HCV Research and News: 04/19/12

April 19, 2012

Collaboration on Hepatitis Drugs Lags

David Paul Morris/Bloomberg News

A machine purifying a drug at a Gilead Sciences laboratory in California.

By ANDREW POLLACK

Published: April 19, 2012

A combination of two pills proved extremely effective in treating hepatitis C in a small trial, raising hopes among researchers that the disease will be curable without an injected drug that has debilitating side effects.

But the combination might not find its way to the market because one pill is owned by Gilead Sciences and the other by Bristol-Myers Squibb. The companies have not agreed to collaborate, to the chagrin of some doctors.

“The only appropriate motivation should be what is the best and fastest way to get cures, not what is best for the shareholders,” said Dr. Scott Friedman, chief of liver diseases at the Mount Sinai School of Medicine in New York, who was not involved in the trial.

Dr. Douglas J. Manion, a senior vice president for Bristol-Myers, said his company was “keen” on working with Gilead but that “thus far, they have been unwilling to engage in that collaboration.”

Norbert W. Bischofberger, executive vice president for research and development at Gilead, said his company wanted to wait several months for data on other treatment options before deciding what path to take.

“We told them it’s too early to jump wildly into this collaboration,” he said.

Both executives spoke separately by telephone from the International Liver Congress in Barcelona, Spain, where data on the drug combination was presented.

Gilead and Bristol are among the leaders of one of the most heated races in the pharmaceutical industry — to develop an all oral treatment for hepatitis C, a liver-damaging virus that infects three million to four million Americans.

New pills introduced last year by Vertex Pharmaceuticals and Merck have sharply improved the cure rate, to about 60 to 80 percent. But those drugs must still be used alpha interferon, which is injected weekly for up to a year and can cause flulike symptoms.

Many companies are trying to develop combinations of pills — similar to those used to treat H.I.V. — that would eradicate the virus without the need for interferon.

Results from several companies presented at the Barcelona conference have given doctors confidence that this will indeed be possible, with the first such combinations reaching the market perhaps by 2014.

Dr. Melissa Palmer, who was a practicing liver specialist until last fall, said that the trials were small and patients were usually not followed long enough to see if they were truly cured.

“It’s going to be important to wait a longer time to see if these results are sustainable,” said Dr. Palmer, who is now a consultant to investors.

Nonetheless, investors were busily predicting from the Barcelona data which companies will capture the billions of dollars a year in possible sales. Besides Gilead and Bristol, some mentioned Abbott Laboratories, which also presented strong preliminary data.

Gilead, a leader in drugs for AIDS, paid $11 billion a few months ago to acquire Pharmasset, based on very preliminary data on its hepatitis drug, now called GS-7977. Subsequent data was not as good and Gilead’s stock sank.

But the data announced on Thursday appeared to restore confidence in 7977. Shares of Gilead gained 12 percent to $52.25. Shares of Bristol rose 1 percent to $33.93.

All 29 of the patients with the strain of the virus that is most common in the United States had no detectable virus in their blood four weeks after finishing 24 weeks of treatment with GS-7977 and Bristol’s pill, daclatasvir. The figure was 28 out of 30 patients with two other virus strains. Each pill was taken once a day.

Doctors usually wait 12 to 24 weeks after finishing treatment to declare a cure, since there can be relapses.

Dr. Bischofberger said that before deciding whether to work with Bristol on a larger trial, Gilead wanted to wait a few months for data showing whether the same two drugs would work with only 12 weeks of treatment instead of 24.

He said he also wanted to see whether Gilead could improve results of using GS-7977 with ribavirin, a drug that is part of the existing treatment.

A combination of GS-7977 with ribavirin, which is generic, would be far less expensive than a combination with daclatasvir, he said, because new hepatitis drugs are expected to cost tens of thousands of dollars for a course of treatment.

A combination with ribavirin would also mean that Gilead would not have to split revenues with Bristol, making it easier to recoup the money it spent to buy Pharmasset.

Dr. Bischofberger said that once both 7977 and daclatasvir won approval, doctors could use them together, so patients would not be shortchanged if the companies did not collaborate.

Source

Also See: Gilead, Bristol Put Profits Ahead of Best Care for Hep C Patients

EASL 2012: Recapitulation of the entire hepatitis C virus life in engineered mouse cell lines

Public release date: 19-Apr-2012

Contact: Travis Taylor
easlpressoffice@cohnwolfe.com
44-789-438-6428
European Association for the Study of the Liver

A US study presented today at The International Liver CongressTM 2012 demonstrates that the entire HCV lifecycle can be recapitulated in murine cells, implying that HCV permissive mouse models could soon be developed.(1)

The data suggests that HCV replication in the murine environment is limited by innate immune responses. Inactivating these pathways and the expression of the appropriate entry factors and miR-122 creates murine fibroblasts that can be infected and support replication.

The study also corroborates previous data that the expression of apoE promotes production of infectious virus.

Although mouse orthologs of MAVS and TRIF could be cleaved by the HCV NS3/4A protease, this was not enough to establish robust HCV replication.

In contrast, impairment of type I and type III IFN signaling enhanced the permissiveness of murine fibroblasts for persistent HCV replication.

The in-depth study of hepatitis C pathogenesis and immune responses is currently hampered by the lack of suitable small animal models. This study is a positive step to addressing this issue.

###

References

1. Vogt A, Recapitulation of the entire Hepatitis C virus life in engineered mouse cell lines. Abstract presented at the International Liver CongressTM 2012

Source

EASL 2012: Gut Microbiota Transplantation may Prevent Development of Diabetes and Fatty Liver Disease

PRESS RELEASE

April 19, 2012, 5:00 a.m. EDT

BARCELONA, Spain, April 19, 2012 /PRNewswire via COMTEX/ -- Exciting new data presented today at the International Liver Congress™ 2012 shows the gut microbiota's causal role in the development of diabetes and non-alcoholic fatty liver disease (NAFLD), independent of obesity[1]. Though an early stage animal model, the French study highlights the possibility of preventing diabetes and NAFLD with gut microbiota transplantation - the engrafting of new microbiota, usually through administering faecal material from a healthy donor into the colon of a diseased recipient.[2]

To view the Multimedia News Release, please click:

http://multivu.prnewswire.com/mnr/prne/easl/53808/

In the 16 week study, two groups of germ free mice received gut microbiota transplants; one set from donor mice displaying symptoms of insulin resistance and liver steatosis (responders), the other from normal mice (non responders). The donor mice were selected due to their response to being fed a high fat diet.

The germ free group that received microbiota from symptomatic mice (responder receivers - RR) showed higher levels of fat concentration in the liver as well as being insulin resistant. The germ free group that received microbiota from healthy mice (non-responder-receivers - NRR) maintained normal glucose levels and sensitivity to insulin.

EASL Scientific Committee Member Dr Frank Lammert said: "The factors leading to Non-Alcoholic Fatty Liver Disease (NAFLD) are poorly understood, but it is known that NAFLD and Type 2 diabetes are characterised, respectively, by liver inflammation and metabolic disorders like insulin resistance."

"This study shows that different microbiota cause different metabolic responses in animals. By implanting microbiota from healthy mice, the study authors prevented the development of liver inflammation and insulin resistance, both indications of liver disease and diabetes. Thus, gut microbiota transplants could have a therapeutic role in the development of these diseases."

The RR mice also showed lower levels of microorganisms than usually found in the healthy gut. Lachnospiraceae was identified as the species most important in developing fatty liver and insulin resistance.

At present, the intestinal microbiota is considered to constitute a "microbial organ": one that has pivotal roles in the body's metabolism as well as immune function. Therefore transplantation aims to restore gut functionality and re-establish a certain state of intestinal flora.

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:

The International Liver Congress™ which is the main scientific and professional event in hepatology worldwide

Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year

Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology

Journal of Hepatology published monthly

Participation in a number of policy initiatives at European level

iLiver iPhone app - a free medical app developed by EASL, with content fully authored, validated and accredited by 42 independent liver specialists

About The International Liver Congress™ 2012

The International Liver Congress™ 2012, the 47th annual meeting of the European Association for the study of the Liver, is being held at the Centre Convencions Internacional (CCIB) in Barcelona from April 18 - 22, 2012. The congress annually attracts over 8,300 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.

References

1. Le Roy T et al. Gut microbiota transplantation demonstrates its causal role in the development of type 2 diabetes and fatty liver. Abstract presented at the International Liver Congress™ 2012

2. Khoruts A and Sadowsky MJ, Therapeutic transplantation of the distal gut microbiota. Mucosal Immunology 2011;4:4-7

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 Travis Taylor +44(0)7894-386-422 Vicky O'Connor +44(0)7894-386-428

Video: http://multivu.prnewswire.com/mnr/prne/easl/53808/

SOURCE European Association for the Study of the Liver

Source

EASL 2012: Abbott Presents Positive Results from Phase 2 "Pilot" Study of an Interferon-Free Combination Regimen for the Treatment of Hepatitis C

Results among the Most Mature Data for an Interferon-Free Regimen, Including 36-Week Post-Treatment Sustained Viral Response for a 12-Week Treatment Regimen

April 19, 2012

Abbott Park, Illinois (NYSE: ABT) and Watertown, Massachusetts — Complete data from the study known as "Pilot" – Abbott's initial interferon-free study of its direct-acting antiviral agents for the treatment of hepatitis C (HCV) – showed that 91 percent of genotype 1 infected, treatment-naïve patients taking ABT-450/r and ABT-072 combined with ribavirin administered for 12 weeks, achieved sustained viral response at 24 weeks (SVR24). 82 percent of patients achieved SVR36. This is among the first 12-week, interferon-free HCV regimen with 36-week post-treatment data in genotype 1 patients. Results were presented today at the International Liver Congress 2012 (ILC 2012), the annual meeting of the European Association for the Study of the Liver (EASL), April 18-22 in Barcelona, Spain.

"The sustained viral response rates in this study are very encouraging as there are currently no treatment options for patients with HCV who cannot take or are intolerant to interferon," said Eric Lawitz, M.D., medical director at Alamo Medical Research in San Antonio, and the lead investigator for the study. "This is one of the earliest looks at mature data and it continues to demonstrate that a 12-week combination regimen of direct-acting antiviral treatments has the potential to offer high cure rates while eliminating the use of interferon."

Current treatments for HCV remain interferon-based. A significant number of HCV patients are unable or unwilling to take interferon due to contraindications and/or side effects, which may include flu-like symptoms, depression and insomnia. Specifically targeted antiviral therapies for HCV, such as protease inhibitors and non-nucleoside polymerase inhibitors, may have the potential to increase the proportion of patients in whom the virus can be eradicated.

About Study M12-267 (Pilot) and Key Findings

The objectives of the 12-week, Phase 2 study were to assess the safety, tolerability, pharmacokinetics and antiviral activity of ABT-450/r 150/100 mg QD and ABT-072 400 mg QD + ribavirin administered for 12 weeks.
The study was conducted in 11 treatment-naïve adults with host IL28B "CC" genotype from multiple ethnic backgrounds with non-cirrhotic HCV GT1
(8 GT 1a, 3 GT 1b). Ribavirin dose was weight-based (1,000-1,200 mg/day) and dosed twice daily.
The primary endpoint was percentage of patients with HCV RNA <25 IU/mL from week 4 through 12. Other trial endpoints include early virologic response, RVR and SVR through 24 weeks.
100 percent of patients maintained HCV RNA levels <25 IU/mL from weeks 4 through 12 of treatment, and all had undetectable HCV RNA from week 5 to the end of treatment.
91 percent of patients (10 of 11) achieved SVR24.
One relapse was observed 8 weeks post therapy and a second 36 weeks post therapy; overall, 82 percent of patients (9 of 11) achieved SVR₃₆.
No additional relapses were seen among the 10 patients with 48-week post-treatment data available / where SVR₄₈ results were available.
In the trial, the most common adverse events were headache (36%), fatigue (27%), nausea (27%) and dry skin (27%). Most adverse events were mild in severity and there were no discontinuations due to adverse events.
Two bilirubin elevations, which consisted of indirect bilirubin with no associated transaminase elevations (i.e. no indication of liver damage), were reported during the study. The bilirubin elevations occurred one week after starting treatment and resolved with continued dosing.

"Abbott is proud to present some of the first sustained viral response data for short course, interferon-free regimens for the treatment of HCV," said Scott Brun, M.D., divisional vice president, Infectious Disease Development, Abbott. "With a research portfolio that encompasses multiple direct-acting antiviral treatments in different drug classes, Abbott has the ability to quickly study a variety of combination regimens for HCV, with a focus on interferon-free regimens, to determine which has the greatest potential to help the largest number of patients."

ABT-450 is being developed with low dose ritonavir which enhances the pharmacokinetic properties of ABT-450. The use of ritonavir 100 mg with ABT-450 for the treatment of HCV is investigational.

ABT-450 was discovered during the course of collaboration between Abbott and Enanta Pharmaceuticals for protease inhibitors. ABT-450 is being developed by Abbott for use in combination with Abbott's non-nucleoside polymerase inhibitors (ABT-333 and ABT-072) and NS5A inhibitor (ABT-267). Additional data from larger, ongoing Phase 2 clinical trials is expected later this year.

About the Hepatitis C Virus

Hepatitis C is a liver disease affecting as many as 170 million people worldwide. The virus is primarily spread through direct contact with the blood of an infected person. HCV increases a person's risk of developing chronic liver disease, cirrhosis, liver cancer and death; and liver disease associated with HCV infection is growing rapidly.

Ritonavir Use in Treatment of HIV

Ritonavir is in a class of medicines called the HIV protease inhibitors. Ritonavir is used in combination with other anti-HIV medicines to treat people with human immunodeficiency virus (HIV) infection. Ritonavir is for adults and for children greater than 1 month in age and older.

Ritonavir does not cure HIV infection or AIDS and does not reduce the risk of passing HIV to others. People taking ritonavir may still get opportunistic infections or other conditions that happen with HIV infection. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections.

Ritonavir Safety in Treatment of HIV

Patients should not take ritonavir with certain medicines, as these can cause serious or life-threatening problems such as irregular heartbeat, breathing difficulties, or excessive sleepiness. Patients should not take ritonavir if they have had a serious allergic reaction to any of its ingredients. Some patients taking ritonavir may develop liver and pancreas problems, which can cause death.

Patients may develop large increases in triglycerides and cholesterol, diabetes, high blood sugar, changes in body fat, increased bleeding in people with hemophilia, allergic reactions, and/or changes in heart rhythm. Patients may develop signs and symptoms of infections that they already have after starting anti-HIV medicines.

For more information, please see the Important Safety Information and full Prescribing Information for ritonavir.

About Enanta

Enanta Pharmaceuticals is a research and development company that uses its novel chemistry approach and drug discovery capabilities to create best in class small molecule drugs in the infectious disease field. Enanta is discovering and developing novel inhibitors and combinations of inhibitors targeted against the hepatitis C virus (HCV). These inhibitors include members of the direct acting antiviral (DAA) inhibitor classes– protease (partnered with Abbott), NS5A (partnered with Novartis), nucleotide polymerase, and a host targeted antiviral (HTA) inhibitor class targeted against cyclophilin. Additionally, the company has created a new class of antibiotics, called Bicyclolides, which overcomes bacterial resistance. Antibacterial focus areas include overcoming resistance to superbugs, treating respiratory tract infections, and developing intravenous and oral treatments for hospital and community MRSA infections. Enanta is a privately held company headquartered in Watertown, Mass. Enanta's news releases and other information are available on the company's web site at www.enanta.com.

About Abbott's HCV Development Programs

In addition to its partnership with Enanta Pharmaceuticals for protease inhibitors, including ABT-450 and ABT-450 containing regimens, Abbott has internal programs focused on additional viral targets. Abbott currently has investigational medicines with three different mechanisms of action in its ongoing clinical trials, including protease, polymerase and NS5A inhibitors. Abbott is well-positioned to explore combinations of these compounds, a strategy with the potential to markedly transform current treatment practices by shortening therapy duration, improving tolerability and increasing cure rates.

About Abbott

Abbott (NYSE: ABT) is a global, broad-based health care company devoted to the discovery, development, manufacturing and marketing of pharmaceuticals and medical products, including nutritionals, devices and diagnostics. The company employs approximately 91,000 people and markets its products in more than 130 countries.

Abbott Contacts
Media:
Tracy Sorrentino
Roseanne Durril
(847) 937-8712
(847) 938-6114

Financial:
Lawrence Peepo
Elizabeth Shea
(847) 935-6722
(847) 935-2211

Enanta Contacts
Media:
Kari Watson
(781) 235-3060

Financial:
Paul Mellett
(617) 607-0761

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EASL 2012: Two studies show true impact of liver disease across Europe

Provided by News-Medical.Net

Published on April 19, 2012 at 6:46 AM

Two studies presented at the International Liver Congress- 2012 show the true impact that liver disease has across Europe. One highlights the financial cost of liver disease to the community and the second highlights the high mortality rates associated with cirrhosis.

A naturalistic, multicenter, retrospective, Cost of Illness study (COME) was developed to assess costs occurring in 1,088 patients over six months. Patients enrolled had liver diseases including hepatitis C, cirrhosis, hepatitis B, hepatic carcinoma and other hepatic diseases (cholestasis, NASH etc.). The study found that liver disease cost the EU on average at least -644.77 per patient per month. Hospitalisations account for 50.6% of the overall mean direct costs per month, with treatment accounting for 41.2% of costs. In addition, patients and family caregivers lost an average of 1.15 days per patient per month of productivity, an important indirect cost.

EASL Vice Secretary Professor Markus Peck-Radosavljeic commented: "These results demonstrate the real life costs involved in the treatment and ongoing management of patients with liver disease. Liver disease is an increasing problem and having concrete information on the financial impact can help us plan our treatment strategies more effectively and more importantly, might engage health authorities more to invest into preventive action like reducing harmful alcohol consumption and fight obesity."

The study concludes that although treatment costs account for just over 40% of direct costs, the use of efficient treatments is necessary to reduce worsening of patients' health, direct and indirect costs.

In a separate study the EASL-CLIF consortium report that 28 day mortality for Acute-on-Chronic liver failure (ACLF) is 35.5%. The consortium set out to address questions around ACLF, a poorly defined syndrome characterized by acute deterioration of cirrhosis, representing a main cause of hospitalisation and death. At present, no diagnostic criteria and information on prevalence, pathogenesis or prognosis are available. The consortium aimed to develop a new score (CLIF-SOFA, derived from the existing sequential organ failure assessment score) to assess the severity and number of organ failures.

1,379 patients, admitted to 29 hospitals due to complications of cirrhosis, were enrolled in this observational prospective European CANONIC study. Data presented at The International Liver Congress-2012 reports on results of the first 920 cases.

Four grades of ACLF were identified:

ACLF-1: renal failure or a nonrenal organ failure associated with creatinine 1.5-2 mg/dL and/or grade I-II encephalopathy
ACLF-2: 2 organ failures
ACLF-3: 3 organ failures
ACLF-4: 4-6 organ failures

The overall prevalence of ACLFwas 22.6% with twenty-eight-day mortality of ACLF patients at 35.3% compared (but as high as 85.7% in ACLF-4 patients) to only 4.1% in patients without ACLF. ACLFoften developed in patients with previously compensated (21%) or recently decompensated (< 3 months, 18%) cirrhosis and was significantly associated with bacterial infections and active alcoholism, but not gastrointestinal hemorrhage. Hepatitis, TIPS, paracentesis without albumin and surgery were infrequent precipitating events. In about 20% of cases no precipitating event was identified. ACLF was associated with an inflammatory reaction (both in infected and not infected patients) as estimated by increased WBC and plasma C-reactive protein levels.

Source: European Association for the Study of the Liver

Source

Modest Alcohol Consumption Lowers Risk and Severity of Liver Disease

News Release

Date: April 19, 2012

People with nonalcoholic fatty liver disease (NALFD) who consume alcohol in modest amounts – no more than one or two servings per day – are half as likely to develop hepatitis as non-drinkers with the same condition, reports a national team of scientists led by researchers at the University of California, San Diego School of Medicine.

The findings are published in the April 19, 2012 online issue of The Journal of Hepatology.

Two forms of nonalcoholic fatty liver disease (NAFLD) are depicted in these images of liver biopsies from adults, taken from this study. The first (top) shows nonalcoholic fatty liver only. The second (bottom) shows nonalcoholic steatohepatitis (NASH), a more serious condition with potential to progress to cirrhosis. Images courtesy of Elizabeth Brunt, MD, of Washington University in Saint Louis.

NALFD is the most common liver disease in the United States, affecting up to one third of American adults. It’s characterized by abnormal fat accumulation in the liver. The specific cause or causes is not known, though obesity and diabetes are risk factors. Most patients with NAFLD have few or no symptoms, but in its most progressive form, known as nonalcoholic steatohepatitis or NASH, there is a significantly heightened risk of cirrhosis, liver cancer and liver-related death.

NALFD is also a known risk factor for cardiovascular disease (CVD). Patients with NAFLD are approximately two times more likely to die from coronary heart disease than from liver disease. The study’s authors wanted to know if the well-documented heart-healthy benefits of modest alcohol consumption outweighed alcohol’s negative effects.

“We know a 50-year-old patient with NAFLD has a higher risk of CVD,” said Jeffrey Schwimmer, MD, associate professor of clinical pediatrics at UC San Diego, director of the Fatty Liver Clinic at Rady Children’s Hospital-San Diego and senior author. “Data would suggest modest alcohol consumption would be beneficial (in reducing the patient’s CVD risk) if you don’t take liver disease into account. When you do take liver disease into account, however, the usual medical recommendation is no alcohol whatsoever.”

Schwimmer and colleagues discovered that the benefits of modest alcohol consumption were compelling, at least in terms of reducing the odds of patients with NAFLD from developing more severe forms of the disease. Patients with NASH are 10 times more likely to progress to cirrhosis, the final phase of chronic liver disease. Cirrhosis is the 12th leading cause of death in the U.S., killing an estimated 27,000 Americans annually.

“Our study showed that those people with modest alcohol intake – two drinks or less daily – had half the odds of developing NASH than people who drank no alcohol,” said Schwimmer. “The reasons aren’t entirely clear. It’s known that alcohol can have beneficial effects on lipid levels, that it increases ‘good’ cholesterol, which tends to be low in NAFLD patients. Alcohol may improve insulin sensitivity, which has a role in NAFLD. And depending upon the type of alcohol, it may have anti-inflammatory effects.”

The study also found that in patients with NAFLD, modest drinkers experienced less severe liver scarring than did lifelong non-drinkers.

The study did not evaluate the effects of different types of alcohol, such as beer or spirits. Schwimmer said to do so would require a much larger study. Also, the study’s findings do not apply to children. All of the participants in the study were age 21 and older.

The current paper is based on analyses of 600 liver biopsies of patient’s with NAFLD by a national panel of pathologists who had no identifying clinical information about the samples. The study excluded anyone who averaged more than two alcoholic drinks per day or who reported consuming five or more drinks in a day (binge-drinking) at least once a month. All of the patients were at least 21 years of age.

Schwimmer said the findings indicate patients with liver disease should be treated individually, with nuance.

“For a patient with cirrhosis or viral hepatitis, the data says even small amounts of alcohol can be bad. But that may not be applicable to all forms of liver disease. Forty million Americans have NAFLD. Physicians need to look at their patient’s overall health, their CVD risk, their liver status, whether they’re already drinking modestly or not. They need to put all of these things into a framework to determine risk. I suspect modest alcohol consumption will be an appropriate recommendation for many patients, but clearly not all.”

Co-authors are Winston Dunn, departments of Pediatrics and Medicine, UC San Diego and Gastroenterology and Hepatology, Department of Medicine, University of Kansas Medical Center; Arun J. Sanyal, Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University Medical Center; Elizabeth M. Brunt, John Cochran VA Medical Center, Saint Louis and Division of Gastroenterology, Saint Louis University School of Medicine; Aynur Unalp-Arida, Department of Epidemilogy, Johns Hopkins Bloomberg School of Public Health; Michael Donohue, Division of Biostatics and Bioinformatics, Department of Family and Preventive Medicine, UC San Diego; and Arthur J. McCullough, Department of Gastroenterology and Hepatology, Cleveland Clinic.

Funding for this research came, in part, from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Child Health and Human Development and the National Cancer Institute.

# # #

Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

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Novel Drug Works Against Hepatitis C

By Todd Neale, Senior Staff Writer, MedPage Today

Published: April 19, 2012

Take Posttest

The investigational drug GS-7977 performed well against hepatitis C virus (HCV) in treatment-naive patients, with or without contributions from pegylated interferon and ribavirin, several studies showed.

In a phase II study, GS-7977 (a nucleotide NS5B inhibitor) combined with daclatasvir (a novel NS5B inhibitor) resulted in rapid and sustained viral responses in patients infected with HCV genotypes 1, 2, or 3, Mark Sulkowski, MD, of Johns Hopkins University, reported at the European Association for the Study of the Liver meeting in Barcelona.

And in another phase II study, presented by Kris Kowdley, MD, of Virginia Mason Medical Center in Seattle, GS-7977 combined with pegylated interferon and ribavirin showed similar efficacy in patients with HCV genotype 1, the hardest-to-treat strain.

GS-7977 and daclatasvir are two of several new drugs being developed that directly target HCV, with the aim of moving away from the use of pegylated interferon and ribavirin, which boost the immune system to battle the virus but come with multiple side effects. Those include flu-like symptoms, depression, neutropenia, thrombocytopenia, and anemia.

In the study presented by Sulkowski, treatment-naive patients with HCV genotype 1, 2, or 3 were randomized to one of three arms:

Daily GS-7977 400 mg for 7 days followed by GS-7977 plus daily daclatasvir 60 mg for 23 weeks
Daily GS-7977 and daclatasvir for 24 weeks
Daily GS-7977 and daclatasvir plus ribavirin for 24 weeks

The 44 patients with genotype 1 were randomized separately from the 44 with genotypes 2 and 3.

By week four of treatment, all patients had a sustained viral response. That figure was no lower than 86% in any group at the end of treatment and at four weeks after the end of treatment.

Ribavirin did not accentuate the virologic response.

The treatment was relatively well tolerated, and the most frequent adverse events were fatigue, headache, and nausea. Grade 3/4 laboratory abnormalities included elevated cholesterol in one patient, elevated glucose in two, low hemoglobin in six, lymphopenia in one, and low phosphorus in two.

The study presented by Kowdley -- the ATOMIC study -- included 316 patients with HCV genotype 1, 11 with genotype 4 and five with genotype 6. They were noncirrhotic, were treatment-naive, and had an HCV RNA of at least 50,000 IU/mL. There were three treatment arms:

Daily GS-7977 400 mg plus pegylated interferon (180 µg weekly injection) and ribavirin (500 mg twice daily) for 12 weeks
Daily GS-7977 400 mg plus pegylated interferon and ribavirin for 24 weeks
Daily GS-7977 400 mg plus pegylated interferon and ribavirin for 12 weeks, with re-randomization at week 12 to GS-7977 alone or GS-7977 plus ribavirin for the rest of the study

By week two of treatment, 78% had HCV RNA below the level of detection, and 97% achieved a rapid viral response (HCV RNA undetectable after 4 weeks of treatment).

At 4 weeks after treatment ended, 92% of patients had a sustained viral response.

Among the patients randomized to the 12-week treatment arm, 90% achieved a sustained virologic response 12 weeks after treatment ended.

As in the other study, GS-7977 was generally well tolerated with adverse events consistent with the safety profile of interferon and ribavirin. Side effects included fatigue (54%), nausea (29%), headache (29%), chills (19%), and insomnia (19%).

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Unreported Clinical Trial Data Rampant, Lead to Research Bias

General Surgery News

ISSUE: APRIL 2012 | VOLUME: 39:04

By George Ochoa

Clinical drug trials often are hailed as the standard for relevant and reliable information on potential new products.

But, according to a new editorial published in the January British Medical Journal, the truth is that researchers often fail to report relevant clinical trial data (BMJ 2012;344:d8158).

“We are not dealing here with trial design, hidden bias or problems of data analysis—we are talking simply about the absence of the data,” the authors wrote. This behavior, in turn, biases research, wastes health care resources and may harm patients, the editorialists said.

“Moreover, researchers or others who deliberately conceal trial results have breached their ethical duty to trial participants,” they wrote.

Asked to account for the current burst of interest in unreported data, editorial co-author and clinical epidemiology editor of BMJ Elizabeth Loder, MD, MPH, said, “A critical mass of interested people may have accumulated by now.”

In fact, a slew of studies accompanying the editorial in the journal “confirm the fact that a large proportion of evidence from human trials is unreported, and much of what is reported is done so inadequately,” Dr. Loder wrote in the editorial. The studies explore the extent and consequences of leaving out data from clinical trials.

In one study, investigators showed that the addition of unpublished data to published meta-analyses of drug trials often changed the results (BMJ 2012;344:d7202). The study researchers integrated previously unpublished data into existing meta-analyses of nine FDA-approved drugs and showed that the recalibrated trial data produced identical estimates of drug efficacy in three of 41 cases (7%), but 46% greater and 46% lower drug efficacy in the remaining 38 cases (19 for each).

The editorialists acknowledged that “it is sometimes assumed that incorporation of missing data will reduce estimates of drug benefits, but this study shows that ‘publication bias’ can cut both ways. Each increment of data can change the overall picture, but in most cases with no certainty that the picture is complete.”

Not only is evidence frequently missing from trials, but the requirements for mandatory trial registration and appropriately timed sharing of results also often are not followed properly. Another study found that fewer than half of trials funded by the National Institutes of Health (NIH) are published in a peer-reviewed journal within 30 months of trial completion, and even at 51 months, one-third of results remained unpublished (BMJ 2012;344:d7292). Furthermore, in the United States, in 2009, only 22% of drug trials subject to mandatory reporting requirements disclosed their results within the required one year after the trial ended (Prayle et al. BMJ 2012;344:d7373).

“So it seems that most trials haven’t reported results, which we think is serious,” lead author Andrew P. Prayle, BMedSci, BMBS, MRCPCH, clinical research fellow, Child Health, University of Nottingham, in Nottingham, United Kingdom, wrote in an email.

A recent Cochrane review provided an example of allegedly unreported data (Cochrane Database Syst Rev 2012;1:CD008965). Attempting to study the anti-influenza antiviral drugs zanamivir (Relenza, GlaxoSmithKline) and oseltamivir (Tamiflu, Genentech USA, Inc., member of the Roche Group), the researchers received cooperation from GlaxoSmithKline, but reported that they were “unable to obtain the full set of clinical study reports or obtain verification of data” from Roche despite five requests between June 2010 and February 2011.

By email, lead author Tom Jefferson, MD, an independent epidemiologist in Rome, wrote: “We have come up with tentative conclusions which are at odds with the manufacturers’ statements,” but “[f]ull testing of all these findings, which may have a profound public health impact, cannot be done in the absence of the complete data set.” Reached for comment, Roche maintained that it does make “detailed clinical trial reports” available and that it “stands behind the robustness and integrity of our data supporting the efficacy and safety of Tamiflu.”

The lack of reporting appears to violate the FDA Amendments Act of 2007, and this violation prompted Rep. Henry A. Waxman (D-Calif.) and congressional colleagues to write to the heads of the NIH and the FDA, asking what had happened and why the penalty of $10,000 per day for violating the law had apparently not been enforced.

When asked about the letter, the NIH reported that it would respond to the representatives, and FDA spokeswoman Pat El-Hinnawy, said by email that numerous factors must be analyzed to determine whether data are due. For example, she said, there may be a delay if a clinical trial sponsor is seeking approval of a new use of the drug or device.

“FDA has identified a number of factors that skew the data and impact the percentage of results Prayle [et al] reported,” wrote Ms. El-Hinnawy. As for enforcement, Ms. El-Hinnawy said that FDA has focused on providing information and assistance “to encourage compliance and to ensure an understanding of the responsibilities.”

“I can’t speak for FDA as to its enforcement decisions,” said Frederick Stearns, JD, partner, Keller and Heckman LLP, in Washington, D.C., in an interview, “but I suspect that policing the clinical trial reporting requirements is a lower-priority issue, given all of the other matters the agency is responsible for.” In addition, he said that the $10,000 per day monetary penalty may seem “unduly harsh for a data submission requirement.”

Dr. Loder pointed out, however, that most clinical interventions in use today are based on trials carried out before the era of mandatory registration. “And here the task of data retrieval by systematic reviewers and national advisory bodies becomes impossible,” the editorialists wrote. “Our patients will have to live with the consequences of these failures for many years to come.”

Potential solutions to the problem of underreporting of data have been proposed. Dr. Prayle suggested that “a greater awareness of the reporting requirement will go a long way,” and Dr. Jefferson commented, “Reform and transparency are needed across the board.”

Dr. Loder proposed a harsher solution: “Penalties for not reporting trial data need to be enforced,” adding that academic institutions and professional organizations need to be involved, and researchers doing meta-analyses need to look beyond published trials.

Sir Iain Chalmers, MBBS, MSc, DSc, editor, James Lind Library, James Lind Initiative, in Oxford, United Kingdom, also took a tough stance. Sir Chalmers wrote by email: “Inform the public about the scandal of biased underreporting of research. Require all studies to which human volunteers have contributed be reported, if necessary by requiring this in law.” This, he said, was important “because patients suffer avoidably as a result of incomplete, biased evidence.”

Looking to the future, the editorialists wrote, “Retrospective disclosure of full individual participant data would be an important first step toward better understanding of the benefits and harms of many kinds of treatment.”

“The optimal systematic review would have complete information about every trial—the full protocol, final study report, raw data set, and any journal publications and regulatory submissions,” they concluded.

Source

Pancreatitis Forces Halt to HCV Drug Trial

By John Gever, Senior Editor, MedPage Today

Published: April 19, 2012

Take Posttest

Three cases of acute pancreatitis, one fatal, have led the FDA to put a clinical hold on a trial of an investigational oral drug for hepatitis C called alisporivir, according to the product's manufacturer.

An official at Novartis broke the news at a press conference held Thursday at the European Association for the Study of the Liver meeting in Barcelona.

Responding to a reporter's question, Nikolai Naoumov, MD, confirmed that the FDA had ordered a halt to a trial involving alisporivir.

"The FDA has notified Novartis to put the program on clinical hold," Naoumov said. "The reason is that in the last few months we had a cluster of three patients who developed acute pancreatitis and one last week who died, unfortunately. So, as a result, this is to assess the risk. All these patients had been treated with alisporivir plus PR [pegylated interferon and ribavirin]. We know pancreatitis is on the label of interferon, and we are working to see if adding alisporivir potentiated a known side effect."

Alisporivir is an orally active inhibitor of cyclophilin, a protein found in most vertebrates that appears to be necessary for hepatitis C virus (HCV) replication. It was initially developed under the name DEB-025 by the Swiss firm Debiopharm, which has licensed rights in most of the world to Novartis.

The HCV community has been hopeful that cyclophilin inhibitors such as alisporivir would not need to be given with interferon drugs, but could instead replace them.

Interferon therapy causes debilitating flu-like symptoms that continue throughout the months-long course of treatment. Results in clinical studies of alisporivir have suggested a more favorable side effect profile and efficacy that has prompted speculation about interferon-free treatment regimens for HCV.

Source

Also See: Novartis: Experimental Hepatitis C Drug Development On Hold

EASL 2012: Investigational Compound Peginterferon Lambda Achieved SVR24 Rates Comparable to Peginterferon Alfa with Fewer Flu-Like and Musculoskeletal Symptoms in Phase IIb Study in Treatment-Naïve Genotype 2 or 3 Hepatitis C Patients

April 19, 2012 12:00 PM Eastern Daylight Time

First report of sustained virologic response (SVR) results for Lambda interferon
Numerically greater virologic response rates consistent at 4 weeks (RVR*), throughout treatment, and maintained through SVR₂₄^†in Lambda 180 µg dose versus alfa

Data presented at The International Liver Congress in Barcelona

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced results from the Phase IIb EMERGE clinical trial in 118 treatment-naïve patients chronically infected with genotype 2 or 3 hepatitis C virus (HCV). In this study, the investigational compound peginterferon lambda-1a (Lambda) plus ribavirin (RBV) achieved sustained virologic response rates 24 weeks post-treatment (SVR₂₄) that were comparable to peginterferon alfa-2a (alfa) plus ribavirin. Rates of SVR₂₄ranged from 60.0% to 75.9% in the Lambda/RBV arms versus 53.3% in the alfa/RBV arm (n=30). The 180 µg dose arm of Lambda/RBV achieved SVR₂₄ in 75.9% (n=29) and was the dose selected for phase III clinical trials.

In this study, adverse events were mostly low grade and self-limited. Overall, rates of serious adverse events and adverse events were similar across treatment arms up to SVR₂₄. There were fewer flu-like and musculoskeletal symptoms in the Lambda/RBV arms. Additionally, lower rates of anemia, neutropenia, and thrombocytopenia were observed and there were fewer interferon and ribavirin dose reductions for anemia in the Lambda/RBV arms. Two (2) cases of hyperbilirubinemia >5x the upper limit of normal (ULN) were observed in the Lambda 240 µg dose arm and zero (0) cases of hyperbilirubinemia >5x the upper limit of normal (ULN) were observed in the Lambda 180 µg, Lambda 120 µg, and alfa arms.

These EMERGE study findings in hepatitis C genotype 2 and 3 patients were presented in an oral session at the International Liver Congress (ILC), the 47^th annual meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain.

“There is a significant unmet medical need for antiviral therapies that can benefit more hepatitis C patients with a goal of decreasing treatment-related adverse events and potentially reducing treatment duration," said Stefan Zeuzem, MD, chief of the department of medicine and professor of medicine at the Goethe University Hospital in Frankfurt, Germany. "The EMERGE study results of peginterferon lambda versus peginterferon alfa in patients infected with HCV genotype 2 or 3 demonstrate that peginterferon lambda, in combination with ribavirin, may have the potential to help address these unmet needs, and these data support further studies of this investigational Lambda interferon.”

Study Results

Viral Response

The primary endpoint of the study was the proportion of patients with complete early virologic response (cEVR^‡). Treatment with all doses of Lambda achieved cEVR rates similar to alfa (Lambda 240 µg: 86.7%, Lambda 180 µg: 96.6%, Lambda 120 µg: 89.7%, and alfa: 86.7%). Higher rates of RVR were achieved in the Lambda arms [Lambda 240 µg: 66.7% (p<0.05), Lambda 180 µg: 75.9% (p<0.05), Lambda 120 µg: 44.8% vs. alfa: 30%]. In patients with HCV genotypes 2 and 3, treatment with all doses of Lambda achieved SVR₂₄ rates similar to PEG-Interferon alfa [Lambda 240 µg: 60.0% (n=30), Lambda 180 µg: 75.9% (n=29), Lambda 120 µg: 65.5% (n=29), and alfa: 53.3%, (n=30)].

Safety

Overall, the rates of serious adverse events and adverse events were similar across treatment arms up to SVR₂₄. In this study, there were some differences seen in the relative frequency of adverse events between lambda and alfa. Some of the adverse events commonly associated with interferon treatment such as flu-like symptoms (Lambda 240 µg: 23.3%; Lambda 180 µg: 20.7%; Lambda 120 µg: 17.2%; alfa: 40.0%), musculoskeletal symptoms (Lambda 240 µg: 16.7%; Lambda 180 µg: 20.7%; Lambda 120 µg: 27.6%; alfa: 63.3%), constitutional symptoms such as fatigue (Lambda 240 µg: 50.0%; Lambda 180 µg: 27.6%; Lambda 120 µg: 41.4%; alfa: 53.3%), neutropenia < 750/mm³ (Lambda 180 µg: 0.0%, n=29; alfa: 27.5%, n=30), anemia with hemoglobin < 10 g/dL or a decline of > 3.4g/dL (Lambda 180 µg: 6.9%, n=29; alfa: 44.8%, n=30), and thrombocytopenia < 100,000/mm³ (Lambda 180 µg: 0.0%, n=29; alfa: 24.1%, n=30) were less frequently seen with Lambda than with alfa. Some others such as psychiatric (Lambda 240 µg: 40.0%; Lambda 180 µg: 41.4%; Lambda 120 µg: 44.8%; alfa: 33.3%) and neurologic (Lambda 240 µg: 36.7%; Lambda 180 µg: 24.1%; Lambda 120 µg: 27.6%; alfa: 33.3%) adverse events were similar across groups.

The proportion of patients that required interferon dose reductions were: Lambda 240 µg: 13.3%; Lambda 180 µg: 6.9%; Lambda 120 µg: 6.9%; alfa: 26.7%, and the proportion of patients that required withheld and/or reduced ribavirin were: Lambda 240 µg: 23.3%; Lambda 180 µg: 6.9%; Lambda 120 µg: 24.1%; alfa: 43.3%. The proportion of patients who required ribavirin dose reductions for low hemoglobin were: Lambda 240 µg: 0.0%; Lambda 180 µg: 0.0%; Lambda 120 µg: 0.0%; alfa: 23.3%.

The proportion of patients with elevated liver enzymes [AST or ALT > 10x the upper limit of normal (ULN)] were: Lambda 240 µg: 3.3%; Lambda 180 µg: 0.0%; Lambda 120 µg: 0.0%; alfa: 0.0%. Total bilirubin was also elevated > 5.0x ULN in the highest-dose Lambda treatment arm compared with PEG-Interferon alfa (Lambda 240 µg: 6.7%; Lambda 180 µg: 0.0%; Lambda 120 µg: 0.0%; alfa: 0.0%); all resolved following interferon dose modification and/or discontinuation.

About the EMERGE Phase IIb Study

The EMERGE study is a two-part, randomized, controlled, multicenter, phase II study of peginterferon lambda-1a in treatment-naïve patients with chronic hepatitis C genotype 1, 2, 3 or 4. Part one of EMERGE was a Phase IIa study, and results were previously presented at The American Association for the Study of Liver Diseases (AASLD) 2010 Liver Meeting.

Part two of EMERGE is an ongoing, blinded Phase IIb study designed to evaluate the safety, efficacy, and pharmacokinetics of Lambda versus alfa, both in combination with ribavirin. In the study, the 526 non-cirrhotic patients were randomized into four dose groups: Lambda 240 µg, Lambda 180 µg, Lambda 120 µg, and alfa 180 µg. Of the 526 patients, 118 patients with genotype 2 or 3 chronic hepatitis C were randomized into four dose groups: Lambda 240 µg (n=30), Lambda 180 µg (n=29), Lambda 120 µg (n=29) and alfa 180 µg (n=30). The results for these 118 patients were presented today at The International Liver Congress 2012.

Phase IIb RVR and cEVR results for genotypes 1, 2, 3, and 4 were previously presented at The International Liver Congress in 2011. The study continued for 24 weeks in genotype 2 and 3 patients and will continue for 48 weeks in genotype 1 and 4 patients. The primary endpoint of the study is the proportion of patients who achieve complete early virologic response (cEVR). HCV RNA and safety were assessed through 48 weeks (24-weeks on-treatment and 24-weeks post-treatment or to SVR₂₄).

About Bristol-Myers Squibb’s Commitment to Liver Disease

Bristol-Myers Squibb is researching a portfolio of compounds that aim to address unmet medical needs across the liver disease continuum, including hepatitis C, hepatitis B and liver cancer. The Company’s hepatitis C pipeline includes a portfolio of compounds with different mechanisms of action, pursuing both biologics as well as small molecule antivirals. These compounds are being studied as part of multiple novel treatment regimens with the goal of increasing SVR rates across diverse patient types and geographies. Peginterferon lambda-1a is the first investigational type III interferon in Phase IIb development for the treatment of hepatitis C. Native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than native human interferon alfa proteins. Lambda receptors are present on fewer cell types within the human body than alfa receptors. This restricted distribution of the interferon lambda receptor offers the potential for more targeted delivery of interferon therapy.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. An estimated 170 million people worldwide are infected with hepatitis C. Up to 90 percent of those infected with hepatitis C will not clear the virus and will become chronically infected. Twenty percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer. Although there is no vaccine to prevent hepatitis C, it is a potentially curable disease.

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 the compounds described in this release will move from exploratory development into full product development, that the clinical trials of these compounds will support regulatory filings, or that the compounds will receive regulatory approvals 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, 2011, 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.

^* Rapid virologic response (RVR): undetectable viral load (HCV RNA <25 IU/mL) at week 4

† Sustained Virologic Response 24 or SVR₂₄: undetectable viral load 24 weeks post-treatment, demonstrative of cure

^‡ Complete Early Virologic Response or cEVR: undetectable viral load at week 12

Contacts

Bristol-Myers Squibb
Media:
Cristi Barnett, 609-252-6028
cristi.barnett@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com

Source

EASL 2012: All-Oral Hepatitis C Virus Treatment with Bristol-Myers Squibb’s Investigational Compounds Daclatasvir and Asunaprevir Achieved Sustained Virologic Response in 77% of Difficult-to-Treat Patients

April 19, 2012 12:00 PM Eastern Daylight Time

Dual oral therapy data demonstrates SVR₂₄ in genotype 1b difficult-to-treat patients, including null responders and patients medically ineligible or intolerant to alfa and ribavirin
Study confirms the sentinel cohort data reported at AASLD in 2011
Data presented at The International Liver Congress in Barcelona

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced results from a Phase II study in which treatment with an all-oral, dual direct-acting antiviral (DAA) regimen of daclatasvir, an investigational NS5A replication complex inhibitor, and asunaprevir, an investigational NS3 protease inhibitor, achieved undetectable viral load 24 weeks post-treatment (SVR₂₄) in 77% (33/43) of difficult-to-treat genotype 1b hepatitis C (HCV) patients. Difficult-to-treat patients in this study included null responders, or patients who had previously not responded to treatment with peginterferon alfa and ribavirin (alfa/RBV), and patients who were medically ineligible or intolerant to previous treatment with alfa/RBV. In this study, serious adverse events (SAE) included three patients with fever (pyrexia), one with hypochondriasis, and one with hyperbilirubinemia which led to treatment discontinuation. The study findings, presented in an oral session at the International Liver Congress (ILC), the 47^th annual meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain, confirmed the previously announced sentinel cohort data.

“Currently there are no treatments available for hepatitis C genotype 1 that can be administered without the concurrent use of alfa and ribavirin, which gives rise to a serious unmet need for patients who are ineligible or intolerant to alfa/ribavirin,” said principal investigator Fumitaka Suzuki, Toranomon Hospital, Tokyo, Japan. “The results of this Phase II study with Bristol-Myers Squibb’s daclatasvir and asunaprevir are encouraging as we study potential hepatitis C therapies for this difficult-to-treat patient population.”

Study Results

The primary endpoint of the study was the proportion of patients with sustained virologic response 12-weeks following treatment (SVR₁₂). In this study, the patents were divided into two treatment groups: Group A consisted of 21 genotype 1b prior null responders and Group B consisted of 22 genotype 1b patients medically ineligible for alfa/RBV or with prior intolerance to alfa/RBV. Overall, 77% (33/43) of patients achieved SVR₁₂ and maintained virologic response through follow-up to SVR₂₄. SVR₂₄ was achieved by 91% (19/21) of patients in Group A and 64% (14/22) of patients in Group B. Of the 43 patients enrolled in the study, 39 completed 24 weeks of treatment. In this study, 94% (33/35) patients who achieved SVR₄ remained undetectable SVR₂₄, and 100% (33/33) of patients who achieved SVR₁₂ remained undetectable at SVR₂₄.

Viral breakthrough was observed in 7.0% (3/43) of patients and post-treatment relapse was observed in 9.3% (4/43) of patients in the study. All occurrences of viral breakthrough and post-treatment relapse took place in the alfa/RBV ineligible/intolerant arm. There were no viral breakthroughs and no post-treatment relapses in prior null responders.

Serious adverse events occurred in five patients. Three patients experienced Grade 2/3 fever (pyrexia), one patient developed Grade 2 hypochondriasis, and one patient developed Grade 4 elevated bilirubin levels (hyperbilirubinemia) that led to study discontinuation at week 2. There were three additional discontinuations due to adverse events: two transaminase elevations at weeks 12 and 16 and one lymphopenia at week 52 (off-study) in a patient with alfa/RBV added at week six. The most commonly reported on-treatment adverse events occurring in at least three patients were headache (14/43), nasopharyngitis (14/43), liver enzyme increases (12/43 ALT increase and 10/43 AST increase), diarrhea (Grade 1, 11/43), and fever (pyrexia, 8/43). There were no deaths in this study and no clinically relevant changes in electrocardiogram parameters.

About the Study

In this Phase II open-label clinical trial (AI447-017), an expanded cohort of 43 Japanese patients with chronic HCV genotype 1b infection with null response to prior alfa/RBV treatment (reduction in HCV RNA <2 log₁₀ IU/mL with 12 weeks of alfa/RBV therapy) or patients ineligible for or intolerant to treatment with alfa/RBV were treated with daclatasvir 60 mg once daily and asunaprevir 200 mg twice daily, for 24 weeks. (Asunaprevir was initially dosed 600 mg twice daily in sentinel cohort of 10 null responders.) The primary efficacy endpoint was the proportion of patients with undetectable viral load (HCV RNA < 15 IU/mL) at 12 weeks post-treatment (SVR₁₂). Patients were followed to 24 weeks post-treatment (SVR₂₄).

About Bristol-Myers Squibb’s Commitment to Liver Disease

Bristol-Myers Squibb is studying a portfolio of compounds that aim to address unmet medical needs across the liver disease continuum, including hepatitis C, hepatitis B and liver cancer. The Company’s hepatitis C pipeline includes a portfolio of compounds with different mechanisms of action, pursuing both biologics as well as small molecule antivirals. These compounds are being studied as part of multiple novel treatment regimens with the goal of increasing SVR rates across diverse patient types and geographies. Discovered by Bristol-Myers Squibb through a genomics approach, daclatasvir, also known as BMS-790052, is the first NS5A replication complex inhibitor to be investigated in hepatitis C clinical trials and is currently in Phase III development. Asunaprevir, also known as BMS-650032, is an NS3 protease inhibitor in Phase III development for hepatitis C.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. An estimated 170 million people worldwide are infected with hepatitis C, with genotype 1 being the most prevalent genotype. Up to 90 percent of those infected with hepatitis C will not clear the virus and will become chronically infected. Twenty percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer. Although there is no vaccine to prevent hepatitis C, it is a potentially curable disease.

About Bristol-Myers Squibb

Bristol-Myers Squibb Forward Looking Statement

Contacts

Bristol-Myers Squibb
Media:
Cristi Barnett, 609-252-6028
cristi.barnett@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com

Source

Vertex at EASL 2012

Vertex will present data on INCIVEK® (telaprevir) tablets, approved for the treatment of hepatitis C, and one of its hepatitis C medicines in development, the non-nucleoside polymerase inhibitor VX-222, at the 47th Annual Meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain, April 18 to 22, 2012.

The titles of the 14 accepted abstracts are included below. The complete abstracts are now available through the EASL website at www.easl.eu.

Oral Presentation: April 20, 2012, 4:00 p.m. – 6:00 p.m. CET

"Futility Rules in Telaprevir Combination Treatment"

Poster Presentations: April 21, 2012, 12:30 p.m. – 1:30 p.m. CET

Poster #1094: "100% SVR in IL28b CC Patients Treated with 12 Weeks of Telaprevir, Peginterferon and Ribavirin in the PROVE2 Trial"
Poster #1203: "All IL28b Genotypes Have High SVR Rates in Patients Treated with VX-222 in Combination with Telaprevir/Peginterferon/Ribavirin in the ZENITH Study"
Poster #1132: "High Concordance Between SVR12 and SVR24 in Patients Receiving Telaprevir Plus Peginterferon and Ribavirin in Three Phase 3 Clinical Trials: ADVANCE, ILLUMINATE and REALIZE"
Poster #1162: "Ribavirin Dose Modification in Treatment-Naïve and Previously Treated Patients Who Received Telaprevir Combination Treatment: No Impact on Sustained Virologic Response in Phase 3 Studies"
Poster #1167: "Pre-Treatment IP-10 Levels and IL28b Genotype in Prediction of SVR in Prior Treatment-Experienced Genotype 1 HCV Patients Treated with Telaprevir/ Peginterferon/ Ribavirin in REALIZE Study"
Poster #1150: "A Comprehensive Review of Patterns of Viral Load Decline in Patients Treated with Telaprevir Plus Peginterferon and Ribavirin"
Poster #1117: "Telaprevir French Cohort Authorisation for Temporary Use in Genotype 1 Hepatitis C Cirrhotic Patients with Prior Partial Response or Relapse"
Poster #1116: "Exposure-Response Relationships in Telaprevir Combination Therapy in Treatment-Naïve Genotype 1 Chronic HCV Patients"
Poster #1174: "Deep Sequencing Screening for Telaprevir-Resistant Viral Variants in Previous Null Responders Fails to Identify Those Patients at Risk of Failing Telaprevir Plus Peginterferon/Ribavirin Therapy”
Poster #1184 "Characterization of HCV Variants in Genotype 1 Treatment-Naïve Patients Administered the Combination of TVR and VX-222 in Dual Arms of ZENITH Study"
Poster #1102: "The Cost-Effectiveness of Telaprevir (TVR) in Combination with Pegylated Interferon-Alfa and Ribavirin (PR) for the Treatment of Genotype 1(G1) Chronic Hepatitis C Patients"
Poster #1169: "Health-Related Quality-of-Life Among Genotype 1 Treatment-Naïve Chronic Hepatitis C Patients Receiving Telaprevir Combination Treatment: Post-Hoc Analyses of Data from the ADVANCE Trial"
Poster #1170: "Predictors of Days Unable to Work Among Genotype 1 Treatment-Naïve Chronic Hepatitis C Patients: Post-Hoc Analyses of Data from Phase 3 ADVANCE and ILLUMINATE Studies"

Media Contacts:
Erin Emlock
Dawn Kalmar
Zachry Barber
617-444-6992

Investor Relations Contacts:
Michael Partridge, 617-444-6108

Source

EASL 2012: Viral cure achieved without interferon in up to 82% of hepatitis C patients (GT-1a & -1b*)

19 April 2012

For media outside of the U.S.A. only

Barcelona, Spain and Ingelheim, Germany [19 April 2012] – New data from the largest Phase II interferon-free trial to date, reveal that up to 82 percent of hepatitis C patients achieved a viral cure after just 28 weeks of treatment. These results were shown in specific patients infected with two prevalent types of hepatitis C (HCV) (genotypes-1a CC and -1b), following treatment with Boehringer Ingelheim’s investigational direct-acting antiviral compounds. ¹

These findings were demonstrated in the largest Phase II interferon-free trial to date, with a total of 362 patients, including those patients with advanced liver disease. The results, due to be presented on Saturday 21st April at The International Liver Congress ^TM, the 47th Annual Meeting of the European Association of the Study of the Liver (EASL) in Barcelona, supplement the abstract findings highlighted in the official EASL press office activities today. All patients in the study received treatment with the interferon-free combination of two investigational compounds, the once daily protease inhibitor BI 201335 and the polymerase inhibitor BI 207127, both with and without ribavirin and with varying treatment durations. ¹

Of all the patients studied, including those with the hardest to cure type of hepatitis C (genotype-1a non-CC), 68 percent achieved a viral cure after 28 weeks of treatment. Most significantly, up to 82 percent of specific patients with one of the most common HCV types found across Europe and Asia (genotypes-1a CC and -1b), achieved viral cure after 28 weeks of treatment. The findings are unprecedented in this patient population and indicate the future potential of eliminating the need for interferon which still has to be administered with all current treatment options.

"Eliminating interferon from HCV treatment is an urgent need. Releasing patients from the side effects and the lengthy treatment commitment seen with interferon would be a huge advance," said Stefan Zeuzem, M.D., Chief of the Department of Medicine and Professor of Medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany and lead investigator of the study. "Such treatments would minimise the impact on patients' lives, and may encourage them to start and stay on treatment, to achieve the ultimate goal of a virologic cure."

The side effects of interferon can be severe and include heart failure, leukopenia (a decrease of white blood cells), sepsis and vision loss. ^{2, 3}

The Boehringer Ingelheim interferon-free treatment combination was generally well tolerated across the five treatment arms of the SOUND-C2 trial. Planning of the Phase III clinical trial programme is underway. This research will further investigate the efficacy and safety of the interferon-free combination therapy BI 201335 and BI 207127 in genotype-1 patients.

*HCV has at least six distinct genotypes, which are different sequences of the virus, identified by a number. Genotype-1 (GT1) patients are currently recognised as the most difficult to cure. ⁴ In addition to genotypes, there are over 50 subtypes within those genotypes, which are identified by a lowercase letter. An individual’s own genetic make-up is another factor that can determine the success of treatment, as represented by uppercase letters (for example CC, non-CC or CT).

Early viral cure is vital in HCV to minimise long term liver damage. ^3,5 Liver damage caused by HCV is the leading cause of chronic liver disease, failure, and ultimately liver transplant. ⁵

"We very much look forward to the final results from this study, that we hope will be a significant step towards an interferon-free future for patients with HCV,"said Professor Klaus Dugi, Corporate Senior Vice President Medicine at Boehringer Ingelheim. "Our commitment to the millions of people around the world who are chronically infected with HCV is to deliver simpler and better tolerated solutions to treatment, including for those with traditionally difficult to cure virus types."

Other Boehringer Ingelheim data being presented at the meeting include:

SOUND-C2 interim analysis: The efficacy and safety of the interferon-free combination of BI 201335 and BI 207127 in genotype-1 HCV patients with cirrhosis (Late breaking poster# 1420, Soriano, V et al, Thurs 19 April, 12:00-1:30 pm CEST)
Characterisation of HCV NS3 variants that emerged during virologic breakthrough and relapse from BI 201335 Phase II SILEN-C2 study in pegylated interferon plus ribavirin treatment-experienced patients (Poster#1185, Kukolj, G et al, Sat 21 April, 12.30 – 1.30pm CEST)
Impact of early response definitions on duration and outcome of treatment with BI 201335 plus pegylated interferon plus ribavirin (Poster# 1209, Sulkowski, M et al, Sat 21 April, 12.30 – 1.30pm CEST)
Preclinical characterisation of the hepatitis C virus NS5B polymerase non-nucleoside inhibitor BI 207127 (Poster# 822, Beaulieu, P.L. et al, Fri 20 April, 12.30 – 2.00pm CEST)

NOTES TO EDITORS

Results of this open-label, randomised, Phase IIb study were presented as an oral presentation of the abstract titled "SVR4 and SVR12 with an interferon-free regimen of BI 201335 and BI 207127, +/- ribavirin, in treatment-naïve patients with chronic genotype-1 HCV infection: Interim results of SOUND-C2", by Professor Stefan Zeuzem. In the Phase IIb study, 362 treatment-naive GT1 HCV patients were randomised into five interferon-free treatment groups, each with 120mg BI 201335 once daily but with different dosing and treatment durations of BI 207127 as follows:

BI 201335 120mg (once-daily) QD + BI 207127 600mg (three times daily) TID + RBV for 16 weeks;
BI 201335 120mg QD + BI 207127 600mg TID + RBV for 28 weeks;
BI 201335 120mg QD + BI 207127 600mg TID + RBV for 40 weeks;
BI 201335 120mg QD + BI 207127 600mg BID (twice daily) + RBV for 28 weeks;
BI 201335 120mg QD + BI 207127 600mg TID without RBV for 28 weeks.

About Hepatitis C Virus (HCV)
Hepatitis C is a viral disease caused by the hepatitis C virus (HCV) that mainly affects the liver. It is a leading cause of chronic liver disease and liver transplant. The number of individuals chronically infected with HCV globally has been estimated at 170 million, with 3–4 million new infections occurring each year. Only about 20–45 percent of patients clear the virus in the acute phase. Of the remaining chronically infected patients, 20 percent will develop cirrhosis within 20 years on average. The mortality rate after cirrhosis has developed is 2-5 percent per year. End-stage liver disease due to HCV infection currently represents the major cause for liver transplantation in the Western world.

About Boehringer Ingelheim in Virology
Boehringer Ingelheim has more than 7,500 scientists working in cross disciplinary teams within our global R&D network in six large therapeutic areas, including virology. In addition to the ongoing research programme for HCV, Boehringer Ingelheim has a long-standing history in virology drug development, including discovery of the first HCV protease inhibitor and compounds for the treatment of HIV (VIRAMUNE® (nevirapine) tablets/oral solution, the first approved HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) and Aptivus®, the first approved second generation HIV protease inhibitor). The company has a well established research centre in Laval, Canada, dedicated to virology research since the early 1990’s, and is committed to developing new therapies for virological diseases with a high unmet medical need.

About Boehringer Ingelheim in Hepatitis C Virus (HCV)
Boehringer Ingelheim has a long-standing commitment to virology, including developing innovative therapies for HIV/AIDS and HCV. Through pioneering science, Boehringer Ingelheim strives to spread the cure in HCV and ease the burden of the disease. Boehringer Ingelheim’s clinical research team is working with HCV experts from all over the world to extend a cure to more patients suffering from the disease, including those who are toughest to cure. Boehringer Ingelheim is investigating BI 201335 and BI 207127 through HCVerso ^TM, our rigorous clinical trial program that is designed to find answers to the challenges that HCV patients face.

BI 201335, an investigational oral HCV NS3/4A next generation protease inhibitor that has the potential to improve cure rates as compared to PegIFN/RBV therapy alone, has completed clinical trials through Phase IIb (SILEN-C studies). A multi-study Phase III trial programme currently is underway to evaluate BI 201335 combined with PegIFN/RBV in treatment-naïve, treatment-experienced and HIV co-infected patients with chronic genotype-1 HCV.

BI 207127, an investigational NS5B RNA-dependent polymerase inhibitor that has the potential to eliminate interferon from HCV treatment when combined with BI 201335 and RBV, is currently being investigated in Phase II trials in interferon-sparing regimens.

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 145 affiliates and more than 42,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. Equal opportunities for all employees and involvement in social projects, such as providing VIRAMUNE® free of charge in developing countries, form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

In 2010, Boehringer Ingelheim posted net sales of about 12.6 billion euro while spending almost 24 percent of net sales in its largest business segment Prescription Medicines on research and development.

Updated information on the corporation’s annual results in 2011 will be available on April 24th, 2012.

For more information please visit www.twitter.com/boehringer

Backgrounder:

References
¹Zeuzem S et al. SVR4 and SVR12 with an interferon-free regimen of BI 201335 and BI 207127 +/- ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection. Abstract#101 presented at the International Liver CongressTM (ILC), 18 -22 April 2012
²National Institutes of Health; US Department of Health and Human Services. Chronic Hepatitis C: Current Disease Management. Bethesda, MD: National Institutes of Health; 2010. NIH Publication 10-4230 4.
³World Health Organisation. Hepatitis C. 2002 http://www.who.int/csr/disease/hepatitis/Hepc.pdf [Last accessed on 16/04/12]
⁴Ghany, M. et al. An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guidelines by the American Association for the Study of Liver Diseases. Hepatology, August 2011.
⁵About.com. 2009. What Is a Sustained Virologic Response or "SVR"? http://hepatitis.about.com/od/treatment/f/SVR.htm [Last accessed on 16/04/12]

A measure of Sustained Viral Response (SVR) is considered viral cure. SVR has recently been defined by the FDA as undetectable hepatitis C virus 12 weeks after treatment has been completed (SVR12).

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EASL 2012: Dramatic data for Gilead, Bristol hepatitis C drugs

Bill Berkrot Reuters

8:57 a.m. CDT, April 19, 2012

(Reuters) - A combination of experimental hepatitis C drugs from Gilead Science Inc and Bristol-Myers Squibb Co showed impressive results in new clinical trial data released on Thursday, helping fuel a 16 percent rise in Gilead shares.

In the mid-stage trial, Gilead's GS-7977, acquired with its $11 billion purchase of Pharmasset, was combined with Bristol's daclatasvir and received very strong response rates from previously untreated patients.

The results were accomplished without using interferon, an injected drug that causes flu-like symptoms and other side effects that often lead hepatitis C patients to discontinue or delay treatment.

"This reinforces that â€˜7977 is the best asset in the Hep C space and restores 'world order' with Gilead ... as the one to beat," Thomas Russo, analyst at Robert W. Baird, said in a research note.

Bristol shares rose 3.3 percent in early trading.

Bristol's daclatasvir is from a new class of drugs known as NS5A inhibitors. GS-7977 is a closely watched hepatitis C drug known as a nucleotide polymerase inhibitor.

All 44 of the patients in the study who had the most common and difficult to treat Genotype 1 version of the disease had undetectable levels of the virus in their blood four weeks after completing treatment, for a 100 percent response rate.

Forty of 44 patients with Genotypes 2 or 3 of the virus had undetectable levels at four weeks following treatment for a 91 percent response rate.

Any patient who still has undetectable levels of the virus 12 weeks after completing treatment, known as a sustained viral response, or SVR12, is considered cured of the serious liver disease.

Separately, Gilead reported results from the ELECTRON study, showing that of 25 patients with genotype 1 hepatitis who completed 12 weeks of treatment with GS-7977 and the older antiviral ribavirin (RBV), 88 percent still had undetectable levels of virus four weeks after completion of treatment.

Mark Schoenebaum, an analyst at ISI Group, said the ELECTRON data was better than expected, since most analysts had expected a result around 50 percent.

"Overall, we'd characterize the phase 2 data as very robust, with SVR rates well above expectations," J.P. Morgan analyst Geoff Meacham said in a research note.

DEVELOPMENT RACE

Hepatitis C is currently one of the hottest areas of medical research, with several companies pursuing treatment regimens that would eliminate the need for interferon. Even the newest hepatitis C drugs approved last year that dramatically improved cure rates must be taken with interferon and ribavirin.

Patients in the various arms of the Bristol-Gilead study were treated for 24 weeks. The interim data looked at the response rates four weeks after they completed the therapy, which is considered to be a fairly accurate predictor of the likely final results.

In one arm of the study, the Gilead drug was given alone for the first week as a lead in therapy. Another arm added the older antiviral drug, ribavirin, which is currently part of all hepatitis C treatment regimens.

Researchers found that using GS-7977 as a lead in drug did not impact response rates and that the addition of ribavirin made no difference other than to add side effects, such as anemia, that were not seen in the non-ribavirin arms of the study, Bristol-Myers said.

One patient in the Genotype 2/3 arm experienced viral breakthrough during treatment and one suffered a relapse. Two patients dropped out for medical reasons believed to be unrelated to the study drugs, according to the data presented on Thursday at a major European liver disease meeting in Barcelona.

The experimental drugs were considered to be well tolerated with the most frequent side effects being fatigue, headache and nausea, Bristol said.

Gilead is commencing a trial of 7977 in combination with its own experimental NS5A inhibitor, while Bristol-Myers is also testing daclatasvir in combination with a drug similar to 7977 that it acquired with its $2.5 billion purchase of Inhibitex, as well as with other experimental drugs in its development pipeline.

(Additional reporting by Michele Gershberg in New York and Ben Hirschler in London; Editing by Andre Grenon, Dave Zimmerman)

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