapy among 104 post-transplant patients with severe recurrent HCV, including fibrosing cholestatic hepatitis, who had exhausted all other treatment options and received pre-approval access to Sovaldi via Gilead's compassionate use program. Patients received up to 48 weeks of Sovaldi plus RBV, with some patients also receiving pegylated interferon (peg-IFN) (180 µg/week) at their physician's discretion. The majority of patients in the study experienced clinical improvements on treatment. Overall, 62 percent of patients achieved SVR12. Sovaldi-based therapy was well tolerated.

"The patients included in these analyses are historically among the most difficult to cure, and many have had no appropriate treatment options until now," said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer, Gilead Sciences. "These data demonstrate that Sovaldi-based oral therapy can improve outcomes, has a favorable safety profile and is well tolerated among hepatitis C patients with severe liver disease."

Additional information about Study GS-US-334-0125 and Study GS-US-334-0126 can be found at www.clinicaltrials.gov.

About Sovaldi

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

Sovaldi was approved in the United States on December 8, 2013 and in the European Union on January 17. In the United States, Sovaldi is approved for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen. Efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection. Treatment response varies based on baseline host and viral factors. Monotherapy is not recommended for treatment of chronic hepatitis C. Studies GS-US-334-0125 and GS-US-334-0126 evaluated investigational uses of Sovaldi, for which safety and efficacy have not yet been established.

IMPORTANT SAFETY INFORMATION

Contraindications

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

Warnings and Precautions
Pregnancy: Use with Ribavirin or Peginterferon Alfa/Ribavirin: Ribavirin therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Female patients of childbearing potential and their male partners must use two forms of non-hormonal contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. Refer to the prescribing information for ribavirin.
Use with Potent P-gp Inducers: Rifampin and St. John's wort should not be used with Sovaldi as they may significantly decrease sofosbuvir plasma concentration, reducing its therapeutic effect.

Adverse Reactions

Most common (=20 percent, all grades) adverse reactions for:
Sovaldi + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia, and anemia
Sovaldi + ribavirin combination therapy were fatigue, and headache

Drug Interactions

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

About Gilead Sciences

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

Forward-Looking Statement

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

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

Sovaldi is a registered trademark of Gilead Sciences, Inc.

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

Download - EASL Recommendations on Treatment of Hepatitis C 2014

http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C/index.htmlEASL Recommendations on Treatment of Hepatitis C 2014

New guidelines for hepatitis C by European Medicines Agency (EMA) was released today at the EASL International Liver Congress 2014 meeting, the World Health Organization (WHO) issued its first guidance for the treatment of hepatitis C earlier this week.

According to an article published yesterday at Medscape Medical News; Jean-Michel Pawlotsky, MD, PhD, director of the French National Reference Centre for Viral Hepatitis stated that this new EASL document constitutes recommendations rather than guidelines because of the need to circumvent the traditional long guideline development process, which "doesn't fit the HCV field any longer."

In addition, Dr. Stefan Z. Wiktor noted both documents are expected to be revised soon. "It's such a rapidly moving field that, even as we were developing the guidelines, we had to modify our schedule to include recommendations on the newest drugs,"

EASL Recommendations on Treatment of Hepatitis C 2014
Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide. The long-term impact of HCV infection is highly variable, ranging from minimal histological changes to extensive fibrosis and cirrhosis with or without hepatocellular carcinoma (HCC)
(read more by viewing or downloading EASL recommendations)
 
Full version:  
EASL Recommendations on Treatment of Hepatitis C 2014
(
download pdf)

Summary:
EASL Recommendations on Treatment of Hepatitis C 2014(download pdf)

Doctors welcome hepatitis C drug rivals, Gilead still leads

Doctors welcome hepatitis C drug rivals, Gilead still leads
LOS ANGELES/LONDON Fri Apr 11, 2014 1:04am EDT

Reuters - Doctors at a key medical conference welcomed the prospect of more new drugs to treat the liver-destroying hepatitis C virus, while agreeing that Gilead Sciences Inc continues to lead the effort.

Gilead, under fire from insurers and legislators for the $1,000-a-pill price of its Sovaldi drug, presented pivotal data on Friday at the European Association for the Study of the Liver conference in London, showing a cure rate of 94 percent after eight weeks of treatment with its experimental two-drug pill.

Midstage trial results from Merck & Co Inc, also presented at the meeting, showed that 12 weeks of therapy with its two-drug combination cured 98 percent of previously-untreated patients.

AbbVie and Bristol-Myers Squibb are also developing new generation all-oral hepatitis C treatments that have demonstrated cure rates in excess of 90 percent.

Citi Research sees Gilead as the clear market leader, but in the long term expects that Merck will be the second largest player, followed by AbbVie.

"We assume Merck will use aggressive pricing to maximize market share," Citi analyst Yaron Werber said in a research note.

Wall Street analysts, on average, forecast Sovaldi sales of $9.1 billion in 2017, according to Thomson Reuters Pharma.

Doctors at the London meeting said the value proposition of the new direct-acting antiviral drugs should stack up for governments and insurers, given the potential huge costs down the line from the disease, which can lead to liver cirrohosis and liver transplants.

"Competition will drive the price down, but probably not far enough," said Markus Peck-Radosavljevic, professor of medicine in the Medical University of Vienna and secretary-general of EASL.

The current U.S. price for a 12-week course of treatment with Sovaldi is $84,000, and Gilead has said the price in the United Kingdom is about $57,000.

"We spend at least this sort of money for cancer drugs, which only prolong patients' lives by a few weeks, and often with much worse side effects," said Dr Mark Thurz, professor of hepatology at Imperial College, London.

AVOIDING STRONGER SIDE EFFECTS

The World Health Organization estimates that 150 million people worldwide are infected with hepatitis C, which can be spread through blood, often via contaminated needles.

Before Sovaldi's launch late last year, patients with hepatitis C had to be treated for at least six months with several drugs, including interferon, an injected medicine that can cause severe flu-like symptoms, and ribavirin, which can cause rash, anemia and other side effects.

The combination of Gilead's Sovaldi and ledipasvir, an experimental drug from a class known as NS5A inhibitors, was shown to work better than the same regimen plus ribavirin.

The trial, also published in the New England Journal of Medicine, involved 647 previously untreated patients with genotype 1 hepatitis C - the hardest to treat, but the most common type in the United States - who had not developed liver cirrhosis.

"The key points useful to clinicians here are the very high rates of sustained virologic response and very good safety profile," said Dr Kris Kowdley, director of the liver center at Seattle's Virginia Mason Medical Center and the study's lead author.

More patients in the ribavirin group suffered side effects such as fatigue, headache and nausea.

The U.S. Food and Drug Administration has granted priority review to Gilead's application for the once-daily combination of Sovaldi, or sofosbuvir, and ledipasvir. The agency is slated to decide on the marketing application by October 10.

(Additional reporting by Bill Berkrot; Editing by Michele Gershberg and Ken Wills)

Thursday, April 10, 2014

EASL AbbVie's ABT-450 - Cure Rate for Experimental Hepatitis C Drug Tops 95 Percent

New England Journal of Medicine:
Retreatment of HCV with ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin
In this phase 3 trial we evaluated the efficacy and safety of the interferon-free combination of ABT-450 with ritonavir (ABT-450/r), ombitasvir (also known as ABT-267), dasabuvir (also known as ABT-333), and ribavirin for the retreatment of HCV in patients who were previously treated with peginterferon–ribavirin...

Coverage@ Healio
SAPPHIRE II: Ritonavir-boosted triple regimen plus ribavirin achieved high SVR12 rates.
LONDON — Sustained virologic response rates at 12 weeks were more than 90% across several treatment groups in a cohort of patients who previously failed pegylated interferon and ribavirin therapy who received ritonavir-boosted ABT-450, ABT-267 and ABT-333 with ribavirin....

Coverage@NATAP
Slides
EASL: SAPPHIRE-II: PHASE 3 PLACEBO-CONTROLLED STUDY OF INTERFERON-FREE, 12-WEEK REGIMEN OF ABT-450/r/ABT-267, ABT-333, AND RIBAVIRIN IN 394 TREATMENT-EXPERIENCED ADULTS WITH HEPATITIS C VIRUS GENOTYPE 1 
(04/10/14) 

Cure Rate for Experimental Hepatitis C Drug Tops 95 Percent
April 10
HealthDay New

Researchers report that an experimental drug has cured more than 95 percent of patients infected with hepatitis C, including some who failed other treatments.

If it wins approval from the U.S. Food and Drug Administration, this new drug, called ABT-450, could potentially compete with another innovative hepatitis C medication that costs $1,000 a day.

Nearly 3 million Americans have hepatitis C, a disease that can cause liver cirrhosis and cancer.

These newer, advanced treatments are better-tolerated and easier to take than interferon, the traditional standard treatment for hepatitis C, researchers say.

"Interferon is no longer required to cure hepatitis C," said Dr. Stefan Zeuzem, a professor of medicine at the J.W. Goethe University Hospital in Frankfurt, Germany, and lead researcher on the ABT-450 study.

His research pairing ABT-450 with other interferon-free medications showed "almost all patients with chronic hepatitis C can be cured even if previous treatments were unsuccessful," Zeuzem said.

The report was published online April 10 in the New England Journal of Medicine, to coincide with presentation of the findings at the annual meeting of the European Association for the Study of the Liver in London. The drug trial was funded by the drug's maker, AbbVie.

"Hepatitis C is a big, bad problem," said Dr. William Carey, a liver specialist at the Cleveland Clinic in Ohio.

This new drug represents "one among many breakthroughs in our ability to deal with hepatitis C," Carey said.

An advantage to this treatment is that it is a pill, while interferon is given in weekly injections. Also, older treatments went on for a year, while this new therapy takes only three months to work, Carey said.

Interferon treatment also has severe side effects, including fatigue and flu-like symptoms.

"This is not the only drug combination that is interferon-free, but it's a very promising one," he said.

One drawback to the therapy is that some pills are taken once a day and some twice, which might make following the treatment tricky. Carey hopes that treatment eventually is simplified. "Wouldn't it be great if we could take one or two pills once a day and be done with it?" he said.

Since many people with hepatitis C remain symptom-free, the medical community has not agreed on whom to treat.

With these new cures, that question becomes easier to answer, Carey said. "When you have a treatment that is this simple, effective and free of side effects, there are fewer and fewer reasons to think about withholding treatment," he noted.

"The major barrier is cost," he added.

Whether the new drug will be priced like Sovaldi, the $1,000-a-day medication, is still unknown.

With Sovaldi, the necessary three-month course costs $90,000, plus any other drug expenses and medical care.

Carey said some insurance companies cover the cost of the drug, while others have denied it.

Cost is even more significant in light of the millions of Baby Boomers who are five times more likely to be infected with hepatitis C than other adults, according to the U.S. Centers for Disease Control and Prevention.

"It's going to get harder as time goes on for insurance companies not to cover the cost of these drugs," Carey said. "This is a curable disease."

According to a CBS News report, lawmakers and insurance companies complain that Gilead Sciences, the maker of Sovaldi, is trying to "milk desperate patients." Gilead says that, despite the high price, Sovaldi is cheaper because it "cures patients quickly and eliminates a long and expensive treatment using other drugs."

For this phase 3 trial of ABT-450 -- typically the last trial needed for FDA approval -- nearly 400 patients were randomly assigned to take a placebo or a combination of ABT-450 and these other pills: ombitasvir, ritonavir, dasabuvir or ribavirin. All patients had been treated before, but saw their diseases return or had a poor response or no response to treatment.

Taking the ABT-450 combination, 96.3 percent of the patients responded, the researchers said.

Previous research showed that patients who had never been treated also responded to this combination.

Dr. Marc Siegel, an associate professor of medicine at NYU Langone Medical Center, New York City, said the results look promising for the millions of people with hepatitis C.

"Hepatitis C is under-diagnosed," said Siegel.

These new treatments, with their high cure rates, make it important to diagnose and treat hepatitis C early to prevent cirrhosis and liver cancer, he said.

Hepatitis C can be spread by injectable drug use or sexual contact with an infected person. The U.S. Centers for Disease Control and Prevention recommends one-time screening for those born between 1945 and 1965 -- that's potentially millions of people who would qualify for treatment.

More information
For more information on hepatitis C, visit the U.S. National Library of Medicine.

Posted: April 2014

Press Release

Enanta Pharmaceuticals Announces Detailed Data from SAPPHIRE-I and SAPPHIRE-II Phase 3 Studies in Patients with Chronic Hepatitis C Virus Being Presented at EASL 2014
April 11, 2014 
— Enanta Pharmaceuticals, Inc. (NASDAQ:ENTA), a research and development-focused biotechnology company dedicated to creating small molecule drugs in the infectious disease field, today announced that detailed results from AbbVie’s pivotal phase 3 SAPPHIRE-I study, will be presented today at the International Liver Congress (ILC), which is the 49th Annual Meeting of the European Association for the Study of the Liver (EASL) and featured in the ILC press conference. Results from the SAPPHIRE-II study were presented at the congress yesterday. Additionally, results from both the SAPPHIRE-I and SAPPHIRE-II studies have been published on-line in the New England Journal of Medicine.

The SAPPHIRE-I and SAPPHIRE-II studies report results from AbbVie’s investigational three direct-acting antiviral regimen containing ABT-450, Enanta’s lead protease inhibitor developed through Enanta’s collaboration with AbbVie. The regimen consists of boosted protease inhibitor ABT-450/ritonavir, NS5A inhibitor ABT-267, and non-nucleoside polymerase inhibitor ABT-333.
In the SAPPHIRE-I (N=631) and SAPPHIRE-II (N=394) placebo-controlled studies, adult, non-cirrhotic patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection receiving the investigational three-direct-acting antiviral regimen with ribavirin (RBV) for 12 weeks achieved sustained virologic response rates 12 weeks post-treatment (SVR12) of 96.2 percent (n=455/473) and 96.3 percent (n=286/297), respectively.

In SAPPHIRE-II, treatment-experienced sub-populations randomized to the three direct-acting antiviral regimen with RBV in the study were prior null responders (49.2 percent), prior relapsers (29.0 percent) and prior partial responders (21.9 percent) to pegylated interferon and RBV.
SAPPHIRE-I and SAPPHIRE-II Results
          SAPPHIRE-I SVR12
(n=473)
        SAPPHIRE-II SVR12
(n=297)
All GT1         96.2% (n=455/473)         96.3% (n=286/297)*
GT1a         95.3% (n=307/322)         96.0% (n=166/173)
GT1b         98.0% (n=148/151)         96.7% (n=119/123)
Treatment-experienced (GT1a and GT1b)
Prior null responders         n/a         95.2% (n=139/146)
Prior relapsers         n/a         95.3% (n=82/86)
Prior partial responders         n/a         100.0% (n=65/65)
               
*Subgenotype could not be determined for one patient

In SAPPHIRE-I, high response rates were seen across patients with certain variable characteristics, including gender, race, body mass index, fibrosis stage and baseline HCV viral load, as some of these patients have historically had a reduced response to treatment.

Discontinuations due to adverse events were reported in 0.6 percent of patients in both arms in SAPPHIRE-I and in 1.0 percent of patients receiving the AbbVie regimen in SAPPHIRE-II and no patients receiving placebo. The most commonly reported treatment-emergent adverse events (>10 percent in either arm) for both SAPPHIRE-I and SAPPHIRE-II were fatigue, headache, nausea, asthenia, insomnia, pruritus and diarrhea. Additional common adverse events occurring in the studies were rash in SAPPHIRE-I and dyspnea, cough and myalgia in SAPPHIRE-II. In SAPPHIRE-I, the adverse events that occurred with a significantly greater frequency in the treatment arm compared to placebo were pruritus, insomnia, diarrhea, nausea and asthenia; in SAPPHIRE-II, only pruritus.

About Study M11-646 (SAPPHIRE-I)
SAPPHIRE-I is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with the three direct-acting antiviral regimen with RBV in non-cirrhotic, GT1a and GT1b HCV-infected adult patients new to therapy.
The study population consisted of 631 patients: 473 were randomized to the three direct-acting antiviral regimen with RBV for 12 weeks, and 158 patients were randomized to placebo for the initial 12 weeks. Patients initially randomized to placebo for the first 12 weeks then received open-label treatment with the AbbVie regimen with RBV for 12 weeks.

Of the 473 patients randomized to the three direct-acting antiviral regimen with RBV, one case (0.2 percent) of on-treatment virologic failure occurred and seven patients (1.5 percent) experienced post-treatment relapse. In addition, three patients (0.6 percent) were lost to follow-up and seven patients (1.5 percent) discontinued the study prematurely. Patients lost to follow-up were considered treatment failures.

About Study M13-098 (SAPPHIRE-II)
SAPPHIRE-II is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with the three direct-acting antiviral regimen with RBV in non-cirrhotic, GT1a and GT1b HCV-infected, treatment-experienced adult patients who previously failed treatment with pegylated interferon and RBV.
The study population consisted of 394 patients: 297 were randomized to the three direct-acting antiviral regimen with RBV for 12 weeks, and 97 patients were randomized to placebo for the initial 12 weeks. Patients initially randomized to placebo for the first 12 weeks then received open-label treatment with the three direct-acting antiviral regimen with RBV for 12 weeks.

Of the 297 patients randomized to the three direct-acting antiviral regimen with RBV, there were no cases of on-treatment virologic failure and seven patients (2.4 percent) experienced post-treatment relapse. Of these patients, six were prior null responders and one was a prior relapser. Three patients (1.0 percent) prematurely discontinued therapy due to adverse events and one patient (0.3 percent) prematurely discontinued the study.

Additional information about AbbVie’s phase III studies can be found on www.clinicaltrials.gov.

About ABT-450
ABT-450 is an NS3 protease inhibitor discovered through Enanta’s collaboration with AbbVie. AbbVie and Enanta have an agreement to collaborate on the discovery, development and commercialization of HCV NS3 and NS3/4A protease inhibitors. Protease inhibitors play an essential role in the viral life cycle of the hepatitis C virus (HCV). Inhibition of the protease prevents non-structural (NS) proteins from forming and thereby prevents replication and survival of the HCV virus. ABT-450 is part of AbbVie’s investigational regimen for HCV that consists of boosted protease inhibitor ABT-450/ritonavir (referred to as ABT-450/r), NS5A inhibitor ABT-267 and non-nucleoside polymerase inhibitor ABT-333.

Source

EASL-Gilead Announces Phase 2 Results for Two Investigational All-Oral Sofosbuvir-Based Regimens for the Treatment of Chronic Hepatitis C


Also See:
(Sovaldi, formerly GS-7977) and NS5A inhibitor ledipasvir (formerly GS-5885) based combinations
Sofosbuvir/Ledipasvir
Sofosbuvir/Ledipasvir and GS-9669
Sofosbuvir/Ledipasvir and GS-9451

****** In addition Sovaldi and GS-5816
alone without ribavirin

Gilead Phase 2 Results for Two Investigational All-Oral Sofosbuvir-Based Regimens for the Treatment of Hepatitis C

PDF Download 

-- Data Support Efficacy of Ledipasvir/Sofosbuvir Fixed-Dose Combination with Ribavirin in Genotype 3 HCV; Product Under Regulatory Review for Genotype 1 in U.S., Europe --
 
-- Combination of Sofosbuvir and GS-5816 Demonstrates Efficacy Against HCV Genotypes 1-6 --
 
LONDON--(BUSINESS WIRE)--Apr. 10, 2014-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced data from two Phase 2 studies evaluating investigational all-oral regimens containing the nucleotide analog polymerase inhibitor sofosbuvir (SOF) for the treatment of chronic hepatitis C virus (HCV) infection.

These data are being presented this week at the 49th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress 2014) in London.

The first study, ELECTRON2 (Oral #6), is an ongoing, open-label Phase 2 clinical trial evaluating a once-daily fixed-dose combination of SOF 400 mg and the NS5A inhibitor ledipasvir (LDV) 90 mg, with and without ribavirin (RBV) twice-daily (1,000 or 1,200 mg/day), among HCV-infected patient populations.

In this study, 100 percent (n=26/26) of treatment-naïve genotype 3 patients receiving 12 weeks of LDV/SOF plus RBV and 64 percent (n=16/25) of treatment-naïve genotype 3 patients receiving 12 weeks of LDV/SOF without RBV achieved a sustained virologic response 12 weeks after completing therapy (SVR12). Among genotype 1-infected patients who had failed prior treatment with SOF plus RBV, 100 percent (19/19) achieved SVR12 following 12 weeks of LDV/SOF plus RBV. Additionally, 65 percent (n=13/20) of genotype 1-infected patients with decompensated or Child-Turcotte-Pugh Class B cirrhosis receiving 12 weeks of LDV/SOF without RBV achieved SVR12. LDV/SOF with and without RBV was well-tolerated, including among patients with more advanced liver disease.

“The ELECTRON2 data suggest that an all-oral regimen of LDV/SOF plus RBV has the potential to provide high cure rates for genotype 3 patients in just 12 weeks – half the duration of current all-oral treatment regimens,” said Professor Edward Gane, MD, Deputy Director and Hepatologist, New Zealand Liver Transplant Unit, Auckland City Hospital in New Zealand, and principal investigator of the ELECTRON2 study. “These results also suggest that LDV/SOF may be an effective treatment regimen for HCV genotype 1-infected patients who have failed a previous sofosbuvir-based regimen and those with advanced liver disease, including decompensated cirrhosis.”

A second study, Study GS-US-342-0102 (Oral #111), is an ongoing randomized Phase 2 clinical trial in which treatment-naïve, non-cirrhotic patients with genotypes 1-6 HCV infection received a 12-week course of SOF plus the pan-genotypic NS5A inhibitor GS-5816. Patients received SOF 400 mg and either GS-5816 25 mg (n=77) or GS-5816 100 mg (n=77). In this study, 94.8 percent (n=73/77) of patients receiving the 25 mg dose of GS-5816 and 96.1 percent (n=74/77) of patients receiving the 100 mg dose achieved SVR12.

“The results of this study of sofosbuvir with a new pan-genotype NS5A inhibitor demonstrate the curative potential of this combination,” said Gregory T. Everson, MD, Professor of Medicine and Director, Section of Hepatology, University of Colorado, Denver, and principal investigator of Study GS-US-342-0102. “The combination was not only effective across all genotypes and patient subgroups, but also was well tolerated. These results warrant additional study in future trials, with the hope of providing a potent, pan-genotypic combination with few side effects and a high chance for cure.”

The most common adverse events occurring in more than 10 percent of patients were fatigue, headache and nausea. There were no treatment discontinuations due to adverse events, and no evidence of treatment-related laboratory abnormalities.

Additional information about ELECTRON2 and GS-US-342-102 can be found at www.clinicaltrials.gov.

About SOF-Based Fixed-Dose Combinations
Full data from three Phase 3 clinical trials of the LDV/SOF fixed-dose combination (ION-1, ION-2 and ION-3) are also being presented at The International Liver Congress 2014. Gilead announced topline results from the ION studies on December 18, 2013. On February 10, 2014, Gilead submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the LDV/SOF fixed-dose combination tablet for the treatment of genotype 1 HCV infection in adults. The FDA has assigned the product a Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options. On April 7, 2014, the company announced that the FDA has granted the application a priority review, setting a target action date under the Prescription Drug User Fee Act (PDUFA) of October 10, 2014.

On March 27, 2014, the European Medicines Agency (EMA) accepted Gilead’s request for accelerated assessment for LDV/SOF, a designation that is granted to new medicines of major public health interest. Accelerated assessment could shorten the EMA’s review time of LDV/SOF by two months, although it does not guarantee a positive opinion from the Committee for Medicinal Products for Human Use, or final approval by the European Commission.

Gilead has developed a once-daily fixed-dose combination tablet containing SOF and GS-5816. A second Phase 2 clinical trial (Study GS-US-342-0109) evaluating 12 weeks of SOF plus GS-5816, with or without RBV, among treatment-experienced cirrhotic and non-cirrhotic patients with genotypes 1 or 3 HCV infection is ongoing. Pending full results from Studies GS-US-334-102 and GS-US-342-0109, Gilead plans to initiate Phase 3 studies evaluating the efficacy and safety of the SOF/GS-5816 fixed-dose combination.

LDV/SOF and SOF/GS-5816 are investigational products and their safety and efficacy have not yet been established.

SOF as a single agent is approved as Sovaldi® in the United States, European Union, Canada, New Zealand and Switzerland.

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

Forward-Looking Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that the FDA, European Commission and other regulatory agencies may not approve the LDV/SOF fixed-dose combination in the currently anticipated timelines or at all, and that any marketing approvals, if granted, may have significant limitations on its use. Further, additional clinical studies of LDV/SOF, including subsequent results from ELECTRON2, may produce unfavorable results. As a result, Gilead may not be able to successfully commercialize LDV/SOF, and may make a strategic decision to discontinue its development if, for example, the market for the product fails to materialize as expected. Additional risks include the possibility of unfavorable results from additional studies of SOF/GS-5816 and the possibility that Gilead may make a strategic decision to discontinue development of the fixed-dose combination of SOF/GS-5816 if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Sovaldi is available at www.gilead.com.
Sovaldi is a registered trademark of Gilead Sciences, Inc.
For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

EASL - Gilead Announces Results from Study of Sovaldi® for Retreatment of Chronic Hepatitis C

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

LONDON --(Business Wire)--

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

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

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

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

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

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

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

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

About Sovaldi

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

Sovaldi was approved in the United States on December 8, 2013 and in the European Union on January 17. In the United States, Sovaldi is approved for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen.

Efficacy has been established in subjects with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection. Treatment response varies based on baseline host and viral factors.

Monotherapy is not recommended for treatment of chronic hepatitis C. Study GS-US-334-0109 evaluated investigational uses of Sovaldi, for which safety and efficacy have not yet been established.

EASL-Merck reports mid-stage data for MK-5172 and MK-8742, all-oral hepatitis C regimen

Investment Commentary
UPDATED: Watch out Gilead, Merck is mounting a hep C combo comeback
Merck may be late to the blockbuster party with its new hepatitis C drugs, but the pharma giant is moving fast with a top contender boasting high cure rates. Merck ($MRK) unveiled interim Phase II results for an oral combination of MK-5172, its NS3/4A protease inhibitor, and MK-8742, an NS5A, among patients with chronic HCV genotype 1 infection. After 12 weeks of therapy 42 of 43 patients--98%--demonstrated a sustained viral response. The combination plus ribavirin hit a 94% cure rate. And the drugs did it without any injections of interferon, which is widely hated by patients.

Merck hepatitis C drugs shine in easier to treat patients: study
By Bill Berkrot
Thu Apr 10, 2014 1:17am EDT 
Reuters - A two-drug combination being tested by Merck & Co to treat hepatitis C cured 98 percent of previously untreated patients without cirrhosis in a midstage clinical trial, providing the latest evidence that the U.S. drugmaker will be highly competitive in the fast evolving field.

Results of the study called C-Worthy were presented on Thursday at the annual meeting of the European Association for the Study of the Liver (EASL) in London. Researchers are due on Friday to present results of how the Merck pills fared in more difficult to treat patients, such as those who failed to be helped by prior treatments and those with more advanced liver disease.

In the arm of the Phase II study presented on Thursday, 43 of 44 patients treated with 100 milligrams of MK-5172 and 50 mg of MK-8742 once a day for 12 weeks achieved sustained virologic response (SVR), which is considered cured. One patient relapsed, researchers said.

Those who have no detectable levels of the hepatitis C virus in their blood 12 weeks after completing the 12 weeks of treatment are deemed to have achieved SVR.

Current standard treatments take 24 or 48 weeks, cure about 75 percent of patients and involve miserable side effects that have led thousands of patients to put off treatment and wait for highly touted new drugs to become available.

The study also included results of patients treated with the two Merck drugs plus the older drug ribavirin for both 12 weeks and eight weeks. But all eyes will be on the ribavirin-free results as several companies race to produce all-oral treatment regimens that include neither ribavirin nor interferon, which are both used in current treatments and cause flu-like symptoms, anemia and other side effects.

Gilead Sciences Inc, AbbVie and Bristol-Myers Squibb Co are also developing a new generation of all-oral hepatitis C treatments that in previous trials have demonstrated cure rates in excess of 90 percent, while cutting treatment duration to 12 weeks with few side effects.

Gilead, which later this year could have a one pill, once a day two-drug regimen approved in the United States, is widely perceived by Wall Street to be the best of the bunch with some analysts forecasting annual sales of $9 billion or more.

Merck is a bit behind the other three companies in its development timeline, but could prove to be the one that gives Gilead a run for its money as it aims to also produce a one pill, once a day regimen. The AbbVie and Bristol-Myers programs involve more pills and more drugs, but equally impressive cure rates so far in clinical testing.

"Merck has begun a Phase III trial in (previously untreated patients) using one pill, once per day. This should increase everyone's confidence that Merck really has a regimen competitive with Gilead's," ISI Group analyst Mark Schoenebaum said in a research note.

The Merck anti-viral medicines, which hamper the virus' ability to replicate in different ways, were tested in patients who had the genotype 1 form of the virus - the most prevalent and considered the most difficult to treat.

The most common side effects seen with the Merck drugs were fatigue, headache and nausea.

An estimated 170 million people are believed to be infected with hepatitis C worldwide. If left untreated, the progressive disease can lead to cirrhosis, liver cancer or the need for a liver transplant.

(Reporting by Bill Berkrot; Editing by Bernard Orr)

Press Release

Merck Announces Results from Studies Evaluating Investigational Hepatitis C Treatments, MK-5172 and MK-8742, in Treatment-Naïve Patients with Genotype 1 Infection

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced additional data from the ongoing C-WORTHy study, a multi-arm Phase 2 clinical trial evaluating the efficacy and safety of a once-daily, all-oral regimen combining MK-5172, an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor, and MK-8742, an investigational HCV NS5A replication complex inhibitor, among patients with chronic HCV Genotype 1 infection (GT1). In an interim analysis of treatment-naïve, non-cirrhotic patients administered a 12-week regimen of MK-5172/MK-8742, with and without ribavirin (RBV), a sustained viral response1 (SVR) was observed in 98 percent (42/43) of patients administered MK-5172/MK-8742 alone and 94 percent (75/80) in those administered MK-5172/MK-8742 plus RBV.

These data were presented, along with data on an 8-week regimen, at the 49th Annual Meeting of the European Association for the Study of the Liver (EASL), also known as The International Liver Congress™ 2014, in London, UK.

“These Phase 2 results add to growing evidence for the potential efficacy of MK-5172 and MK-8742 for treatment of chronic HCV infection,” said Dr. Eliav Barr, vice president, Infectious Diseases, Merck Research Laboratories. “These findings are integral to advancing our research of these investigational candidates into C-EDGE, the Phase 3 clinical program that will seek to more broadly evaluate the potential of MK-5172/MK-8742 in diverse patient populations.”

C-WORTHy Study Design
C-WORTHy is a two-part, parallel-group, randomized (within group) clinical trial evaluating a range of subpopulations of patients with HCV GT1 infection. The study evaluated different treatment durations of MK-5172 (100 mg once daily) plus MK-8742 (50 mg once daily), with or without RBV. A total of 471 patients with HCV GT1 RNA levels of ≥10,000 IU/mL were enrolled in C-WORTHy across 16 arms.

Key Findings for MK-5172/MK-8742
The interim results presented were from treatment-naïve, non-cirrhotic patients who received one of 3 regimens: A) MK-5172/MK-8742 + RBV for 8 weeks (N=30), B) MK-5172/MK-8742 + RBV for 12 weeks (N=85), and C) MK-5172/MK-8742 (without RBV) for 12 weeks (N=44), (see table 1).

Table 1 – Interim Results from the C-WORTHy Trial Showing Treatment-Naïve, Non-Cirrhotic Patients with HCV GT1 Infection (Intention-to-Treat (ITT) Analysis)
                   
Parameter     MK-5172 + MK-8742
(NO RBV)
(12 Weeks)
(N =44)
    MK-5172 + MK-8742 + RBV
(12 Weeks)
(N = 85)
    MK-5172 + MK-8742 +
RBV
(8 Weeks)
(N =30)
SVR4-24, % (n)     98% (43)     94% (80)     83% (25)
No SVR, % (n)
Breakthrough     0     1% (1)     0
Relapse     2% (1)     1% (1)     17% (5)
Non-virologic Discontinuation     0     4% (3)     0
By Sub-genotype
GT1a     97% (29)     94% (49)     83% (25)
GT1b§     100% (14)     94% (31)     --

† Part A: 100% of patients completed Follow-up week (FU)24; Part B: 8 week arm: 93% have completed FU8; 12 week arm: 100% of patients have completed FU4; 2 patients (Part A) and 1 patient (Part B) discontinued early and are counted as failures. 
§ Two patients with GT1 (non-a, non-b) were enrolled; these are analyzed with GT1b.

Among the five patients who relapsed in the eight-week regimen arm of PN035B, two patients had very low MK-5172 and MK-8742 levels during the course of therapy. The relationship between this finding and the relapse is being investigated. 

The most common adverse events recorded in the RBV and RBV-free treatment groups, respectively, were fatigue (32%, 23%), headache (20%, 33%), nausea (21%, 16%), diarrhea (13%, 9%) and insomnia (13%, 7%). There were no early discontinuations due to drug-related adverse events and no clinically significant abnormalities detected in routine laboratory analysis of hematologic markers.

PN038 Study Design and Findings
Additionally, new data from PN038, a Phase 2 dose-ranging clinical trial evaluating MK-5172 once-daily with peginterferon alfa-2b and ribavirin (PR, weekly), were presented, evaluating SVR24 in treatment-naïve, non-cirrhotic patients with GT1 infection. PN038 is a Phase 2 clinical trial investigating the efficacy and safety of MK-5172 doses (25 mg, 50 mg, and 100 mg) once-daily with PR over a 12-week treatment cycle in GT1 treatment-naïve, non-cirrhotic patients (n=87). The analysis presented was ITT, in which all patients who did not achieve SVR (including those who dropped out for non-virologic reasons), were recorded as failures.

MK-5172 at doses of 50 mg and 100 mg with PR for 12 weeks of treatment achieved SVR24 rates of 75.0 percent (21/28) and 83.3 percent (25/30), respectively, supporting use of MK-5172 below 100 mg dose (see table 2).

Table 2: PN038 Virologic Responses – (ITT Analysis)
 
Patients with HCV RNA <25 IU/mL / total # of patients (%)
        MK-5172 25 mg
with PR
(N=29)
      MK-5172 50 mg
with PR
(N=28)
      MK-5172 100 mg
with PR
(N=30)
TW*4       93.1% (27/29)       96.4% (27/28)       100.0% (30/30)
TW12       93.1% (27/29)       96.4% (27/28)       96.7% (29/30)
SVR12       48.3% (14/29)       75.0% (21/28)       86.7% (26/30)
SVR24       48.3% (14/29)       75.0% (21/28)       83.3% (25/30)

*Treatment week

The most common recorded adverse experiences recorded across all treatment arms were: fatigue (61%), headache (46%), nausea (43%), and decreased appetite (43%). These adverse experiences did not appear to be dose-related.
One patient discontinued therapy after seven days of dosing with MK-5172 100 mg, plus PR and experienced muscle inflammation (creatine kinase >5x upper limits of normal [ULN]), elevated transaminases to >3x ULN, and total bilirubin >2x ULN, associated with a positive toxicology screen for ethanol. There were no other clinically significant transaminase elevations recorded in this study.

About Merck’s Phase 3 HCV Program: C-EDGE
Based on the results of the Phase 2 clinical program, Merck has initiated Phase 3 clinical trials for MK-5172/MK-8742. The Phase 3 program, called C-EDGE, will evaluate the safety and efficacy of MK-5172/MK-8742 with and without ribavirin in various genotypes and across a broad range of patient populations with chronic HCV. Study cohorts will include: C-EDGE TN (GT1, GT4-6; treatment-naive ± cirrhosis), C-EDGE CO-INFXN (GT1, GT4-6; treatment-naive ± cirrhosis with HIV/HCV co-infection), C-EDGE RECOVERY (GT1, GT4-6; treatment-naive ± cirrhosis; ± HIV/HCV co-infection on opiate substitution therapy), and C-EDGE TE (GT1, GT4-6; prior failed treatment with peginterferon/ribavirin; ± HIV/HCV co-infection). Study information can be found at www.clinicaltrials.gov.

Merck’s Commitment to HCV
For more than 25 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 healthcare solutions that support people living with HCV worldwide.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside of the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care 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 healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Merck Forward-Looking Statement
This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States 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’s 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. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2013 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 Defined as HCV RNA below the limit of quantification or below the limit of detection at the last visit on record – 4, 8, 12, or 24 weeks after the completion of therapy

EASL-Bristol-Myers hepatitis C treatment cures up to 90 pct -study

Bristol-Myers hepatitis C treatment cures up to 90 pct -study
By Bill Berkrot

April 10 Thu Apr 10, 2014 4:30pm IST
(Reuters) - A combination of two anti-viral drugs developed by Bristol-Myers Squibb Co cured 90 percent of previously untreated hepatitis C patients and 82 percent of those who failed to respond to prior therapy, according to results from a late stage study presented on Thursday.

The Phase III trial of more than 700 patients called Hallmark-Dual tested a combination of Bristol's daclatasvir and asunaprevir over 24 weeks of therapy in patients with genotype 1b of the virus that causes progressive liver disease.

The cure rate was also 82 percent among patients unable to tolerate treatment with the older standard drugs interferon and ribavirin and 84 percent in patients who had cirrhosis, which accounted for nearly a third of those in the trial.

Patients for whom the virus was undetectable in the blood 12 weeks after completing 24 weeks of treatment were deemed to have achieved sustained virologic response (SVR), which is considered cured.

"Not only was the daclatasvir and asunaprevir regimen highly effective among study participants, it was also very well tolerated, even among sicker patients with more advanced liver disease," Professor Michael Manns, the study's lead investigator from Hannover Medical School in Germany, said in a statement.

The study results were presented at the annual meeting of the European Association for the Study of the Liver (EASL) in London.

Genotype 1 is the most prevalent and considered the most difficult to treat form of the virus. Genotype 1b tends to be more common in Europe and 1a is more widely seen in the United States.

Several drugmakers, including Gilead Sciences Inc, AbbVie and Merck & Co are developing a new generation of all-oral hepatitis C treatments that do not include interferon or ribavirin, which cause miserable side effects that have led thousands of patients to put off treatment to wait for the highly touted new drugs.

In clinical trials, the new drugs have demonstrated cure rates in excess of 90 percent while cutting treatment duration to 12 weeks with few side effects, leading to Wall Street forecasts of multibillion-dollar annual sales in what is shaping up to be a fiercely competitive market.

Prior to the recent approval of the first of Gilead's new drugs, standard treatments cured about 75 percent of patients and required either 24 or 48 weeks of therapy.

Bristol this week applied for U.S. approval of the two drug combination and said it expects to file for approval of a three-drug combination early next year.

Based on earlier studies, Bristol's three-drug combination is likely to further boost cure rates with 12 weeks of treatment, which would be more competitive to results seen so far from rival drugmakers.

Patients in the Hallmark-Dual trial received 60 mg of daclatasvir once a day and 100 mg of asunaprevir twice daily. The drugs belong to new classes of medicines that work in different ways to prevent the virus from replicating.

The discontinuation rate due to adverse side effects was between 1 and 3 percent, the company said. Headache was the most common side effect, and serious side effects, such as elevations in liver enzymes, were seen in 5 percent to 7 percent of patients.

Liver enzyme elevations were reversible and resolved following treatment, the company said.

About 170 million people are believed to be infected with hepatitis C worldwide. If left untreated the disease can lead to cirrhosis, liver cancer or need for a liver transplant. (Reporting by Bill Berkrot; Editing by Cynthia Osterman)

FILED UNDER:
Regulatory News

Thursday, April 10, 2014 7:00 am EDT
Bristol-Myers Squibb Presents Phase III Data Demonstrating that Investigational All-oral Daclatasvir and Asunaprevir Therapy Achieved SVR12 Rates of up to 90% Among Broad Range of Genotype 1b Hepatitis C Patients

Results of the HALLMARK-Dual study include data among genotype 1b cirrhotic and non-cirrhotic, treatment-naïve, non-responder, and peginterferon/ribavirin ineligible and intolerant patients

Study reinforces the potential of daclatasvir-based regimens to treat HCV patients with high unmet needs

Data to be presented during late-breaker session at EASL The International Liver Congress 

"In addition to the HALLMARK-Dual study, we are pleased to be presenting data at EASL on our investigational 3DAA fixed-dose-combination, as well as daclatasvir in combination with other HCV compounds."
 
PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced Phase III results from the global HALLMARK-Dual study investigating the all-oral, interferon- and ribavirin-free regimen of daclatasvir (DCV), a NS5A inhibitor, and asunaprevir (ASV), a NS3 inhibitor, among genotype 1b hepatitis C virus (HCV) infected patients. Results showed that the 24-week regimen achieved an overall sustained virologic response (a functional cure) 12 weeks after the end of treatment (SVR12) among treatment-naïve (90%), peginterferon/ribavirin non-responder (82%), and peginterferon/ribavirin ineligible/intolerant (82%) patients, including cirrhotic and non-cirrhotic patients (84% and 85%). In the study the DCV+ASV regimen was generally well tolerated.

These data will be presented this week at the 49th annual meeting of the European Association for the Study of the Liver (EASL) The International Liver CongressTM in London, April 9-13.

Globally, there are 170 million people infected with HCV, with genotype 1 being the most prevalent. There are 9 million people infected in Europe, where there is a high prevalence of HCV genotype 1b.
“Not only was the daclatasvir and asunaprevir regimen highly effective among study participants, it was also very well tolerated, even among sicker patients with more advanced liver disease and higher unmet needs,” said lead study investigator Professor Michael P. Manns, director of the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School, Germany. “Despite a rapidly evolving HCV treatment paradigm, physicians and patients remain in need of new all-oral, interferon- and ribavirin-free regimens that have the potential to achieve virologic cure across a broad range of patients, including those with advanced liver disease and cirrhosis.”

These data were part of the company’s recent DCV and ASV new drug application (NDA) submissions to the U.S. Food and Drug Administration (FDA), and helped support the validated marketing authorization application to the European Medicines Agency for the use of DCV in combination with other agents for the treatment of adults with HCV with compensated liver disease, including genotypes 1, 2, 3, and 4. These data are comparable to a similar Phase III study of this regimen in Japanese patients, which led to the submission of a New Drug Application with Japan’s Pharmaceutical and Medical Devices Agency.

“Daclatasvir has unique scientific characteristics that support ongoing research for its use in multiple all-oral HCV regimens,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “In addition to the HALLMARK-Dual study, we are pleased to be presenting data at EASL on our investigational 3DAA fixed-dose-combination, as well as daclatasvir in combination with other HCV compounds.”

Study Design and Results
This Phase III multinational clinical trial involved 116 sites in 18 countries, including countries that have a high prevalence of genotype 1b such as Korea and Taiwan. In the study, treatment-naïve patients (n=205) received DCV 60 mg once daily plus ASV 100 mg twice daily for 12 weeks, and 102 patients received matching placebo for 12 weeks. The DCV+ASV treatment-naïve group continued treatment through week 24; placebo recipients entered another DCV+ASV study. The peginterferon/ribavirin-ineligible/intolerant (n=235) and non-responder patients (n=205) received the same doses of DCV and ASV for 24 weeks. The primary endpoint was the percentage of patients with a sustained virologic response at 12 weeks after the end of treatment (SVR12).

Virologic Response
  • 90% of treatment-naïve patients achieved SVR12
  • 82% of patients with prior null or partial response to peginterferon/ribavirin (non-responders) achieved SVR12
  • 82% of peginterferon/ribavirin ineligible/intolerant patients achieved SVR12
    • Among peginterferon/ribavirin ineligible/intolerant patients, SVR12 was achieved by patients with anemia/neutropenia (91%); depression (80%) and compensated advanced fibrosis/cirrhosis with thrombocytopenia (73%).
Results among Cirrhotic Patients treated with DCV+ASV
  • At baseline, 33 treatment-naïve, 63 non-responders, and 111 ineligible/intolerant patients had cirrhosis. Cirrhotic patients made up ~32% of the study population.
  • SVR rates were similar in cirrhotic (84%) and non-cirrhotic (85%) patients.
The regimen used in this Phase III study resulted in low rates of discontinuation (1-3%) due to adverse events (AEs). In addition, the rate of serious adverse events (SAEs) was low (5-7%). Headache was the most common AE in the study (24-25%). No deaths occurred, and no clinically meaningful differences were observed in frequencies of SAEs, AEs leading to discontinuation, or grade 3/4 ALT/AST (liver enzymes) elevations in patients with or without cirrhosis. Importantly, all grade 3/4 ALT/AST elevations observed were reversible and resolved off-treatment.

About Hepatitis C
Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. Up to 90 percent of those infected with hepatitis C will not spontaneously clear the virus and will become chronically infected. According to the World Health Organization, up to 20 percent of people with chronic hepatitis C will develop cirrhosis; of those, up to 25 percent may progress to liver cancer.

About Bristol-Myers Squibb’s HCV Portfolio
Bristol-Myers Squibb’s research efforts are focused on advancing late-stage compounds to deliver the most value to patients with hepatitis C. At the core of our pipeline is daclatasvir (DCV), an investigational NS5A replication complex inhibitor that has been studied in more than 5,500 patients as part of multiple direct-acting antiviral (DAA) based combination therapies. DCV has shown a low drug-drug interaction profile, supporting its potential use in multiple treatment regimens and in people with co-morbidities. 

Daclatasvir is being investigated in combination with sofosbuvir in high unmet need patients, such as pre- and post-transplant patients, HIV/HCV co-infected patients, and patients with genotype 3, as part of the ongoing Phase III ALLY Program.

In 2014, the U.S. Food and Drug Administration (FDA) granted Bristol-Myers Squibb’s investigational DCV Dual Regimen Breakthrough Therapy Designation for use as a combination therapy in the treatment of genotype 1b HCV infection.

In 2013, Bristol-Myers Squibb’s investigational all-oral 3DAA Regimen (daclatasvir/ asunaprevir/BMS-791325) also received Breakthrough Therapy Designation, which helped to expedite the start of the ongoing Phase III UNITY Program. Study populations include non-cirrhotic naïve, cirrhotic naïve and previously treated patients. The daclatasvir 3DAA regimen is being studied as a fixed-dose-combination treatment with twice daily dosing.

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