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)

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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

Bristol-Myers Squibb to Present Data for Daclatasvir in Multiple Investigational All-oral Combinations across Hepatitis C Genotypes at The International Liver CongressTM

Daclatasvir data demonstrates potential to address high unmet needs, including cirrhotic and treatment-experienced patients, and those with genotypes 1, 2, 3 and 4

Breadth of viral hepatitis data underscores Company’s commitment to advancing research of liver diseases

Monday, March 24, 2014 5:39 am EDT

"The wealth of data we are sharing at the International Liver Congress continue the positive momentum for daclatasvir after the Marketing Authorization Application was validated for Accelerated Regulatory Review by the European Medicines Agency, highlighting the important potential role for daclatasvir-based regimens in Europe."

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that 12 abstracts have been accepted for presentation at The International Liver CongressTM, the 49th annual meeting of the European Association for the Study of the Liver (EASL), in London, April 9 – 13.

Key presentations include:

• Two sets of pivotal results from a global, Phase III study (HALLMARK DUAL) investigating the efficacy and safety of an all-oral, interferon- and ribavirin-free regimen of daclatasvir and asunaprevir, including data in cirrhotic and non-cirrhotic patients with HCV genotype 1b infection, will be presented as late-breakers.
• Virologic response results from analyses investigating daclatasvir in combination with sofosbuvir across genotypes 1, 2 and 3.
• Virologic response and safety data for the investigational all-oral 3DAA regimen (daclatasvir/asunaprevir/BMS-791325) in genotype 4 patients, as well as bioequivalence data for the daclatasvir 3DAA regimen, which is being studied as a fixed-dose-combination treatment with twice daily dosing.

“These results are encouraging and show the potential of daclatasvir across multiple treatment regimens, with the goal of helping patients achieve cure regardless of genotype, stage of disease or response to previous therapies,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “The wealth of data we are sharing at the International Liver Congress continue the positive momentum for daclatasvir after the Marketing Authorization Application was validated for Accelerated Regulatory Review by the European Medicines Agency, highlighting the important potential role for daclatasvir-based regimens in Europe.”

Bristol-Myers Squibb is studying a broad portfolio of compounds in hopes of providing flexible treatment options to address the diverse unmet medical needs of a global HCV patient population. These investigational compounds include daclatasvir, an investigational NS5A replication complex inhibitor that has shown high antiviral potency and pan-genotypic activity across HCV genotypes in vitro; asunaprevir, an investigational NS3 protease inhibitor; BMS-791325, an investigational non-nucleoside inhibitor of the NS5B polymerase; and peginterferon lambda-1a (Lambda), an investigational type III interferon that has the potential to offer an alternative to alfa-interferon.

The complete list of Bristol-Myers Squibb data presentations is below. Abstracts can be accessed on the ILC/EASL website at http://www.ilc-congress.eu.

Title Date/Time Hepatitis C: Direct-Acting Antiviral Data

Oral Presentation (late-breaker): All-oral dual therapy with daclatasvir and asunaprevir in patients with HCV genotype 1b infection: Phase 3 study results -- April 12, 15:30 - 17:30

Poster (late-breaker): Efficacy and safety of daclatasvir in combination with asunaprevir (DCV+ASV) in cirrhotic and non-cirrhotic patients with HCV genotype 1b: Results of the HALLMARK DUAL study -- April 10, 09:00 - April 12, 18:00

Oral Presentation: Effect of baseline NS5A polymorphisms on virologic response to the all-oral combination of daclatasvir + sofosbuvir ± ribavirin in patients with chronic HCV infection -- April 11, 16:00 - 18:00

Poster: Effect of ribavirin on the safety profile of daclatasvir + sofosbuvir for patients with chronic HCV infection -- April 12, 09:00 - 18:00

Poster: All-oral therapy with daclatasvir in combination with asunaprevir and BMS-791325 for treatment-naive patients with chronic HCV genotype 4 infection -- April 12, 09:00 - 18:00

Poster: Daclatasvir, asunaprevir, and BMS-791325 in a fixed-dose combination: A phase 1 bioavailability study in healthy volunteers -- April 12, 09:00 - 18:00

Hepatitis B: Peginterferon Lambda-1a Data

Poster: Peginterferon Lambda-1a pharmacokinetics in subjects with impaired renal function -- April 12, 09:00 - 18:00

Oral: Peginterferon Lambda for the treatment of chronic hepatitis B (CHB): A phase 2b comparison with peginterferon alfa in patients with HBeAg-positive disease -- April 12, 15:30 - 17:30

Hepatitis C: Global Health Economics and Outcomes Research (GHEOR)

Oral Presentation: External validation of the risk-prediction model for hepatocellular carcinoma (HCC) from the REVEAL-HCV study using data from the U.S. Veterans Affairs (VA) health system -- April 10, 16:00 - 18:00

Poster: The impact of fibrosis on the risk of long-term morbidity and mortality in chronic hepatitis C patients treated in the veterans administration health care system -- April 11, 09:00 - 18:00

Poster: Early virologic responses and adverse events from the comparative assessment of effectiveness of antiviral therapies in hepatitis C study (CMPASS) -- April 12, 09:00 - 18:00

Poster: Determining the comparative effectiveness of emerging treatment regimens for hepatitis C virus (HCV) infection from single arm phase III trials -- April 12, 09:00 - 18:00 

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. In the European Union (EU) an estimated 9 million people are living with hepatitis C, and an estimated 170 million people worldwide are infected with the virus.

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.

In 2014, the U.S. Food and Drug Administration (FDA) granted Bristol-Myers Squibb’s investigational DCV Dual Regimen (daclatasvir and asunaprevir) 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.

Daclatasvir is also 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.

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.

Contact:

Bristol-Myers Squibb Company
Media:
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jr.smith.paeurope@bms.com
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carrie.fernandez@bms.com
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Source

Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection

Hepatology

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

Viral Hepatitis

Hiromitsu Kumada MD¹, Yoshiyuki Suzuki MD¹, Kenji Ikeda MD¹, Joji Toyota MD², Yoshiyasu Karino MD², Kazuaki Chayama MD³, Yoshiiku Kawakami MD³, Akio Ido MD⁴, Kazuhide Yamamoto MD⁵, Koichi Takaguchi MD⁶, Namiki Izumi MD⁷, Kazuhiko Koike MD⁸, Tetsuo Takehara MD⁹, Norifumi Kawada MD¹⁰, Michio Sata MD¹¹, Hidetaka Miyagoshi¹², Timothy Eley PhD¹³, Fiona McPhee PhD¹³, Andrew Damokosh PhD¹³, Hiroki Ishikawa¹², Eric Hughes MD^13,*

DOI: 10.1002/hep.27113

Copyright © 2014 American Association for the Study of Liver Diseasews

Publication History
Accepted manuscript online: 6 MAR 2014 06:10AM EST
Manuscript Accepted: 28 FEB 2014
Manuscript Revised: 21 FEB 2014
Manuscript Received: 10 FEB 2014

Keywords: Direct-acting antiviral; nonresponder; interferon-ineligible; interferon-intolerant; all-oral

Abstract

All-oral combinations of direct-acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin-based regimens. In this open-label, phase 3 study, 135 interferon-ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary end point was sustained virologic response 24 weeks after treatment (SVR₂₄). This study is registered with ClinicalTrials.gov (NCT01497834). SVR₂₄ was achieved by 87.4% of interferon-ineligible/intolerant patients and 80.5% of nonresponder (null and partial) patients; rates were similar in cirrhotic (90.9%) and non-cirrhotic (84.0%) patients, and in patients with IL28B CC (84.5%) or non-CC (84.8%) genotypes. Fourteen patients in each group (12.6%) discontinued dual therapy, mainly due to adverse events or lack of efficacy. Nine nonresponder patients received additional treatment with peginterferon/ribavirin per protocol-defined criteria. The rate of serious adverse events was low (5.9%) and varied among patients. The most common adverse events were nasopharyngitis, increased ALT and AST, headache, diarrhea, and pyrexia.

Conclusion: Interferon-free, ribavirin-free all oral therapy with daclatasvir and asunaprevir for 24 weeks is well tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon-based therapy. (Hepatology 2014;)

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