April 10, 2014

Effectiveness of Hepatitis C Drugs Praised; Cost a Concern

Provided by Voice of America

Jessica Berman
April 10, 2014

Doctors who treat hepatitis C are hailing the development of drugs that can effectively eradicate the infection, which is a leading cause of cirrhosis and liver cancer worldwide.  At the same time, their focus now has turned to reducing the high cost of treatment so that it’s accessible to developing countries, where 80 percent of people are infected.

An estimated 150 to 185 million people worldwide are infected with hepatitis C and many don’t know it.  That’s because the virus is largely silent until late symptoms appear, including grinding fatigue, joint pain, abdominal pain and jaundice, a yellowing of the skin and eyes.

But pivotal studies of new antiviral drugs conducted in developed countries show they knock out upwards of 90 percent of all hepatitis C infections, promising to revolutionize treatment in low- and middle income countries.

Channa Jayasekera is with the Division of Gastroenterology and Hepatology at Stanford University in California. 

Jayasekera spoke via Skype from the International Liver Congress meeting in London, where the new treatment options for hepatitis C are getting a lot of attention.

“This is really a landmark achievement in all of medicine, I would say, because it’s one of the few times where we’ve been able to definitively eradicate a disease with a short course of oral therapy," said Jayasekera.

Experts say the oral medications may even be more effective in the developing world because people there harbor different, possibly more responsive, types of the virus than in the West. 

But a three-month course of the second generation antiviral drugs in the West costs between $85,000 and $90,000, according to Jayasekera.

However, with the issuance of guidelines by the World Health Organization for the diagnosis and treatment of hepatitis C with oral medications in low- and moderate income countries, there are moves to bring down the cost.

Jayasekera says competition among the handful of pharmaceutical companies, and negotiations between manufacturers and governments as well as insurers, eventually will make treatment affordable.

The companies that produce the pills, according to Jayasekera, also are in the process of securing licenses for the manufacture of generic drugs for distribution in countries where they are most needed.

“So, if a company that is selling these drugs feels that it is ethical and moral and in the spirit of corporate social responsibility appropriate to ensure that these drugs are also available to people outside of richer countries, then that prerogative is there," said  Jayasekera.

Jayasekera adds it will be necessary for each country to prioritize who gets treated first, in order to hold down costs and not overwhelm health care systems. 

Jayasekera made his observations in an article in New England Journal of Medicine. 

Source

Why Hepatitis C Is Vastly Underreported

Provided by Albert Einstein College of Medicine -- The Doctor's Tablet Blog

by Kristina R. Chacko, M.D. on April 10, 2014

Hepatitis-C-text

Hepatitis C virus (HCV) continues to be the number one cause of cirrhosis and liver cancer and the primary indicator for liver transplantation in the United States, yet it remains vastly underdiagnosed.

More than three million people in the U.S. are infected. Guidelines support widespread screening for HCV, and excellent treatments are now available.

So the question remains: why is HCV underreported?

When “Good” News Disguises Bad
A recently published study in the Annals of Internal Medicine found that, according to the National Health and Nutrition Examination Survey (NHANES), the estimated prevalence of chronic HCV infection has decreased from 1.3 percent of the population (3.2 million persons) to 1.0 percent (2.7 million persons).

That would seem like a sign of notable progress. But the study has important limitations.

One major limitation of this estimate is that it excludes the homeless and people who are incarcerated. In a recently published systemic review and meta-analysis in Hepatology, approximately 668,500 prisoners and others in enclosed environments in North America were projected to be HCV antibody positive. That’s 24 percent of the entire North American prison population.

While the study in question focused on the United States, it’s useful to look at global trends. According to the Global Burden of Diseases, Injuries and Risk Factors 2010 Study, the prevalence of HCV rose from 2.3 to 2.8 percent globally (>122 million to >185 million) between 1990 and 2005.

The NHANES findings also suggest that the decrease in disease prevalence appears to be related to an increase in HCV-related deaths rather than to cured infections. Since 2006, deaths related to HCV have outnumbered those from HIV infection, according to an analysis by the Centers for Disease Control (CDC). Several studies have shown a marked increase in the number of HCV-associated hospitalizations and deaths over the past decade, and most experts suspect that this is a gross underestimate.

While the CDC estimates that from 2.7 to 3.9 million people in the United States are chronically infected with HCV, most remain unaware that they are infected. I’ve seen this firsthand, as many newly diagnosed patients who present with advanced liver disease say “My liver tests were always normal.” Patients who are chronically infected are frequently asymptomatic, with normal or only mildly elevated liver enzymes.

Chronic HCV infection is an indolent infection (meaning it’s slow to develop) that causes ongoing inflammation and scarring in the liver, with complications from chronic infection, including cirrhosis and liver cancer, appearing after several decades of living with the virus.

More Rigorous HCV Testing Needed
More effective and rigorous screening with HCV antibody testing is necessary to identify asymptomatic individuals. The CDC published guidelines for screening in 1998, recommending that doctors test individuals for HCV if they have used intravenous drugs, have certain medical conditions or received a blood transfusion or transplant before 1992. Subgroups of the population with a high prevalence of HCV infection include HIV-positive people, Vietnam-era veterans, incarcerated persons and black males ages 40 to 49, with prevalence rates ranging from 11 to 15 percent.

Almost half of people with positive HCV antibodies had no known exposure risk, and it has become clear that risk-based approaches are not adequate to identify infected persons in the general population.

In 2012, the screening guidelines were updated to include all adults born between 1945 and 1965, as people born during this time period accounted for up to 75 percent of all chronic HCV infections. In 2013, the U.S. Preventive Services Task Force took note of the CDC’s recommendations and updated its screening guidelines to reinforce the importance of screening for viral hepatitis; its “grade B” recommendation means there is either high certainty that the benefits of such screening are moderate or a moderate certainty that the benefits are moderate to substantial.

This is not enough, though. In a busy primary-care practice, screening for HCV infection often falls by the wayside as doctors manage diabetes and heart disease. In one study, only 36 percent of physicians adhered to the screening guidelines. Outreach efforts are needed to educate patients and physicians regarding the value of early identification of HCV infection and referral for treatment.

More Effective Drugs Can Mean Cure
The landscape of HCV treatment has changed dramatically. For years, patients and physicians struggled to cure the virus with interferon-based therapies that were difficult to tolerate and successful in only 15 to 40 percent of patients. Recent advances in research have given us an understanding of HCV replication, which has led to the development of direct-acting antiviral agents. These medications (two of which, sofosbuvir and simeprevir, were approved by the Food and Drug Administration in late 2013, with many more in the clinical-trial pipeline) have made it possible to treat and cure more patients with much less risk.

With the successful treatment of HCV, there is a clear reduction in all-cause mortality, cirrhosis, liver cancer and the need for liver transplants.

The high cost of this treatment is considered a barrier for some. The regimen can cost $150,000 for a three-month course of treatment, which usually includes more than one antiviral drug. Justifying that cost and exploring ways to increase access to treatment are hotly debated topics.

The burden of HCV is increasing, with an estimated 165,900 deaths from chronic liver disease and $10.7 billion in direct medical expenditures expected to occur between 2010 and 2019. Liver transplantation is a lifesaving operation for patients with advanced liver disease or liver cancer, but due to organ shortages, it remains an option only for a select few.

What I can say, as a Montefiore specialist who treats liver disease and an Einstein assistant professor who joins colleagues in researching the ravages of chronic HCV, is that we need to be aggressive about getting as many people tested as possible (within guidelines) and raising awareness about a virus that is often a silent pathogen until it’s too late.

We have the tests to diagnose HCV and the drugs to cure a high percentage of HCV cases. We should use them fully.

Source

Embargoed until 6am on Thursday 10 April 2014

London, UK, Thursday 10 April 2014: Two new studies presented today at the International Liver CongressTM 2014 have provided more evidence to clarify the role of non-alcoholic fatty liver disease (NAFLD) as an independent risk factor for the development of cardiovascular disease (CVD).

In the first long-term study[1], in patients at high CVD risk, NAFLD was shown to contribute to the progression of early atherosclerosis independently of traditional CVD risk factors. In a second long-term study[2], NAFLD was confirmed as a significant long-term risk factor for the development of diabetes mellitus (DM). Importantly, those patients showing signs of an improvement in the fatty appearance of their liver in response to treatment then had a reduced risk of going on to develop diabetes. 

NAFLD describes a range of conditions where there is a build-up of fat in the liver cells in people who do not drink alcohol excessively. It is rapidly becoming the most common liver disease worldwide, particularly so in the Western world with an estimated prevalence of 20 – 30%. In many cases, NAFLD is linked to being obese or overweight.

Presenting the results of these two studies, EASL’s Educational Councillor Professor Jean-Francois Dufour of the University Clinic for Visceral Surgery and Medicine, University of Bern, Switzerland said: “We now have a strong body of evidence that NAFLD may pose a CVD risk above and beyond that conferred by traditional CVD risk factors, such as dyslipidemia, diabetes and smoking. This means that healthcare providers managing patients with NAFLD should take this factor into account in the CVD risk stratification, although the best way to implement this remains to be defined,” he added.

NAFLD an early independent predictor of carotid atherosclerotic disease

In a long-term study, patients with NAFLD had a higher prevalence of carotid plaques (44 vs. 37%; p< 0.001), a higher carotid intima-media thickness (C-IMT) (0.64±0.14 vs. 0.61±0.13; p< 0.001), and a higher Framingham score, which measured their 10-year CVD risk (15±9% vs. 8±7%; p< 0.001).

The presence of NAFLD also predicted whether that patient had thickening of the carotid intima-media (beta=0.037; p=0.005), and evidence of early carotid plaques (OR=1.21; 95%CI: 1.03-1.42; p=0.02), independently of the patients’ age, sex, BMI, hypertension and tobacco use.

C-IMT significantly increased in those patients who developed signs of NAFLD (0.60±0.13 to 0.64±0.14; p=0.01). Using a Cox model, NAFLD at baseline predicted the occurrence of carotid plaques (OR=1.27; 95%CI: 1.009-1.613; p< 0.05), independently of age, sex, diabetes and high BP.

“Whether NAFLD is incidentally or causally associated to early carotid atherosclerosis has previously been the subject of much debate,” said Professor Dufour. “While there are case-control studies that have demonstrated a significant and independent relationship between NAFLD and carotid atherosclerotic disease, up until now, long-term follow-up data have been missing.”

Patients recruited to this study had more than two CVD risk factors without previous CVD events, known liver disease, and drinking < 50g of alcohol/day. C-IMT was measured using carotid ultrasonography with carotid plaques defined as C-IMT>1mm at the carotid bifurcation. Results were validated in a long-term follow-up cohort of patients with two C-IMT measurements at >1-year interval.

The Fatty Liver Index (FLI), a surrogate marker of hepatic steatosis when ≥60 years old, and the Framingham cardiovascular risk score (FRS) were calculated.

5,671 patients underwent at least one C-IMT measurement: 52% males; mean age 52±11years; mean BMI = 26.1±4.7; 33% NAFLD; 39% CP, mean C-IMT 0.62±0.13mm. 1,872 patients had 2 C-IMT measurements.

During the 8±4 year follow-up, NAFLD occurred in 12% and carotid plaques in 22% of the patients.

Improvement of NAFLD is associated with a reduced risk of developing DM

A 10-year longitudinal study has confirmed that NAFLD is a significant risk factor for the development of diabetes, and improvement of NAFLD through treatment is associated with a reduced risk of developing diabetes (in submission).

In this study of 3,074 Japanese patients, 117 participants (16.1%) in the NAFLD group developed diabetes during a 10 year follow-up period, compared to only 72 participants (3.1%) in the non-NAFLD group (p< 0.001). The multivariate odds ratio was 2.82 (95% confidence interval: 1.91-4.15) in the NAFLD group compared to the non-NAFLD group.

Moreover, 7 participants (6.4%) in the improved group developed diabetes compared to 110 participants (17.8%) in the non-improved group. In the improved group, the multivariate odds ratio was 0.30 (95% CI: 0.13-0.66), in comparison to the non-improved group.

“Evidence from previous longitudinal studies has demonstrated a clear link between NAFLD and the development of DM,” said Professor Dufour. “However, this is the first study to show that DM can be prevented if NAFLD is improved,” he explained.

“A multidisciplinary approach is therefore required in the treatment of NAFLD patients, taking into account the presence of NAFLD as a critical part of diabetes prevention and care. New clinical trials to investigate the beneficial effects of anti-diabetes drugs on NAFLD histology, and the potential impact of anti-diabetes drugs on diabetes incidence and cardiovascular risk in non-diabetic patients with early-stage NAFLD are now underway,” Professor Dufour concluded.

8,070 participants who had a health check twice between 2000 and 2012 with 10 years between each check were enrolled into this study. An inclusion criterion included having had abdominal ultrasounds during the first and second visits. Exclusion criteria included alcohol use ≧20g/day, positive HBs antigen, positive HCV antibody, and diabetes mellitus at baseline.

The 3,074 eligible participants were divided into the NAFLD group (n=728) and non-NAFLD group (n=2,346), according to ultrasonography-detected fatty liver.

The NAFLD group was then further categorised into the improved group (n=110) and non-improved group (n=618), based on fatty liver disappearance at the second health check. Multivariate odds ratios for the development of DM were estimated by a logistic regression model.

Disclaimer: the data referenced in this release is based on the submitted abstracts. More recent data may be presented at the International Liver Congress™ 2014.

- Ends -

Notes to Editors

About EASL

EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

EASL’s main focus on education and research is delivered through numerous events and initiatives, including:

About The International Liver CongressTM 2014

The International Liver Congress™ 2014, the 49th annual meeting of the European Association for the study of the Liver, is being held at ExCel London from April 9 – 13, 2014. The congress annually attracts in excess of 9000 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.

For further information on the studies, or to request an interview, please do not hesitate to contact the EASL Press Office on:

Email: easlpressoffice@cohnwolfe.com

Helena Symeou  +44 7976 562 430

Courtney Lock +44 7894 386 422

[1] R.Pais et al. NAFLD IS AN INDEPENDENT PREDICTOR OF EARLY CAROTID ATHEROSCLEROSIS: RESULTS FROM A LARGE TRANSVERSAL STUDY AND LONG-TERM FOLLOW-UP VALIDATION COHORT. Abstract presented at the International Liver CongressTM 2014

[2] H.Yamazaki et al. DECREASED DEVELOPMENT OF DIABETES MELLITUS WITH IMPROVEMENT OF NONALCOHOLIC FATTY LIVER DISEASE: A 10-YEAR JAPANESE COHORT STUDY Abstract presented at the International Liver CongressTM 2014

Source

Single-Pill HCV Combo Shines With Older Drug

Published: Apr 10, 2014

By Michael Smith, North American Correspondent, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

Action Points

  • Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • Note that this nonrandomized trial demonstrated good efficacy of the novel agent ledipasvir when combined with sofusbuvir and ribavirin for the treatment of hepatitis C.
  • Be aware that larger studies in more diverse groups of patients will be needed to further characterize the appropriate use of this agent.

LONDON -- An investigational drug combination for hepatitis C virus (HCV) was efficacious in three groups of hard-to-treat patients, a researcher said here.

The fixed-dose, once-daily combination of sofosbuvir (Sovaldi) and ledipasvir, given for 12 weeks, yielded cure rates of between 64% and 100%, according to Edward Gane, MD, of Auckland Clinical Studies in New Zealand, and colleagues.

But the combination appears to need the help of an old HCV therapeutic standby, ribavirin, to achieve its highest cure rates, Gane told MedPage Today at the annual meeting of the European Association for the Study of the Liver.

But with ribavirin, he said, "you can cure genotype 3 ... remarkable!"

For several years, genotypes 2 and 3 of the virus had been regarded as easier to treat than genotype 1, but recent evidence suggests that genotype 3 is actually more difficult. When sofosbuvir, a nucleotide analog polymerase inhibitor, was approved in the U.S., the treatment duration was set at 24 weeks for genotype 3 patients and 12 weeks for those with genotype 2, reflecting that realization.

Ledipasvir, an NS5A inhibitor, remains investigational, but a New Drug Application for the combination has been given priority review by the FDA.

The drugs are part of a new wave of so-called direct-acting agents which attack the virus itself, in contrast to earlier therapies. The first to be approved in 2011 were the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis), followed in 2013 by sofosbuvir and the protease inhibitor simeprevir (Olysio).

But for years, the only therapy was pegylated interferon-alfa combined with ribavirin, which was regarded as both dangerously toxic and difficult to tolerate.

As a result, many patients with HCV have been waiting for treatment with the new agents, largely because they want to avoid peginterferon, commented Andrew Talal, MD, of the University at Buffalo in New York, who was not part of the trial.

"We've been treating people who need treatment or desperately want treatment," Talal told MedPage Today. But his institution, like many others, has "a significant number of people who self-select not to be treated at this time, who are waiting for the elimination of interferon from the therapeutic armamentarium."

The sofosbuvir/ledipasvir combination, he said, "is very promising, particularly in the populations that were studied," even though it might not completely eliminate the use of ribavirin.

But the role the combination will play in clinical practice is likely to depend, not on its efficacy, Talal said, but on its cost. "The major factor that determines, at this point, which drug or which combination of compounds will be the front-runner is price," he said.

He said he has been asked regularly about the cost of the new agents, including that of sofosbuvir, which has been set at $84,000 for a course of treatment in the U.S.

Gane reported on the so-called ELECTRON-2 study, which enrolled three cohorts -- 51 treatment-naive genotype 3 patients, 19 genotype 1 patients who had been treated previously with sofosbuvir in various studies but who had relapsed, and 20 genotype 1 patients with decompensated cirrhosis (Child Pugh Turcotte B).

All patients were treated with the single-pill combination for 12 weeks but some -- including all of the relapsed patients and half of the genotype 3 volunteers -- were also given ribavirin, Gane reported.

The primary endpoint was a sustained virologic response 12 weeks after the end of therapy (SVR12), defined as no detectable HCV RNA. An SVR12 is currently regarded as tantamount to a cure, since relapses among people who reach that landmark are rare.

The researchers found:

  • Among the 26 treatment-naive genotype 3 patients given ribavirin, the SVR12 rate was 100%.
  • Among the 25 patients in the group who did not get ribavirin, it was 64%.
  • Among the 20 patients with cirrhosis (who did not get ribavirin), seven relapsed, yielding an SVR12 rate of 65%.
  • Among the 19 previous relapsers (all given ribavirin), the SVR12 rate was 100%.

Almost all patients reported some adverse events, but there were no new toxicity signals, Gane told the opening plenary session of the meeting. There were only four grades 3 or 4 adverse events and only six serious adverse events.

Only one patient stopped therapy owing to an adverse event -- a patient who developed perforated sigmoid diverticulitis on the seventh day of participation and did not resume therapy after it was treated, Gane said.

The most common adverse events included headache, upper respiratory tract infection, nausea, and fatigue, he said.

Grades 3 and 4 lab abnormalities affected 13 patients, with seven of those among the genotype 3 patients getting ribavirin, Gane said. On the other hand, only seven patients (all but one on ribavirin) had hemoglobin below 10 g/dL, and none fell below 8.5.

The ELECTRON-2 study is just the first of several to be presented here that showcase the fixed-dose combination in various patient groups.

The study was supported by Gilead. Gane disclosed relevant relationships with the company, as well as with AbbVie, Janssen, Idenix, Novartis, Merck, Roche, and Vertex.

Talal disclosed relevant relationships with Gilead and AbbVie.

Primary source: European Association for the Study of the Liver
Source reference:
Gane EJ, et al "Sofosbuvir/ledipasvir fixed dose combination is safe and effective in difficult-to-treat populations including genotype-3 patients, decompensated genotype-1 patients, and genotype-1 patients with prior sofosbuvir treatment experience" EASL 2014; Abstract 06.

Source

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

Bristol-Myers hepatitis C treatment cures up to 90 percent: study

By Bill Berkrot
Thu Apr 10, 2014 7:02am EDT

(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)

Source

Also See: 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

Merck hepatitis C drugs shine in easier to treat patients -study

By Bill Berkrot
April 10  Thu Apr 10, 2014 10:30am IST

(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 has 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)

Source

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

U.S. drug industry group defends price of Gilead hepatitis drug

Thu Apr 10, 2014 10:34pm IST

* Gilead drug costs $84,000 for 12-week treatment

* Insurers, WHO, congressmen critical of pricing

* New drugs feature high cure rates, few side effects

By Susan Heavey

WASHINGTON, April 10 (Reuters) - The leading U.S. pharmaceutical industry trade group on Thursday defended the cost of Gilead Sciences Inc's new hepatitis C drug, Sovaldi, saying such treatments offer a priceless breakthrough for patients with the liver-destroying virus.

"Their lives, in short, will be transformed," Pharmaceutical Research and Manufacturers of America (PhRMA) President John Castellani said at the group's annual meeting in Washington. "The value to these patients, and to their loved ones and society - you can't put a price tag on it."

Gilead's Sovaldi costs about $84,000 for a 12-week course of treatment, or $1,000 a day.

That has drawn fire from health insurers, including state Medicaid programs, as well as U.S. lawmakers who are investigating Sovaldi's hefty price tag. This week, the World Health Organization joined the chorus of those seeking affordability for such drugs.

While Gilead has said it is working to offer lower prices in dozens of developing countries, critics say such treatments should cost hundreds of dollars, rather than tens of thousands. Another treatment from Johnson & Johnson that some doctors have been combining with Sovaldi as other new medicines advance toward approval, costs about $66,000.

Sovaldi, which was approved by the U.S. Food and Drug Administration late last year, is well on track to post record-breaking sales in its first year on the market.

Analysts with Capital Alpha have said 2014 sales of the drug could reach up to $15 billion, a figure that would top peak sales of Pfizer Inc's cholesterol fighter Lipitor, which had been the world's top-selling medicine before its patent protection lapsed.

As many as 150 million people worldwide, including about 3.2 million in the United States, have hepatitis C, which is caused by contact with contaminated blood, often through shared needles by drug abusers or, prior to routine blood screening, from blood and organ transplants.

Many people can carry the virus for decades before symptoms appear. But if untreated, it can cause serious liver damage and lead to cirrhosis, liver cancer, the need for a liver transplant or death.

"For the first time, 150 million people who are chronically infected with hepatitis C can be treated and cured of this terrible disease," Castellani said.

He said debate over the price of new anti-viral drugs to treat the chronic condition, and the value they bring to patients, has gone "askew," and warned that researching and developing them comes at a high cost to manufacturers.

Defenders of the new medicines point out that older current multi-drug regimens cost at least as much, cure about 75 percent of patients, require 24 or 48 weeks of treatment and have miserable side effects that lead many to delay or discontinue treatment.

The newer medicines being developed by several companies have demonstrated in clinical trials cure rates well in excess of 90 percent with minimal side effects and will require 12 weeks or fewer of treatment.

Those companies, including AbbVie Inc, Merck & Co and Bristol-Myers Squibb Co, are likely to be drawn into the pricing controversy as their new medicines edge closer to approval amid fears that millions of patients will now come forward to seek treatment, causing a massive cost burden to insurers and governments.

Merck and Bristol-Myers presented new hepatitis C data on Thursday at a major liver disease meeting in London . Gilead, AbbVie and others will also present clinical trial data at the meeting.

"Policy makers ... need to value innovation and stop implying that it comes cheap," Castellani said.

Foster City, California-based Gilead, which paid $11 billion to acquire the company that had the rights to Sovaldi, has said it is working with government officials and others to help create a globally tiered pricing structure.

That plan includes licensing the drug to three or four Indian generic manufacturers to allow sale of the medicine at lower prices in some 60 developing nations.

Separately on Thursday, Indian generic drugmaker Natco Pharma Ltd called on the government to deny Sovaldi a patent in India, a source with knowledge of the matter said, potentially clearing the way to launch a much cheaper version of the drug.

(Additional reporting by Bill Berkrot in New York; editing by Matthew Lewis)

Source

New Hepatitis C Guidelines Are Evolving Documents

Medscape Medical News > Conference News

Miriam E. Tucker
April 09, 2014

LONDON, United Kingdom — New guidelines for hepatitis C virus infection from the World Health Organization (WHO) and the European Association for the Study of the Liver (EASL) will be released here at the EASL International Liver Congress 2014.

The WHO guidelines on the screening, care, and treatment of people with hepatitis C infection are the first-ever to take a public health approach primarily aimed at influencing policy in the developing world.

The EASL recommendations on the management of hepatitis C focus specifically on evidence-based treatment, and incorporate the anticipated approval of 3 new direct-acting antivirals in 2014 by the European Medicines Agency (EMA). They will be released April  11.

Both documents reflect recent developments in hepatitis C, and both are expected to require revision 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," Dr. Stefan Z. Wiktor, team lead of the WHO Global Hepatitis Programme in Geneva, told Medscape Medical News.

The EASL document, which is being released online only, updates guidelines that were just issued in January.

Jean-Michel Pawlotsky, MD, PhD, director of the French National Reference Centre for Viral Hepatitis, told Medscape Medical News 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."

"At this stage, the field isn't stable enough to allow us to do it as a print version. We will regularly update the recommendations. It's a new strategy," said Dr. Pawlotsky.

Approximately 185 million people worldwide are infected with hepatitis C; about 150 million are chronically infected, and 350,000 to 500,000 die from hepatitis C complications each year. In Europe, from 7.3 million to 8.8 million people are infected with hepatitis C, and there are approximately 3 to 4 million new infections annually, according to an EASL statement.

Dr. Wiktor told Medscape Medical News that the WHO guidelines "are meant primarily to guide policymakers who are thinking of starting hepatitis C programs and who look to WHO for the official word on what is recommended. That is really the primary goal," he said, adding that the WHO document is targeted mainly at low- and middle-income countries.

The EASL recommendations are meant to impart the best science, said Dr. Pawlotsky. They are designed "to guide treatment decisions based on the available knowledge. It's really a clinical document."

The EASL recommendations also have a political purpose. "We want to help doctors put pressure on their national governments for access to care and reimbursement. It's a guidance for what should be done and not done," he explained.

WHO Guidelines

The WHO guidelines call for risk-based screening and follow-up testing for people with hepatitis C infection, and for screening and counseling related to alcohol use and other behaviors that increase transmission risk. The treatment guidelines address interferon injections and the new all-oral regimens, with acknowledgement that cost and access could limit options for low- and middle-income countries in the near term. The guidelines also emphasize prevention.

Dr. Wiktor told Medscape Medical News that he expects the prices of the new direct-acting antivirals to drop, as they did for HIV drugs. In fact, in some places they already have. Notably, Egypt has negotiated with Gilead to provide a 12-week treatment course of sofosbuvir — which costs $84,000 in the United States — for just $900.

"They were able to guarantee volume. That's what we're hoping these guidelines do — move countries to think about national programs that will give them more leverage with the pharmaceutical companies to make these drugs affordable," said Dr. Wiktor.

"We really hope that some of the big global health funders will step in and say, here's an opportunity to invest," he added. "The big difference with hepatitis C is that there is a cure. That's a very unusual situation for a chronic viral infection."

It is expected that the WHO's next official document on hepatitis C will be released in 2016, but an interim guidance is planned for the end of 2014. In the meantime, the WHO is working on guidance for hepatitis B.

EASL Recommendations

By the time they were issued in January, the EASL hepatitis C guidelines were already out of date. The online recommendations include the latest data pertaining to the 3 new direct-acting antivirals for hepatitis C, which are expected to be on the European market in the next few months for use as part of combination therapies.

Sofosbuvir, a nucleotide analogue inhibitor of hepatitis C RNA-dependent RNA polymerase, was approved in January. Simeprevir, a second-wave, first-generation NS3/4A protease inhibitor will be approved in May. Daclatasvir, an NS5A inhibitor, is likely to be approved in August or September, according to the EASL statement.

Next in line are investigational combinations from Gilead and AbbVie, Dr. Pawlotsky told Medscape Medical News. "It depends on the EMA. When they approve, we will update. We are reactive."

Dr. Wiktor has disclosed no relevant financial relationships. Dr. Pawlotsky has received grant and research support from Gilead; is on advisory boards for Abbott, AbbVie, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Idenix, Janssen, Merck, Novartis, and Roche; and is on the speakers/teachers bureaus for AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, Merck, Novartis, and Roche.

Source

Also See:

Curing Chronic Hepatitis C — The Arc of a Medical Triumph

The New England Journal of Medicine

Perspective

Raymond T. Chung, M.D., and Thomas F. Baumert, M.D.

April 10, 2014DOI: 10.1056/NEJMp1400986

Chronic hepatitis C is a major cause of liver cirrhosis and hepatocellular carcinoma worldwide. Some 130 million to 170 million people, or about 3% of the world's population, are chronically infected with the hepatitis C virus (HCV). In the United States, chronic hepatitis C, the most common cause of liver-related death and reason for liver transplantation, recently eclipsed human immunodeficiency virus (HIV) infection as a cause of death. The development of direct-acting antiviral agents (DAAs) has revolutionized HCV treatment by offering genuine prospects for the first comprehensive cure of a chronic viral infection in humans. This success can be traced to important scientific, clinical, and regulatory developments.

The history of HCV's discovery and antiviral-drug development offers a striking example of the effect of advances in biomedical research on disease outcome (see table). The discovery of HCV 25 years ago showed the importance of new scientific approaches: whereas past virus discovery had relied on direct visualization of viral particles, the previously elusive HCV was isolated with the use of a new expression-cloning approach that generated a library of complementary DNA from infectious plasma.1

The subsequent molecular characterization of the viral genome enabled several important discoveries. First, it revealed HCV to be a positive-stranded RNA virus that replicates its genome directly into RNA without traversing a DNA intermediate, so that unlike HIV or hepatitis B virus, it lacks a latent, nuclear form that defies ready immunologic clearance. Instead, it requires continuous replication for its existence — an observation that would be leveraged for the design of strategies to permanently clear the virus. In addition, molecular characterization resulted in an appreciation of viral genotypes, which led to critical epidemiologic discoveries and the development of appropriate genotype-specific therapeutic regimens.

Finally, it fostered the creation of several cell-culture systems to explicate the viral life cycle, virus–host interactions, and pathogenesis.2 Because of initial difficulty in cultivating the virus, an important milestone was the construction of subgenomic selectable replicons harboring the viral nonstructural proteins (NS3–5) responsible for genome replication. The use of replicons permitted efficient screening, testing, or both of several classes of DAAs that blocked these proteins, whose structures were themselves successfully crystallized and elucidated. These include inhibitors of NS3/4A protease, NS5A, and both nucleoside and nonnucleoside NS5B polymerase inhibitors.3

The subsequent discovery of a viral isolate that efficiently infected a human hepatoma cell line enabled the expansion of the arsenal of therapeutic classes to include inhibitors of viral entry, translation, and assembly, as well as inhibitors that block host proteins or microRNAs that are essential for maintenance of the viral life cycle. Because replicons and tissue-culture models largely recapitulate in vivo viral-replication behavior, researchers were able to develop DAA candidates rapidly by circumventing lengthy and costly efficacy studies in the chimpanzee, the only viable animal model of HCV.

In many ways, antiviral development in HCV was guided by the HIV therapeutic experience and, accordingly, quickly moved to more practicable paradigms. HCV encodes a highly error-prone RNA polymerase that generates extraordinary heterogeneity of the viral species within infected persons. Thus, it came as little surprise that initial monotherapy trials of the first HCV protease inhibitors were thwarted by rapid selection of preexisting resistant variants. Fortunately, the long-running standard of care, the broadly acting antiviral cytokine interferon alfa, which inhibits HCV replication not by binding viral proteins but by inducing hundreds of host genes to produce an antiviral intracellular state, combined with ribavirin, an agent with both antiviral and immunomodulatory properties, showed activity against both protease-inhibitor–resistant and wild-type virus. Thus, a key first step in the therapeutic revolution was the addition of a protease inhibitor to the backbone of peginterferon and ribavirin. This strategy succeeded in boosting rates of sustained virologic response, or viral cure, from about 45% to approximately 75% among patients with HCV genotype 1 infection and proved that a DAA was clinically effective. It amounted to a holding strategy, however, since its effectiveness was limited by the side-effect profile of injected interferon regimens and first-generation protease inhibitors, which induce cytopenias, depression, autoimmunity, and rash; these toxic effects were particularly prominent in patients with cirrhosis.

Against this backdrop, the development of HCV nucleoside inhibitors, nonnucleoside inhibitors, and NS5A inhibitors presented the opportunity to apply to HCV the HIV combination-therapy principle, whereby a combination of potent agents from two or more classes with nonoverlapping resistance profiles could provide rapid and potent suppression of viral replication and prevent emergence of resistant variants. In theory, this regimen, applied for sufficient duration, could achieve the goal of high cure rates and freedom from dependence on interferon.

But additional steps were required to get from these interferon-tethered regimens to trials of investigational DAAs in combination. Traditional study designs had, until recently, used a standard-of-care comparator for new agents, which in the case of HCV meant using an interferon-based therapy in the control group — an unappealing prospect for many patients. Buoyed by the success of combination HIV therapies and the knowledge that resistance variants in HCV were not predicted to persist as they do in HIV, the Food and Drug Administration agreed to permit phase 2 trials to use new combinations of HCV DAAs without requiring a standard-of-care comparator. This decision proved catalytic. Because of the short durations of, and rapid enrollment in, these studies, the pace of ensuing clinical drug development has been breathtaking.

These trials have shown that the combination approach is not only viable in concept, but also capable of producing sustained virologic response rates exceeding 90%, with the use of interferon-free, all-oral combinations. Just as impressively, several roads appear to be capable of leading to the same destination; combinations of several different classes have all yielded high rates of sustained virologic response in phase 2 studies. Phase 3 studies of many of these combinations are completed or under way, and approvals of the first of these regimens should be forthcoming within the year. Late-phase studies also show that DAA combinations are capable of bridging most of the performance gap between more-conventional populations of previously untreated patients and populations that have historically been difficult to treat, including patients with cirrhosis, HIV-coinfected persons, and patients who have not had a response to conventional interferon-based therapies.4

Still, some drug-development hurdles lie ahead. Although they have achieved spectacular response rates in late-stage clinical trials, DAAs must fulfill their promise in the real world. Given historical trends in real-world populations, a minor but substantial fraction of some patient groups will probably need alternative approaches; these include patients with coexisting conditions such as renal failure, hepatic decompensation, or a liver transplant, as well as those with previous failure of a DAA combination. For such patients, new treatments may be required, including host-targeting agents or inhibitors of viral entry or assembly.5

It may now be possible to imagine the global eradication of HCV infection, but three major challenges remain. First, in the absence of effective screening programs, HCV infection is often diagnosed at a late stage (in high-income countries) or seldom diagnosed at all (in low- or middle-income countries). Second, the high cost of DAAs will preclude their use in most infected patients in low- or middle-income countries; in high-income countries, the need for payers to provide major resources for HCV treatment may lead to the selective use of DAAs for certain patient subgroups. Third, reinfection remains possible even after successful curative therapy.

Ultimately, a preventive vaccine would be desirable for the global eradication of HCV, but the virus's extraordinary sequence heterogeneity and ability to evade host immune responses pose challenges for the development of a broadly protective vaccine. In the meantime, effective HCV screening programs, including full implementation of birth-cohort screening in the United States, the establishment of access to affordable treatment in low- and middle-income countries, and strategies for reducing the risk of transmission (e.g., safe injection practices) will probably be needed to control HCV infection on a global scale. The introduction of DAAs represents a major breakthrough, but it is only a first step toward eliminating HCV globally.


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

This article was published on April 10, 2014, at NEJM.org.

Source Information

From the Liver Center, Gastrointestinal Division, and the Department of Medicine, Massachusetts General Hospital, and Harvard Medical School — both in Boston (R.T.C., T.F.B.); and INSERM Unité 1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg; and Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg — all in Strasbourg, France (T.F.B.).

Source

The New England Journal of Medicine

Original Article

Stefan Zeuzem, M.D., Ira M. Jacobson, M.D., Tolga Baykal, M.D., Rui T. Marinho, M.D., Ph.D., Fred Poordad, M.D., Marc Bourlière, M.D., Mark S. Sulkowski, M.D., Heiner Wedemeyer, M.D., Edward Tam, M.D., Paul Desmond, M.D., Donald M. Jensen, M.D., Adrian M. Di Bisceglie, M.D., Peter Varunok, M.D., Tarek Hassanein, M.D., Junyuan Xiong, M.S., Tami Pilot-Matias, Ph.D., Barbara DaSilva-Tillmann, M.D., Lois Larsen, Ph.D., Thomas Podsadecki, M.D., and Barry Bernstein, M.D.

April 10, 2014DOI: 10.1056/NEJMoa1401561

Patients with chronic hepatitis C virus (HCV) infection are at risk for progressive liver fibrosis, cirrhosis, portal hypertension, hepatocellular carcinoma, and decompensated liver disease. HCV infection can be cured with antiviral therapy, reducing the risk of illness and death associated with end-stage liver disease.1-3

For more than a decade, patients with HCV genotype 1 infection have been treated with peginterferon–ribavirin dual therapy, resulting in rates of sustained virologic response of approximately 40 to 50%.4-6 Response rates among previously untreated patients have been shown to increase to 68 to 75% with peginterferon–ribavirin plus a protease inhibitor (telaprevir or boceprevir, both introduced in 2011).7,8 However, rates of response to this triple therapy among patients previously treated with peginterferon–ribavirin dual therapy vary according to the prior treatment response, with rates of 69 to 88% among patients with a prior relapse (an undetectable level of HCV RNA during treatment but a detectable level after the end of treatment), 40 to 59% among patients with a partial response (a decrease in the HCV RNA level of ≥2 log10 IU per milliliter at treatment week 12 but with a detectable level), and 29 to 33% among patients with a null response (a decrease in the HCV RNA level of <2 log10 IU per milliliter at treatment week 12).9,10 Furthermore, peginterferon–ribavirin therapy is associated with clinically significant and frequent side effects, including influenza-like symptoms, neuropsychiatric disorders, and cytopenias. Side effects of telaprevir and boceprevir include rash and anemia.7-10

ABT-450 is an inhibitor of the HCV nonstructural 3/4A (NS3/4A) protease, which is administered with ritonavir (ABT-450/r). Ritonavir is a pharmacoenhancer that inhibits ABT-450 metabolism. Administration of ritonavir with ABT-450 increases peak and trough drug exposures, allowing for once-daily dosing.11 Ombitasvir (also known as ABT-267) is an HCV NS5A inhibitor; dasabuvir (also known as ABT-333) is a nonnucleoside HCV NS5B RNA polymerase inhibitor.12,13

A phase 2b study involving patients with HCV genotype 1 infection who had a null response to prior therapy with peginterferon–ribavirin showed that the rate of sustained virologic response to 12 weeks of treatment with ABT-450/r, ombitasvir, dasabuvir, and ribavirin was 93% 24 weeks after the end of treatment.14 We report the results of SAPPHIRE-II, an international, randomized, placebo-controlled, double-blind, phase 3 trial assessing the efficacy and safety of 12 weeks of the all-oral regimen of ABT-450/r–ombitasvir and dasabuvir with ribavirin in patients with HCV genotype 1 infection and no cirrhosis who had received previous treatment with peginterferon–ribavirin.

Methods

Patients

Patients 18 to 70 years of age were eligible for enrollment if they had chronic HCV genotype 1 infection and a plasma HCV RNA level of more than 10,000 IU per milliliter, without cirrhosis. Eligible patients had documentation of prior peginterferon–ribavirin dual therapy with a relapse (an undetectable level of HCV RNA at the end of treatment but a detectable level within 52 weeks after treatment), a partial response (a decrease in the HCV RNA level of ≥2 log10 IU per milliliter at treatment week 12 but a detectable level at the end of treatment), or a null response (a decrease in the HCV RNA level of <2 log10 IU per milliliter at week 12 or <1 log10 IU per milliliter at week 4). (Details are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.)

Patients were excluded if they did not have a response to prior triple therapy with peginterferon–ribavirin and a protease inhibitor. Additional exclusion criteria were a positive screening result for hepatitis B surface antigen or anti–human immunodeficiency virus (HIV) antibodies, a recent history of drug or alcohol abuse or a positive screening result for drugs or alcohol, and use of specified concomitant medications, including those contraindicated for use with ribavirin and ritonavir. Patients with an advanced stage of fibrosis (Metavir score >3, Ishak score >4, aspartate aminotransferase:platelet ratio index >2, and FibroTest score >0.72 or FibroScan result ≥9.6 kPa without a qualifying liver biopsy) were also excluded. (For details, see the Supplementary Appendix.)

Study Design and Conduct

The SAPPHIRE-II study was performed at 76 sites in Australia, North America, and Europe. Patients were randomly assigned in a 3:1 ratio to receive an active regimen or placebo (Figure S1 in the Supplementary Appendix). The randomization schedule was stratified according to the type of response to previous peginterferon–ribavirin treatment (relapse, partial response, or null response) and HCV genotype (1a or non-1a). During the double-blind period, patients assigned to the active regimen received 12 weeks of treatment with oral coformulated ABT-450/r–ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin administered twice daily according to body weight (1000 mg daily if the body weight was <75 kg and 1200 mg daily if the body weight was ≥75 kg). Patients assigned to placebo received matching placebo pills during this period. After the double-blind period, patients in the placebo group received the active regimen on an open-label basis for 12 weeks.

The study sponsor (AbbVie), investigators, and patients were unaware of the study-group assignments during the double-blind period. Laboratory results for levels of HCV RNA, hemoglobin, hematocrit, alanine aminotransferase, aspartate aminotransferase, and bilirubin (indirect and total) were not disclosed to these parties in order to prevent implicit unblinding. The study is ongoing, and all patients who received the active regimen will be followed for 48 weeks after the end of treatment.

All patients provided written informed consent. The study was conducted in accordance with International Conference on Harmonisation guidelines, other guidelines governing clinical-study conduct, applicable regulations, and ethical principles enumerated in the Declaration of Helsinki. An independent ethics committee or institutional review board at each participating site approved the study.

The study was designed jointly by the investigators and the sponsor. The investigators gathered the data. The sponsor conducted the data analyses. All the authors had full access to the data and signed confidentiality agreements with the sponsor regarding the data. The first draft of the manuscript was written by a sponsor-employed medical writer with input from all the authors. All the authors reviewed and provided feedback on all versions of the manuscript and made the final decision to submit it for publication. All the authors assume responsibility for the completeness and accuracy of the data and analyses presented and for the fidelity of the study to the protocol, available at NEJM.org.

Efficacy Assessments

HCV genotype and subtype were evaluated from plasma samples with the use of the Versant HCV Genotype Inno-LiPA Assay, version 2.0 (Siemens Healthcare Diagnostics). Plasma HCV RNA levels were measured by a central laboratory with the use of the COBAS TaqMan real-time reverse-transcriptase–polymerase-chain-reaction assay, version 2.0 (Roche), with a lower limit of detection of 15 IU per milliliter and a lower limit of quantification of 25 IU per milliliter. Details of the collection of plasma samples, protocol-specified criteria for virologic failure, and resistance testing are provided in the Supplementary Appendix.

Safety Assessments

Adverse events were assessed at each study visit. The site investigator classified events as mild, moderate, or severe. Data on all adverse events were collected from the start of study-drug administration until 30 days after the last dose. Data on serious adverse events were collected throughout the entire study period. Adverse events and serious adverse events occurring during the double-blind period plus 30 days after the last dose of active study drugs are reported. Clinical laboratory testing occurred at visits during the double-blind treatment period and at post-treatment weeks 4 and 48.

Efficacy End Points

The primary efficacy end point was a sustained virologic response (i.e., an HCV RNA level of <25 IU per milliliter 12 weeks after the end of study treatment). Secondary efficacy end points were normalization of the alanine aminotransferase level, sustained virologic response at post-treatment week 12 according to HCV genotype (1a or 1b), virologic failure during treatment, and post-treatment relapse. Analyses were performed in the modified intention-to-treat population, defined as all randomly assigned patients who received at least one dose of the study drug during the double-blind treatment period.

Virologic failure during study treatment was defined as a confirmed HCV RNA level of 25 IU per milliliter or more after an HCV RNA level of less than 25 IU per milliliter during treatment, a confirmed increase in the HCV RNA level of more than 1 log10 IU per milliliter above the nadir during treatment, or an HCV RNA level of 25 IU per milliliter or more at all assessments during treatment among patients who received at least 6 weeks of treatment. Virologic relapse was defined as a confirmed HCV RNA level of 25 IU per milliliter or more between the final visit during the double-blind treatment period and 12 weeks after the last dose of study drug among patients who completed treatment (duration of study-drug exposure, ≥77 days), had an HCV RNA level of less than 25 IU per milliliter at the final visit during the double-blind treatment period, and had data on HCV RNA levels available after the completion of treatment. Normalization of the alanine aminotransferase level was defined as a final value that did not exceed the upper limit of the normal range (as defined by the processing laboratory) during the double-blind period among patients with a baseline level above the upper limit of the normal range.

Statistical Analysis

The primary efficacy analyses assessed the noninferiority and superiority of the rate of sustained virologic response at post-treatment week 12 with ABT-450/r–ombitasvir, dasabuvir, and ribavirin, as compared with a calculated historical control rate of 65% (95% confidence interval [CI], 60 to 70). This control rate was based on response rates among patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon–ribavirin and who received retreatment with telaprevir and peginterferon–ribavirin.15,16 The control rate was weighted for the proportions of patients with a prior relapse, partial response, or null response that were expected in the current study (details in the Supplementary Appendix).

To establish that the rate of sustained virologic response with ABT-450/r–ombitasvir, dasabuvir, and ribavirin was noninferior to the historical rate, the lower boundary of the 95% confidence interval for the rate among patients receiving the active regimen during the double-blind period had to exceed the upper confidence boundary of the control rate minus 10.5 percentage points (60%). To establish that the rate of sustained virologic response with ABT-450/r–ombitasvir, dasabuvir, and ribavirin was superior to the historical rate, the lower boundary of the 95% confidence interval for the rate among patients receiving the active regimen during the double-blind period had to exceed the upper confidence boundary of the historical rate (70%). We calculated that a sample of 400 patients (300 recipients of the active regimen during the double-blind period) would provide more than 90% power to show noninferiority and superiority of the active regimen with a rate of sustained virologic response at post-treatment week 12 of 85%. A fixed-sequence testing procedure was used to maintain a type I error rate of 0.05 for the analyses of the primary and secondary efficacy end points. Details of the noninferiority and superiority analyses, sample-size determination, fixed-sequence testing procedure, and all secondary efficacy end points are provided in the Supplementary Appendix.

The primary analysis was performed after all patients receiving the active regimen during the double-blind period reached post-treatment week 12 and all patients receiving placebo reached week 12 of open-label treatment. Data regarding the primary analysis are reported.

SAS software, version 9.3, for the UNIX operating system (SAS Institute) was used for all analyses. All statistical tests and 95% confidence intervals were two-sided with a significance level of 0.05. For analysis of efficacy, normal approximation to binomial distribution was used to calculate 95% confidence intervals. For analyses of adverse events, abnormal laboratory values, and rates of normalization of the alanine aminotransferase level during the double-blind period, the active-regimen group and the placebo group were compared with the use of Fisher's exact test.

Results

Patients

A total of 562 patients were screened, 395 underwent randomization, and 394 received at least one dose of study drug (Figure S2 in the Supplementary Appendix). Patients were screened from November 2012 through May 2013. The final date for data collection regarding the analysis of the rate of sustained virologic response at post-treatment week 12 among patients receiving the active regimen during the double-blind period was December 3, 2013. Baseline demographic and clinical characteristics of the study patients are shown in Table 1

Efficacy

Among 297 patients receiving the active regimen during the double-blind period, 98.7% had an HCV RNA level of less than 25 IU per milliliter at treatment week 4 (95% CI, 97.3 to 100); 99.0% had an HCV RNA level of less than 25 IU per milliliter at treatment week 12 (95% CI, 97.9 to 100). A total of 286 patients in the active-regimen group had a sustained virologic response at post-treatment week 12, for an overall rate of 96.3% (95% CI, 94.2 to 98.4) (Figure 1); this was noninferior and superior to the historical control rate with telaprevir and peginterferon–ribavirin. A total of 166 of 173 patients with HCV genotype 1a infection had a sustained virologic response, for a rate of 96.0% (95% CI, 93.0 to 98.9); 119 of 123 patients with HCV genotype 1b had a sustained virologic response, for a rate of 96.7% (95% CI, 93.6 to 99.9). The HCV genotype (1a or 1b) could not be determined for 1 patient, who had a sustained virologic response.

The rates of sustained virologic response were 95.3% among patients with a prior relapse (82 of 86 patients), 100% among patients with a prior partial response (65 of 65 patients), and 95.2% among patients with a prior null response (139 of 146 patients) (Table 2) Rates of sustained virologic response were high across subgroups defined by race, age, fibrosis score, and IL28B genotype (Figure 2). No patient had virologic failure during treatment; all patients completing treatment (≥77 days of study-drug exposure) had an HCV RNA level of less than 25 IU per milliliter at the end of treatment.

Seven of 293 patients who completed therapy (2.4%) had a post-treatment viral relapse (Table 2). All patients with a relapse reported high adherence to study drugs. At the time of relapse, 4 of the 5 patients with HCV genotype 1a infection and 1 of the 2 patients with HCV genotype 1b infection had at least one amino acid variant known to confer resistance to one of the three direct-acting antiviral agents included in the regimen. The most frequently detected variants in the 4 patients with HCV genotype 1a infection who had variants at the time of relapse were D168V in NS3 (2 patients), M28V (3 patients) and Q30R (2 patients) in NS5A, and S556G in NS5B (2 patients). The patient with HCV genotype 1b infection who had resistance-associated variants present at the time of relapse had Y56H and D168A in NS3, Y93H in NS5A, and C316N and S556G in NS5B. The rate of normalization of the alanine aminotransferase level was significantly higher in the active-regimen group than in the placebo group (96.9% [217 of 224 patients] vs. 12.8% [10 of 78 patients], P<0.001).

Safety

During the double-blind treatment period, 91.2% of patients in the active-regimen group and 82.5% of patients in the placebo group had an adverse event (Table 3). In both groups, the two most common adverse events were headache (in 36.4% of patients in the active-regimen group and in 35.1% of those in the placebo group, P=0.90) and fatigue (33.3% and 22.7%, respectively; P=0.06). Among adverse events occurring in more than 10% of patients in either group, only pruritus had a higher frequency in the active-regimen group than in the placebo group (13.8% vs. 5.2%, P=0.03). Among adverse events occurring in less than 10% of patients in both groups, those with a higher frequency in the active-regimen group were anemia (P=0.01), a decrease in the hemoglobin level (P=0.04), and vomiting (P=0.006), and those with a higher frequency in the placebo group were constipation (P=0.02), erythema (P=0.05), neck pain (P=0.05), and neutropenia (P=0.01)

There were no moderate or severe adverse events that occurred more frequently with the active regimen than with placebo (P>0.10 for all comparisons). Six patients in the active-regimen group (2.0%) and one patient in the placebo group (1.0%) had at least one serious adverse event (Table S5 in the Supplementary Appendix). Three patients in the active-regimen group (1.0%) and no patients in the placebo group discontinued the study drug owing to adverse events. Discontinuation was due to elevated aminotransferase levels (grade 3), diarrhea, and acute renal failure in one patient each. The case of acute renal failure was a serious adverse event; the site investigator deemed this event to be unrelated to direct-acting antiviral treatment (details in Table S5 in the Supplementary Appendix).

Abnormalities in laboratory values of grade 3 or 4 that occurred during the double-blind period are shown in Table 3. The most common abnormality of grade 3 or 4 in patients in the active-regimen group was an elevated total bilirubin level, occurring in seven patients (2.4%) (maximum total bilirubin level, 173 μmol per liter [10.1 mg per deciliter]); in six of the patients, these elevations were classified as grade 3. None of these patients had concomitant grade 3 or 4 elevations in the alanine aminotransferase or aspartate aminotransferase level. Elevations in the total bilirubin level were predominantly due to indirect bilirubin and resolved in all patients by post-treatment week 4. Four patients with hyperbilirubinemia of grade 3 or 4 had jaundice or ocular icterus. No patient discontinued treatment owing to hyperbilirubinemia.

During the double-blind period, elevations in the alanine aminotransferase level of grade 3 or 4 occurred in 1.7% of patients in the active-regimen group and in 3.1% of patients in the placebo group. Elevations in the aspartate aminotransferase level of grade 3 or 4 occurred in 1.0% of patients in each group.

During the double-blind period, abnormalities in the hemoglobin value of grade 1 (below the lower limit of the normal range to 10.0 g per deciliter) and grade 2 (8 to <10.0 g per deciliter) occurred in 52.0% and 4.7% of patients in the active-regimen group, respectively. One patient in the active-regimen group (0.3%) had a hemoglobin value of grade 3 (6.5 to <8.0 g per deciliter). No patient had a hemoglobin value of grade 4 (<6.5 g per deciliter) (Table S6 in the Supplementary Appendix). No patient discontinued the study drug owing to anemia. In 6.4% of patients in the active-regimen group, the ribavirin dose was modified owing to adverse events. No patient received erythropoietin or a transfusion. There were no deaths from any cause in the active-regimen group or the placebo group.

Discussion

In this large, multicenter, phase 3 trial involving patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon–ribavirin, 96.3% of patients who received retreatment with ABT-450/r–ombitasvir and dasabuvir with ribavirin had a sustained virologic response at post-treatment week 12. According to a modified intention-to-treat analysis, the rate of sustained virologic response with this combination regimen was noninferior and superior to the historical control rate with telaprevir plus peginterferon–ribavirin in a similar patient population. This rate of sustained virologic response also exceeds reported response rates of 59 to 80% in retreatment studies involving patients with HCV genotype 1 infection who received boceprevir or simeprevir with peginterferon–ribavirin.9,18

The results of our study confirm previous data suggesting that this 12-week regimen combining antiviral drugs with multiple mechanisms of action is effective regardless of the prior response to peginterferon–ribavirin.14 The rates of sustained virologic response in this study were high even among patients with a null response to prior treatment, who made up nearly half the study population; such patients have been the least likely to have a response to retreatment regimens comprising peginterferon–ribavirin plus a protease inhibitor.10,18 In patients with a prior null response, 12 weeks of telaprevir with 48 weeks of peginterferon–ribavirin resulted in rates of sustained virologic response of 29 to 33%, whereas the use of simeprevir with peginterferon–ribavirin for similar durations resulted in rates of 38 to 53%.10,18 In contrast, in this study the 12-week regimen resulted in a 95.2% rate of sustained virologic response among patients with a prior null response.

Data from trials of peginterferon-containing and peginterferon-free regimens have suggested that the HCV genotype (1a or 1b) affects the efficacy of some regimens.19-21 However, in this trial, high rates of sustained virologic response were observed among patients with HCV genotype 1a and among those with HCV genotype 1b (96.0% and 96.7%, respectively), with few true virologic failures.

The double-blind design of this trial allowed a comparison of adverse events in patients receiving the active regimen with events in those receiving placebo. One percent of patients discontinued active therapy owing to an adverse event. Pruritus was the only adverse event occurring in more than 10% of patients in either study group that was significantly more frequent with the active regimen than with placebo. Although there were three adverse events occurring in less than 10% of patients in each group that were significantly more frequent with the active regimen (anemia, a decrease in the hemoglobin level, and vomiting), four adverse events occurring in less than 10% of patients in each group were significantly more frequent with placebo (constipation, erythema, neck pain, and neutropenia).

The most common laboratory abnormality in the active-regimen group was a transient elevation in the total bilirubin level, occurring in 2.4% of patients. These elevations are consistent with the known role of ABT-450 as an inhibitor of the OATP1B1 transporter.22,23 Hemoglobin values of 8.0 to less than 10.0 g per deciliter (grade 2), 6.5 to less than 8.0 g per deciliter (grade 3), and less than 6.5 g per deciliter (grade 4) occurred in 4.7%, 0.3%, and 0% of patients in the active-regimen group, respectively. No patient discontinued the study treatment owing to anemia.

Patients who did not have a response to triple therapy with an approved protease inhibitor and peginterferon–ribavirin were excluded from this study. Thus, the results cannot be extrapolated to that population. Although this study did not include previously untreated patients, Feld et al. now report in the Journal that treatment with the same regimen of new antiviral agents and ribavirin in such patients was associated with a high rate of sustained virologic response at post-treatment week 12.24

In conclusion, an all-oral combination regimen of ABT-450/r, ombitasvir, and dasabuvir with ribavirin resulted in rates of sustained virologic response at post-treatment week 12 of more than 95%, regardless of HCV genotype (1a or 1b) and with low rates of treatment discontinuation, in previously treated patients with HCV genotype 1 infection and no cirrhosis, including those with a prior null response. The similarity of safety and efficacy data in the previous phase 2 trial and this phase 3 trial supports further exploration of this all-oral regimen in other difficult-to-cure populations, such as patients with HCV and HIV coinfection and liver-transplant recipients.


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 April 10, 2014, at NEJM.org.

We thank the trial participants, investigators, and coordinators who made this study possible; George Liossis, Jun Sun, Kevin Howieson, Christine Collins, Gretja Schnell, Jill Beyer, Michelle Irvin, Preethi Krishnan, Thomas Reisch, and Rakesh Tripathi of AbbVie for their contributions; and Christine Ratajczak (AbbVie) for medical-writing services.

Source Information

From Johann Wolfgang Goethe University, Frankfurt am Main (S.Z.), and Medizinische Hochschule Hannover, Hannover (H.W.) — both in Germany; Weill Cornell Medical College, New York (I.M.J.), and Premier Medical Group of the Hudson Valley, Poughkeepsie (P.V.) — both in New York; AbbVie, North Chicago (T.B., J.X., T.P.-M., B.D.-T., L.L., T.P., B.B.), and Center for Liver Diseases, University of Chicago Medical Center, Chicago (D.M.J.) — both in Illinois; Centro Hospitalar de Lisboa Norte and Medical School of Lisbon, Lisbon, Portugal (R.T.M.); Texas Liver Institute, University of Texas Health Science Center, San Antonio (F.P.); Hôpital Saint Joseph, Marseille, France (M.B.); Johns Hopkins University, Baltimore (M.S.S.); Liver and Intestinal Research Centre, Vancouver, BC, Canada (E.T.); St. Vincent's Hospital (Melbourne), Fitzroy, Australia (P.D.); Saint Louis University, St. Louis (A.M.D.); and Southern California Liver Centers and Southern California Research Center, Coronado (T.H.).

Address reprint requests to Dr. Zeuzem at Johann Wolfgang Goethe University Hospital, Theodor Stern Kai 7, 60590 Frankfurt, Germany, or at zeuzem@em.uni-frankfurt.de.

Source

  • 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 CongressTM

Category: R&D News

Thursday, April 10, 2014 7:00 am EDT

"Daclatasvir has unique scientific characteristics that support ongoing research for its use in multiple all-oral HCV regimens"

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.

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that clinical trials of these compounds will support regulatory filings, or that DCV or any other compounds mentioned in this release will receive regulatory approval or, if approved, that they will become commercially successful products. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2013 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

EASL The International Liver Congress is a registered trademark of European Association for the Study of the Liver.

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Bristol-Myers Squibb
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Jeff Smith,
Office: +33(0) 1 58 83 83 21
Cell: +33(0) 6 03 99 40 18
jr.smith.paeurope@bms.com
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Carrie Fernandez
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carrie.fernandez@bms.com
or
Investors:
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ranya.dajani@bms.com
or
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ryan.asay@bms.com

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