JAMA Author Interview: Daclatasvir, Asunaprevir, and Beclabuvir for HCV Genotype 1

Press Release - Provided by Duke University Medical Center

Interferon-free therapy daclatasvir, asunaprevir, and beclabuvir clears hepatitis C in 93 percent of patients in trial

JAMA

Original Investigations | May 5, 2015

Oral Antiviral Treatment of Hepatitis C Genotype 1 Infection

Author Interview @ JAMA - Daclatasvir, Asunaprevir, and Beclabuvir for HCV Infection With Cirrhosis; These cohort studies describe outcomes for HCV genotype-1 infected patients with and without cirrhosis who were treated with an all-oral antiviral regimen.

Full Text Available @ NATAP
Editorial: Continued Progress Against Hepatitis C Infection

Daclatasvir in Combination With Asunaprevir and Beclabuvir for Hepatitis C Virus Genotype 1 Infection With Compensated Cirrhosis 

Fixed-Dose Combination Therapy With Daclatasvir, Asunaprevir, and Beclabuvir for Noncirrhotic Patients With HCV Genotype 1 Infection 

JAMA
Abstract Free - Full content is available to subscribers only

Daclatasvir, Asunaprevir, and Beclabuvir for HCV Genotype 1
DCV/ASV/BCV for HCV Infection With Cirrhosis
Editorial: Continued Progress Against Hepatitis C Infection

Interferon-free therapy daclatasvir, asunaprevir,and beclabuvir clears hepatitis C in 93 percent of patients in trial

Related - JAMA Author Interview: Daclatasvir, Asunaprevir, and Beclabuvir for HCV Genotype 1

Interferon-free therapy clears hepatitis C in 93 percent of patients in trial

A 12-week dose of an investigational three-drug hepatitis C combination cleared the virus in 93 percent of patients with liver cirrhosis who hadn't previously been treated, according to a study in the May 5, 2015, issue of The Journal of the American Medical Association.

Bristol-Myers Squibb funded the trial of the combination of three drugs—daclatasvir, asunaprevir, and beclabuvir. None of the three drugs are FDA-approved, but daclatasvir is currently under review by the FDA. Duke Medicine researchers collaborated on the design and analysis of the trial and authored the findings.

The trial recruited patients with hepatitis C-related cirrhosis, or scarring of the liver, 112 of whom had not previously been treated for hepatitis C, and 90 who had previous unsuccessful therapies. For those with past failed therapies and potential resistance, the drugs were slightly less successful, eliminating the virus in 87 percent.

However, for those with past failed therapies, incorporating a fourth drug, ribavirin, appeared to enhance results. Ribavirin is a commonly used hepatitis C treatment. When added to the investigational regimen, success rates in previously treated patients reached 93 percent—on par with those receiving treatment for the first time.

No vaccine has been developed to protect patients from the hepatitis C virus, which is spread through blood and can lead to liver failure and death if untreated. Most who are infected don't know they have the disease until they have symptoms and have already sustained liver damage, said Andrew Muir, M.D., M.H.S., chief of the division of gastroenterology at Duke and the study's lead author. For this reason, Americans born between 1945 and 1965—baby boomers—should automatically be tested, he urged.

For most of the past 20 years, therapies for hepatitis C relied on interferon drugs, which require regular injections for as long as one year and trigger miserable, flu-like side effects that prompt many patients to quit the regimen. Some patients aren't eligible for this treatment if they have anemia, low platelets or other conditions, Muir said.

"Those with more advanced disease were unlikely to tolerate interferons, and many patients would decide against even getting treatment," Muir said. "For those who could tolerate it, it was only moderately effective."

Since late 2013, several drug companies have released new, interferon-free regimens. In many cases, these have proven to be more effective than previous treatments.

"The development of interferon-free treatments has been a tremendous step forward in the standard of care," Muir said. "These drugs are highly effective and well-tolerated by patients at all stages of liver disease."

The trial was conducted between December 2013 and September 2014 at nearly 50 sites across the United States, Canada, France, and Australia. All patients were infected with genotype 1 hepatitis, a common strain of the C virus in North America, Western Europe and Australia.

The drugs had minimal side effects for most participants. Nine patients experienced serious adverse events three of which were considered related to treatment, the study states.

Among the study's limitations were the absence of a placebo group that could pinpoint the sources of side effects, and a lack of racial diversity, with 88 percent white participants. The study also did not statistically distinguish the impact of the addition of ribavirin to some participants' daily regimen.

In addition to Muir, study authors include Fred Poordad; Jacob Lalezari; Gregory Everson; Gregory J. Dore; Robert Herring; Aasim Sheikh; Paul Kwo; Christophe Hézode; Paul J. Pockros; Albert Tran; Joseph Yozviak; Nancy Reau; Alnoor Ramji; Katherine Stuart; Alexander J. Thompson; John Vierling; Bradley Freilich; James Cooper; Wayne Ghesquiere; Rong Yang; Fiona McPhee; Eric A. Hughes; E. Scott Swenson; and Philip D. Yin.

Bristol-Myers Squibb sponsored the study. Muir received grant funding from Bristol-Myers Squibb during the conduct of the trial, as well as grant funding and personal fees from AbbVie, Achillion, Bristol-Myers Squibb, Gilead, and Merck, personal fees from Theravance, and grant funding from Roche outside of the work submitted for this JAMA article.

Provided by Duke University Medical Center

HCV genotype 4 patients achieved SVR12 with triple therapy

HCV genotype 4 patients achieved SVR12 with triple therapy
May 23, 2014
Source - Healio

CHICAGO — Hepatitis C virus genotype 4-infected patients met sustained virologic response at 12 weeks with an all-oral triple therapy of daclatasvir, asunaprevir and the non-nucleoside NS5B inhibitor BMS-791325, according to research presented at Digestive Disease Week 2014.

Researcher Tarek Hassanein, MD, of the Southern California Liver Centers, and colleagues randomly assigned 21 treatment-naive hepatitis C virus genotype 4-infected patients to either 30 mg daclatasvir, 200 mg asunaprevir, and 75 mg BMS-791325 (Bristol-Myers Squibb; n=11) twice daily or 150 mg BMS-791325 (n=10) twice daily for 12 weeks. Patients were primarily men (62%), white (91%) and noncirrhotic.

According to data, 10 of the 75-mg BMS-791325 patients achieved sustained virologic response at 12 weeks (SVR12), with the other missing patient meeting SVR24. Nine patients in the 150-mg BMS-791325 group achieved SVR12, with one patient still being followed.

There were no reports of patients experiencing virologic failure or post-treatment relapses; no serious adverse events (AE) were reported. The most common AE were headache (29%), nausea (14%) and pain (14%).

“One hundred percent of the patients with genotype-4 achieved an SVR at or after post-treatment week 12,” Hassanein said during his presentation. “There were no differences between the doses of [BMS-791325], and they were both effective.”

For more information:
Hassanein T. #763. Presented at: Digestive Disease Week 2014; May 3-6; Chicago.
Disclosure: The researchers report numerous relevant financial disclosures.

View Slides and DDW Coverage @ NATAP
DDW: All-Oral Therapy With Daclatasvir in Combination With Asunaprevir and BMS-791325 for Treatment-Naive Patients With Chronic HCV Genotype 4 Infection - (05/06/14) 

Hepatitis C Genotype 4 - Triple Antiviral Therapy Achieves Near 100% Response

Digestive Disease Week 2014 

Triple Antiviral Therapy Achieves Near 100% Response in Patients with HCV Genotype 4

By Marcia Frellick | May 06, 2014

An all-oral, ribavirin-free, interferon-free combination of three direct-acting antiviral agents that had achieved sustained virologic response (SVR) in 92% of patients with chronic HCV genotype 1 infection has demonstrated even greater response in patients with genotype 4 infection.

Twelve weeks of treatment with a combination of daclatasvir (an NS5A inhibitor), asunaprevir (an NS3 inhibitor), and BMS-791325 (a non-nucleoside NS5B polymerase inhibitor) achieved SVR12 in all patients with observed post-treatment data, with no virologic failures.

“Within the first two weeks, 100% of patients dropped their viral load to undetectable levels with the approved assay. That effect continued through the entire study and the SVR rate was 100% on week 12 or post week12,” said Tarek Hassanein, MD, of the Southern California GI and Liver Centers in Coronado, CA, who presented study results at Digestive Disease Week 2014 in Chicago, IL.

These results broaden the powerful antiviral activity of this regimen to genotype 4 (GT4) patients, while maintaining the safety and tolerability documented previously in GT1 patients.

Previous standard treatment for GT4 patients had been pegylated interferon and ribavirin for 24-28 weeks which achieved SVR rates of 60-70%. But rates were even lower in real experience where adherence to interferon regimens is low, Hassanein said.

Treatment-naïve, hepatitis C virus (HCV) GT4-infected patients were randomly assigned (1:1) to receive a twice-daily regimen of daclatasvir (DCV) 30 mg, asunaprevir (ASV) 200 mg, and BMS-791325 75 mg or 150 mg for 12 weeks.

Patients were 62% male, 91% white, and non-cirrhotic. All patients completed 12 weeks of therapy. HCV RNA was undetectable in 21/21 (100%) patients at the end of treatment. SVR at post-treatment week 12 (SVR12) was achieved by 10/11 patients in the BMS-791325 75 mg group and 9/10 patients in the 150 mg group.

Adverse reactions were mild and centered on headache, insomnia, pain, and nausea. None led to discontinuation of participation, Hassanein said.

Genotype 4 HCV patients are heavily concentrated in Middle Eastern and African countries, but there are populations all over the world, including in some immigrant populations in the US.

A phase 3 trial with a twice-daily fixed-dose combination of the 3 direct-acting antivirals is ongoing. Hassanein said because the results were achieved so quickly after start of treatment and with such high success, the next steps may be to see whether they can get those results at a shorter duration of therapy or by eliminating one of the drugs in the combination. Further studies should also look at whether the combination can be used to help patients with cirrhosis, he said.
Source 

View Slides and DDW Coverage @ NATAP
DDW: All-Oral Therapy With Daclatasvir in Combination With Asunaprevir and BMS-791325 for Treatment-Naive Patients With Chronic HCV Genotype 4 Infection - (05/06/14) 

Related

Combination Treatment with Sofosbuvir plus Ledipasvir Highly Effective After Only Eight Weeks

By Marcia Frellick

Treatment with an 8-week regimen of combination sofosbuvir plus ledipasvir with or without ribavirin produced sustained virologic response rates (SVR) similar to those achieved with a 12-week regimen in non-cirrhotic, previously untreated, genotype 1 hepatitis C patients, according to results from the ION-3 trial.

Approval of Newer, More Effective Hepatitis C Drugs Means a Cure Is Within Reach for Most Patients

By Marcia Frellick

Within the next two years, treatments for hepatitis C with 95% cure rates that are all-oral, interferon-free, and effective within 12 weeks or less with negligible side effects will be readily available.

New Regimen Effective for HCV Genotype 1a, 1b

A new regimen shows promise for hepatitis C virus (HCV) genotype 1 infection, and sofosbuvir and ribavirin are active in HCV genotypes 2 and 3 infection, according to two studies published online May 4 in the New England Journal of Medicine. This research was published to coincide with the annual Digestive Disease Week, held from May 3 to 6 in Chicago.

DDW Tuesday News

Liver biopsy is becoming an endangered procedure.

EASL - Bristol-Myers to Present Data for Daclatasvir in Multiple Investigational All-oral Combinations

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

Dateline:

"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.

Daclatasvir/asunaprevir/BMS-791325: All-Oral HCV Regimen Works in 9 Out of 10

Related
Bristol-Myers' Hepatitis C combo Daclatasvir and Asunaprevir gets breakthrough designation
All-Oral HCV Regimen Works in 9 Out of 10

Published: Mar 4, 2014
By Ed Susman , Contributing Writer, MedPage Today

BOSTON -- An all-oral, 12-week regimen appears to successfully treat hepatitis C virus (HCV) infection in about 90% of patients, researchers reported here.

Of the 166 treatment-naive patients in the study, 92% achieved a sustained virologic response at 12 weeks (SVR-12) on the combination of the investigative NS5A inhibitor daclatasvir, the protease inhibitor asunaprevir and the non-nucleoside BMS-791325, said Trevor Hawkins, MD, chief medical officer at Southwest CARE Center and professor of medicine at the University of New Mexico in Santa Fe.

"The observed analysis showed a 92% SVR12, and in the modified intent-to-treat analysis -- wherein data at week 12 is counted as failure if it is missing -- [it] was 89%," Hawkins told MedPage Today at the annual Conference on Retroviruses and Opportunistic Infections.

A cure in the context of HCV is a sustained virologic response (SVR) -- defined as undetectable viral RNA at some prespecified point after ending therapy, usually 12 or 24 weeks.

At the end of treatment in Hawkins' study, 97.5% of those in the low-dose BMS-971325 group showed a complete viral response compared with 94.2% of those taking the high dose; the SVR4 was 92.4% in the low-dose group and 91.7% in the high-dose-treated patients. The SVR12 was achieved by 92.2% in the low-dose treatment group and by 91.7% of those taking high-dose BMS-791325, the researchers reported.

In the trial, Hawkins said that 9% of the patients were diagnosed with cirrhosis. He said that there did not appear to be a difference in outcome among the cirrhotic patients compared with those who were not cirrhotic -- 13 of the 15 cirrhotic patients achieved an SVR12.

Hawkins said that the next trials -- called UNITY 1 and UNITY 2 -- will separate cirrhotic and noncirrhotic patients to examine if there are differences in outcomes depending on the extent of liver disease. These trials will use the 75-mg dose of BMS-791325.

The trial he reported here showed that patients were able to tolerate the regimen. "There were two discontinuations due to adverse events in the entire 166-patient cohort," he said at a press conference.

The patients diagnosed with HCV genotype 1 were randomly assigned to receive a twice-daily regimen of daclatasvir 30 mg, asunaprevir 200 mg and BMS-791325 at 75 mg or 150 mg for 12 weeks. Hawkins said outcomes were similar for the 80 patients on BMS-791325 given 75 mg twice daily and the 86 patients given BMS-791325 at a dose of 150 mg twice daily.

"There were 11 virologic failures and we attempted to find out if there were any predictors of failure," he said. "The only thing that appeared to predict failure was being of genotype 1a. We tried to determine if there were any polymorphisms at baseline that would predict virologic failure, but we were unable to do that. There really was no obvious correlation."

In pilot studies, the 24-week SVR was 94% and the 12-week SVR was 94% with use of the 75-mg dose of BMS-791325; with the 150-mg dose, the 24-week SVR was 94% and the 12- week SVR was 89%.

The patients were about 54 years old, 67% were men, 83% were white, 82% were genotype 1a, and 15 patients in the study -- 9% -- were diagnosed with cirrhosis.

"This looks good," press conference moderator Jean-Michel Pawlotsky, MD, of the Hôpital Henri Mondor Creteil/University of Paris-Est, told MedPage Today. "There are several potential combinations that are going to work in patients with HCV. This combination with three drugs has good potency and a high barrier to resistance. This is promising."

The study was sponsored by Bristol-Myers Squibb.

Hawkins disclosed commercial interests with Gilead, Janssen, AbbVie, Bristol-Myers Squibb, BMS, Vertex, GlaxoSmithKline, Sangamo, Salix, Merck and ViiV. Co-authors include Bristol-Myers Squibb employees.

Pawlotsky had no disclosures.

Watch - Dr. Gregory T. Everson discuss Interferon-and Ribavirin-Free HCV Regimen of Daclatasvir, Asunaprevir, and BMS-791325

Weekend Reading

Hello everyone, welcome to Weekend Reading, a chance for you to catch up, or review those HCV research articles, videos, or learning activities you might have missed over the last few weeks.

Today you're in for treat, sit back and listen to Dr. Gregory T. Everson, one of the country's leading hepatologist discuss his manuscript; "Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection."

The Phase II study is exciting folks, up to 94% treatment-naive genotype 1 participants achieved SVR12 using the triple-antiviral combination without interferon or ribavirin, currently Phase III clinical trials are underway which included treatment-experienced, naive and patients with cirrhosis.

In Case You Missed It - Published on Jan 15, 2014

 

Dr. Gregory T. Everson discusses his manuscript "Efficacy of an Interferon- and Ribavirin-Free Regimen of Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With HCV Genotype 1 Infection." 

To view abstract http://bit.ly/1astcIL.

 

Related: January 9 2014

Triple-antiviral therapy achieves 94% response without interferon, ribavirin

By: MICHELE G. SULLIVAN

Internal Medicine News Digital Network

Both a 12-week and a 24-week regimen of three oral antiviral drugs achieved sustained viral remissions at 12 weeks in up to 94% of treatment-naive patients with genotype 1 hepatitis C virus infections.

The three oral antivirals included daclatasvir, an NS5A replication complex inhibitor; asunaprevir, an NS3 protease inhibitor; and BMS-791325, an investigational selective non-nucleoside polymerase inhibitor. A key point of the study is its proof that short-duration treatment – even without interferon or ribavirin – can result in sustained remission, Dr. Gregory T. Everson and his colleagues wrote in the February issue of Gastroenterology (doi.org/10.1053/j.gastro.2013.10.057).

"Shorter treatment durations are preferable because they may improve patient compliance. In this study, treatment periods of both 12 and 24 weeks yielded high SVR (sustained viral remission) rates, suggesting no advantage for extending treatment duration to 24 weeks."

Further, the triple-antiviral combination apparently controlled viral replication without using interferon or ribavirin, thus avoiding their side effects. The current regimen for treatment-naive patients with genotype 1 hepatitis C virus infections calls for a 48-week treatment with peginterferon and ribavirin with telaprevir or boceprevir.

"Ribavirin contributes to anemia and it is teratogenic; thus, effective treatments without ribavirin are desirable," wrote Dr. Everson of the University of Colorado, Denver, and his coauthors. "This interferon- and ribavirin-free regimen did not alter hemoglobin levels in a clinically meaningfully manner, as evidenced by no grade 1 or higher hemoglobin reductions and no adverse events of anemia."

Dr. Everson and his colleagues gave the regimen for periods of 12 and 24 weeks and with two different doses of BMS-791325, resulting in a four-way randomized study. Groups 1 and 2 were treated for 12 weeks with the combination of daclatasvir 60 mg once daily, asunaprevir 200 mg twice daily, and BMS-791325 (twice daily 75 mg or 150 mg). Groups 3 and 4 had exactly the same two-treatment regimen, but took the drugs for 24 weeks. After treatment, there was a 48-week follow-up period.

Among the 66 patients in the study, the average age was about 50 years old, and the mean HCV-RNA level was 6 log10 IU/mL. Most (75%) had HCV genotype 1a; the rest had 1b. All were treatment naive. Four patients withdrew before the study’s end; none of the withdrawals were for adverse events.

In groups 1 and 2 (75 mg BMS-791325, twice daily for 12 and 24 weeks), the viral load decreased rapidly. By week 4, all of these patients achieved a HCV-RNA level of less than 25 IU/mL; 97% maintained that level through the end of treatment. In a modified intent-to-treat analysis, 94% achieved a sustained viral response by week 12.

In groups 3 and 4 (150 mg BMS-791325, twice daily for 12 or 24 weeks), HCV-RNA levels also fell rapidly in the first month, By week 4, all of those in the 12-week group and all but one in the 24-week group had levels of less than 25 IU/mL, which were sustained through the end of treatment. In the intent-to-treat analysis, 91% overall had an HCV-RNA load of less than 25 IU/mL by the end of treatment.

Overall, there were three treatment failures: one each in groups 3 and 4 had viral breakthrough, and one in group 4 experienced a relapse at week 4.

Both breakthrough patients were given peginterferon-alfa/ribavirin in addition to the direct-acting antivirals. After 16 weeks, one discontinued treatment because of interferon-related cerebral vasoconstriction. That patient had an undetectable HCV-RNA level at the end of treatment, but relapsed by post treatment week 4. The other patient had a sustained viral response.

The study was sponsored by Bristol-Myers Squibb. Dr. Everson listed financial and research relationships with numerous pharmaceutical companies, including Bristol-Myers. His coauthors also declared relationships with numerous drug manufacturers, including Bristol-Myers.

Related:
HCV Genotypes and Treatment
News and research is offered on this page with a focus on treatment options for HCV genotypes 1-6, including FDA approved drugs, and investigational agents currently in clinical trials. Information is extracted from news articles, peer-reviewed journals, as well as liver meetings/conferences, research manuscripts and interactive learning activities.

Hepatitis C Triple-therapy; daclatasvir/asunaprevir/BMS-791325 achieves 94% response without interferon, ribavirin

Infectious Diseases

Triple-antiviral therapy achieves 94% response without interferon, ribavirin

By: MICHELE G. SULLIVAN, Internal Medicine News Digital Network

Both a 12-week and a 24-week regimen of three oral antiviral drugs achieved sustained viral remissions at 12 weeks in up to 94% of treatment-naive patients with genotype 1 hepatitis C virus infections.

The three oral antivirals included daclatasvir, an NS5A replication complex inhibitor; asunaprevir, an NS3 protease inhibitor; and BMS-791325, an investigational selective non-nucleoside polymerase inhibitor. A key point of the study is its proof that short-duration treatment – even without interferon or ribavirin – can result in sustained remission, Dr. Gregory T. Everson and his colleagues wrote in the February issue of Gastroenterology (doi.org/10.1053/j.gastro.2013.10.057).

"Shorter treatment durations are preferable because they may improve patient compliance. In this study, treatment periods of both 12 and 24 weeks yielded high SVR (sustained viral remission) rates, suggesting no advantage for extending treatment duration to 24 weeks."

Further, the triple-antiviral combination apparently controlled viral replication without using interferon or ribavirin, thus avoiding their side effects. The current regimen for treatment-naive patients with genotype 1 hepatitis C virus infections calls for a 48-week treatment with peginterferon and ribavirin with telaprevir or boceprevir.

"Ribavirin contributes to anemia and it is teratogenic; thus, effective treatments without ribavirin are desirable," wrote Dr. Everson of the University of Colorado, Denver, and his coauthors. "This interferon- and ribavirin-free regimen did not alter hemoglobin levels in a clinically meaningfully manner, as evidenced by no grade 1 or higher hemoglobin reductions and no adverse events of anemia."

Dr. Everson and his colleagues gave the regimen for periods of 12 and 24 weeks and with two different doses of BMS-791325, resulting in a four-way randomized study. Groups 1 and 2 were treated for 12 weeks with the combination of daclatasvir 60 mg once daily, asunaprevir 200 mg twice daily, and BMS-791325 (twice daily 75 mg or 150 mg). Groups 3 and 4 had exactly the same two-treatment regimen, but took the drugs for 24 weeks. After treatment, there was a 48-week follow-up period.

Among the 66 patients in the study, the average age was about 50 years old, and the mean HCV-RNA level was 6 log10 IU/mL. Most (75%) had HCV genotype 1a; the rest had 1b. All were treatment naive. Four patients withdrew before the study’s end; none of the withdrawals were for adverse events.

In groups 1 and 2 (75 mg BMS-791325, twice daily for 12 and 24 weeks), the viral load decreased rapidly. By week 4, all of these patients achieved a HCV-RNA level of less than 25 IU/mL; 97% maintained that level through the end of treatment. In a modified intent-to-treat analysis, 94% achieved a sustained viral response by week 12.

In groups 3 and 4 (150 mg BMS-791325, twice daily for 12 or 24 weeks), HCV-RNA levels also fell rapidly in the first month, By week 4, all of those in the 12-week group and all but one in the 24-week group had levels of less than 25 IU/mL, which were sustained through the end of treatment. In the intent-to-treat analysis, 91% overall had an HCV-RNA load of less than 25 IU/mL by the end of treatment.

Overall, there were three treatment failures: one each in groups 3 and 4 had viral breakthrough, and one in group 4 experienced a relapse at week 4.

Both breakthrough patients were given peginterferon-alfa/ribavirin in addition to the direct-acting antivirals. After 16 weeks, one discontinued treatment because of interferon-related cerebral vasoconstriction. That patient had an undetectable HCV-RNA level at the end of treatment, but relapsed by post treatment week 4. The other patient had a sustained viral response.

The study was sponsored by Bristol-Myers Squibb. Dr. Everson listed financial and research relationships with numerous pharmaceutical companies, including Bristol-Myers. His coauthors also declared relationships with numerous drug manufacturers, including Bristol-Myers.

msullivan@frontlinemedcom.com 

EASL 2013 - Internet Symposium: Watch Advances in Chronic Hepatitis C Management and Treatment

ViralEd Presents

 

The 48th Annual EASL: Advances in Chronic Hepatitis C Management and Treatment

 

 

Today, ViralEd released a 2-hour Internet symposium reviewing key studies on chronic hepatitis C management and treatment presented at this years meeting.

Watch and listen to Mark Sulkowski, MD, K. Rajender Reddy, MD, Fred Poordad, MD and Nezam Afdhal, MD review and discuss the following topics:

 

Updates On Current Status Of HCV Therapy

 

Boceprevir And Telaprevir

 

Novel Therapies And Strategies With Interferon

 

What's In The Near Future?

More Triple Therapy

 

Introduction To Faldaprevir

 

Interferon Free, All Oral Regimens 

 

 

NO registration required!

Takes only a few moments to load 

 

ViralEd, LLC is a physician-owned and directed medical education company whose mission is to provide thought-provoking, effective, and evidence-based CME to help improve health care provider knowledge and professional development. For over a decade, ViralEd's team of dedicated professionals have specialized in using a blended learning approach that combines innovative technology with live programming to provide programs and medical education content that is unique and of high quality.

 

EASL 2013 Highlights - CCO's independent conference coverage

 

Program Overview

 

2013 Annual Meeting of the European Association for the Study of the Liver*

 

April 24-28, 2013 | Amsterdam, The Netherlands

   

CCO's independent conference coverage of the 2013 Annual Meeting of the European Association for the Study of the Liver includes 2 CME-certified slidesets with faculty analysis and downloadable slidesets that focuses on key issues highlighted at the conference.

 

**Free registration required

 

Latest Content
Daclatasvir Plus Asunaprevir Plus BMS-791325 Achieves ≥ 88% SVR Rates in Noncirrhotic Treatment-Naive Patients With Genotype 1 HCV

The all-oral regimen combining an NS5a inhibitor, a protease inhibitor, and a nonnucleoside polymerase inhibitor was well tolerated at both doses of BMS-791325 studied.

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 5/3/2013

HBV DNA Seroclearance Significantly Reduces Risk of HCC in Patients With High Baseline Viral Loads
Seroclearance of HBeAg, HBsAg did not significantly decrease HCC risk in adjusted analysis.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 5/2/2013

CONCISE: Interim Results Show High SVR Rates With Either 12 or 24 Weeks of Telaprevir Plus Peginterferon/Ribavirin in Patients With HCV Genotype 1 and IL28B CC Genotype
Among patients who completed 12 weeks of triple therapy, 100% SVR12 rate among patients who continued to receive peginterferon/ribavirin through 24 weeks vs 89% SVR4 rate among patients who stopped all therapy at 12 weeks.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 5/2/2013

QUEST-1: Simeprevir Plus PegIFN/RBV Significantly Improves SVR12 Rate vs PegIFN/RBV Alone in Treatment-Naive Patients With Genotype 1 HCV
Triple therapy was well tolerated and 85% of patients were able to shorten treatment to 24 weeks, of whom 91% achieved SVR12.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 5/1/2013

COMMAND: Daclatasvir Plus PegIFN/RBV Improves SVR24 Rate vs PegIFN/RBV Alone in Treatment-Naive Patients With Genotype 2/3 HCV
The triple-drug regimen allowed 83% of patients to receive shorter treatment durations of only 12 or 16 weeks, and safety and tolerability was comparable to pegIFN/RBV alone.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/30/2013

QUEST-2: Simeprevir Plus PegIFN/RBV Superior to PegIFN/RBV for SVR12 in Treatment-Naive Patients With Genotype 1 HCV
Triple therapy was well tolerated and enabled most patients (91%) to shorten the duration of therapy to 24 weeks while maintaining a high SVR12 rate of 86% in this subgroup.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/30/2013

POSITRON: Sofosbuvir/Ribavirin Superior to Placebo With 78% SVR12 Rate in Genotype 2/3 HCV–Infected Patients Intolerant of, Ineligible for, or Unwilling to Receive IFN
Sofosbuvir plus ribavirin is a safe, effective, IFN-free alternative for patients chronically infected with genotype 2/3 HCV who have no other treatment options available.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/30/2013

Observed HCC Incidence Lower Than Predicted in Patients With Chronic Hepatitis B Receiving Tenofovir in Phase III Clinical Trials
The effect of tenofovir was more noticeable in noncirrhotic patients, emerging at 2 years of treatment and reaching statistical significance by 6 years of treatment.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/30/2013

Prolonged Tenofovir-Based Antiviral Therapy Maintains HBV DNA Suppression in Patients With Chronic HBV, Normal ALT Levels, and High HBV DNA Levels
HBV DNA suppression was increased with tenofovir plus emtricitabine vs tenofovir alone, but safety profiles of both regimens were favorable through 192 weeks of study.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/30/2013

Ledipasvir, GS-9451, and Peginterferon/Ribavirin Achieves 70% SVR12 With Good Tolerability in Treatment-Experienced Patients With Genotype 1 HCV Infection
In this single-arm study, 71% of patients were eligible to received truncated 24-week therapy; safety profile was consistent with that of peginterferon/ribavirin alone.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/28/2013

FISSION: Sofosbuvir/Ribavirin Noninferior to Peginterferon/Ribavirin for SVR12 in Treatment-Naive Patients With HCV Genotype 2/3

Efficacy was similar between the 2 treatment arms, but sofosbuvir/ribavirin demonstrated superior safety and tolerability with shorter therapy compared with peginterferon/ribavirin.

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013

 

NEUTRINO: Sofosbuvir Plus Peginterferon/Ribavirin Achieves High SVR12 Rate, Well Tolerated in Treatment-Naive Patients With Genotype 1, 4, 5, or 6 HCV

The triple-therapy regimen yielded 90% SVR12 in the overall population, and all patient subgroups attained at least 80% SVR12 rate, including patients with cirrhosis and those with IL28B non-CC genotype.

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013

FUSION: Sofosbuvir/Ribavirin Superior to Historical Controls for SVR12 in Treatment-Experienced Patients With Genotype 2/3 HCV

Significantly better rates of SVR12 with both 12 and 16 weeks of therapy compared with historical controls, with better outcomes with 16 weeks of therapy among patients with genotype 3 HCV

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013

 

STARTVerso1: Faldaprevir Plus Peginterferon/Ribavirin Highly Effective, Well Tolerated in Treatment-Naive Patients Infected With Genotype 1 HCV

Most patients receiving faldaprevir (88%) were able to shorten therapy to 24 weeks total, without compromising sustained virologic response, which was 88% in this subgroup.

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013 

Daclatasvir Plus Sofosbuvir ± Ribavirin Achieves 95% to 100% SVR12 Rate in Patients With Previous Virologic Failure on Telaprevir or Boceprevir            

Virologic response rates to all-oral, once-daily 24-week regimen unaffected by baseline NS3 variants conferring protease inhibitor resistance

Source: 2013 Annual Meeting of the European Association for the Study of the Liver

Date Posted: 4/28/2013

QUANTUM: Interferon-Free Sofosbuvir/Ribavirin Regimen Achieves 52% to 72% SVR12 Rate in Treatment-Naive Patients With Chronic HCV Infection
QUANTUM also identified marked elevations in ALT and/or AST associated with the guanidine nucleotide analog GS-0938, which resulted in GS-0938—containing arms being halted.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/28/2013

 

Ledipasvir, GS-9451, and Peginterferon/Ribavirin Achieves 70% SVR12 With Good Tolerability in Treatment-Experienced Patients With Genotype 1 HCV Infection
In this single-arm study, 71% of patients were eligible to received truncated 24-week therapy; safety profile was consistent with that of peginterferon/ribavirin alone.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/28/2013

AVIATOR: ABT-450/Ritonavir, ABT-267 and/or ABT-333, and RBV Achieves SVR24 Rates ≥ 90% in Treatment-Naive Patients and Previous Null Responders With Genotype 1 HCV
The 4-drug peginterferon-free regimens also yielded SVR rates ≥ 89% in treatment-naive patients and previous null responders regardless of sex, HCV subtype, baseline HCV RNA, IL28B genotype, and fibrosis severity.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/26/2013

High Rate of Advanced Fibrosis in Patients With HBV/HIV Coinfection, Despite HBV Suppression With Antiretroviral Therapy
Patients with HBV/HIV coinfection treated with HBV-suppressing antiretrovirals continue to demonstrate high rates of advanced fibrosis.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver
Date Posted: 4/26/2013

ELECTRON: Addition of Second DAA to Sofosbuvir and Ribavirin Yields Rapid, Sustained Antiviral Suppression in Both Treatment-Naive Patients and Previous Null Responders With Genotype 1 HCV
Combining ledipasvir with sofosbuvir/ribavirin yielded SVR12 rates of 100% in both treatment-naive patients and previous null responders, lending further support to ongoing development of the sofosbuvir/ledipasvir fixed-dose combination tablet.
Source: 2013 Annual Meeting of the European Association for the Study of the Liver

 

EASL: Direct-acting antivirals now ready for prime time with promising alternatives on the way

Direct-acting antivirals now ready for prime time with promising alternatives on the way

Studies show encouraging data in a wide range of HCV patient populations

Amsterdam, The Netherlands, Wednesday 24 April 2013: New data from a number of clinical trials presented for the first time at the International Liver Congress™ 2013 demonstrate encouraging results in the use of new direct-acting antiviral agents (DAAs) for the treatment of hepatitis C.

The following covers key results from the much anticipated Phase III trials conducted among HCV patients with a range of genotypes (GT 1 to 6) on DAA treatment.

POSITRON

A study of interferon (IFN)-ineligible, IFN-intolerant, or IFN-unwilling cirrhotic and non-cirrhotic GT 2 and 3 HCV-infected patients treated with a combination of sofosbuvir and ribavirin for 12 weeks achieved a high SVR12 rate without evidence of resistance.1 In the POSITRON Phase III trial, the SVR12 rate of 78% for sofosbuvir and ribavirin (161/207) was superior to placebo (0%, p< 0.001) and all 278 patients became HCV RNA negative on treatment. In terms of adverse events only 2% of patients discontinued treatment in the sofosbuvir + ribavirin group due to adverse events vs. 4% in the placebo group.

NEUTRINO

Treatment with a combination of sofosbuvir, peginterferon alfa-2a and ribavirin for 12 weeks achieved 90% SVR12 in treatment naïve genotype 1, 4, 5, or 6 HCV-infected patients with no viral resistance detected in failures, according to the results of the Phase III NEUTRINO study.2 The regimen was well tolerated and is a short, simple and effective treatment option for patients with these genotypes. A total of 327 patients (292 genotype 1, 28 genotype 4, 7 genotype 5/6) were enrolled and received the study drug.

EASL Secretary General Prof. Mark Thursz commented on the studies: “Unlike the US, in Europe and Asia genotype 3 is quite common. As such for European audiences the interferon-free results in genotype 3 are not as impressive as expected; however the side effect profile and lack of viral resistance means that longer treatment durations will be evaluated in the near future. In the meantime, we feel it’s not time to bury pegylated interferon just yet.”

“Many patients can tolerate 12 weeks of an interferon based regime particularly when it produces SVR rates of more than 90%; so clearly the results of the NEUTRINO study will be welcomed by clinicians and patients” added Prof. Thursz.

STARTVerso™1

Faldaprevir, an oral once-daily protease inhibitor, in combination with peginterferon alfa-2a and ribavirin (PegIFN/RBV) significantly increased SVR12 rates in treatment-naïve HCV GT-1 patients in Europe and Japan compared with PegIFN/RBV alone and was well tolerated.3 In total 652 patients were treated and 88% of patients treated with faldaprevir were eligible to stop all treatment at week 24.

QUEST-1 and -2

QUEST-1: Simeprevir, an oral once-daily protease inhibitor, in combination with peginterferon alfa-2a and ribavirin (PegIFN/RBV) achieved SVR12 rates of 80% compared to placebo, 50% (p<0.001).4 Of the 394 patients, 85% in the simeprevir treatment group were eligible to complete treatments at week 24. On-treatment failure rate was also much lower with simeprevir treatment, compared to placebo.
QUEST-2: Simeprevir versus placebo as part of regimen including PegIFN or PegIFN/RBV was well tolerated.5 SVR12 rates significantly increased in the simeprevir group compared to placebo (81 vs. 50% respectively (p<0.001) and of the 391 patients treated, 91% were eligible to stop all treatment at week 24.

Prof. Mark Thursz commented on the exciting protease inhibitor data showcased at the congress: “With genotype-1 the most common and most challenging type of HCV to cure, both studies have demonstrated extremely encouraging results with cleaner profiles than existing protease inhibitors. It is unlikely telaprevir and boceprevir will remain in the hepatic armoury for much longer.”

“We truly are in a prime time for HCV therapy; these effective new treatment options have the potential to pave the way for future interferon-sparing regimens and we look forward to using them in the clinic” added Prof Thursz.

Other promising Phase II data presented at the congress may provide further options:

ELECTRON

Results of the ELECTRON study6 show that all-oral regimens containing sofosbuvir in combination with a second DAA and ribavirin show promising efficacy, with rapid and consistent antiviral suppression in both treatment-naïve patients and prior null responders. High response rates in those treatment arms employing a second agent supports the hypothesis that the addition of another DAA with a different mechanism of action and non-overlapping resistance profile would improve rates of SVR.

IFN and RBV Free Regimen

Interim analysis of a Phase II study7 show that an interferon (IFN)- and ribavirin (RBV)-free regimen of daclatasvir (NS5A inhibitor), asunaprevir (protease inhibitor) and BMS-791325 (non-nucleoside NS5B inhibitor) achieved, overall, an SVR4 of 92% (46/50), SVR12 of 94% (30/32), and SVR24 of 94% (15/16) in treatment-naive genotype (GT) 1 patients, mainly GT1a and IL28B non-CC. Patients were initially randomised (1:1) to daclatasvir 60mg QD, asunaprevir 200mg BID, and BMS-791325 75mg BID for a period of 24 or 12 weeks. Following one month of safety observation, a second cohort was randomized (1:1) to the same regimen but including BMS-791325 150mg BID (24 or 12 weeks). The primary end point was HCV RNA < 25 IU/mL at 12 weeks post-treatment (SVR12). Sixty four of the 66 patients had a HCV RNA < 25 IU/mL by week 4, with no difference in virological responses between 12 and 24 weeks of treatment.

AVIATOR

Latest results from the AVIATOR study8, using a combination of ABT-450/r (HCV protease inhibitor dosed with ritonavir 100 mg) with ABT-267 (NS5A inhibitor) and/or ABT-333 (non-nucleoside NS5B inhibitor) +/- ribavirin, demonstrate impressive SVR12 in patients with chronic HCV GT1 infection. The overall intention-to-treat SVR12 rate for 12-week treatment with three DAAs in combination with ribavirin was 98.7% (78/79) in treatment-naïve patients, and 93% (42/45) in null responders.

EASL Secretary General Prof. Mark Thursz commented further: “With such high success rates and increased safety and tolerability with novel DAAs, patients can be optimistic about oral treatment regimens in the not-too-distant future.”

Disclaimer: The data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2013.

References 

[1] Jacobson, I et al, TREATMENT WITH SOFOSBUVIR+RIBAVIRIN FOR 12 WEEKS ACHIEVES SVR12 OF 78% IN GT2/3 INTERFERON- INELIGIBLE, -INTOLERANT, OR -UNWILLING PATIENTS: RESULTS OF THE PHASE 3 POSITRON TRIAL. Presented at the International Liver Congress™ 2013

[2] Lawitz, E et al, SOFOSBUVIR + PEGINTERFERON + RIBAVIRIN FOR 12 WEEKS ACHIEVES 90% SVR12 IN GENOTYPE 1, 4, 5, OR 6 HCV INFECTED PATIENTS: THE NEUTRINO STUDY. Presented at the International Liver Congress™ 2013

[3] Ferenci, P et al, FALDAPREVIR PLUS PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN CHRONIC HCV GENOTYPE-1 TREATMENT-NAÏVE PATIENTS: FINAL RESULTS FROM STARTVERSO1, A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE III TRIAL. Presented at the International Liver Congress™ 2013

[4] Jacobson, I et al, SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR CHRONIC HCV GENOTYPE-1 INFECTION IN TREATMENT-NAÏVE PATIENTS; RESULTS FROM QUEST-1, A PHASE III TRIAL. Presented at the International Liver Congress™ 2013

[5] Manns M, et al, SIMEPREVIR (TMC435) WITH PEGINTERFERON/RIBAVIRIN FOR CHRONIC HCV GENOTYPE-1 INFECTION IN TREATMENT-NAÏVE PATIENTS; RESULTS FROM QUEST-2, A PHASE III TRIAL. Presented at the International Liver Congress™ 2013

[6] Gane EJ, et al, ALL-ORAL SOFOSBUVIR-BASED 12-WEEK REGIMENS FOR THE TREATMENT OF CHRONIC HCV INFECTION: THE ELECTRON STUDY Presented at the International Liver Congress™ 2013

[7] Everson, GT et al, INTERIM ANALYSIS OF AN INTERFERON (IFN)- AND RIBAVIRIN (RBV)-FREE REGIMEN OF DACLATASVIR (DCV), ASUNAPREVIR (ASV), AND BMS-791325 IN TREATMENT-NAIVE, HEPATITIS C VIRUS GENOTYPE 1-INFECTED PATIENTS. Presented at the International Liver Congress™ 2013

[8] Kowdley, KV et al, SAFETY AND EFFICACY OF INTERFERON-FREE REGIMENS OF ABT-450/R, ABT-267, ABT-333 +/- RIBAVIRIN IN PATIENTS WITH CHRONIC HCV GT1 INFECTION: RESULTS FROM THE AVIATOR STUDY. Presented at the International Liver Congress™ 2013

[9] EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. European Association for the Study of the Liver. Journal of Hepatology 2011;55:245–264

[10] Hepatitis C Fact Sheet. World Health Organisation factsheet. Available at http://www.who.int/mediacentre/factsheets/fs164/en/index.html. Last accessed 28.03.13

http://virtualpressoffice.easl.eu/direct-acting-antivirals-now-ready-for-prime-time-with-promising-alternatives-on-the-way/

EASL- Bristol-Myers oral hepatitis C regimen daclatasvir/asunaprevir/BMS-791325

Study: Bristol-Myers oral hepatitis C regimen looks competitive

April 23, 2013 6:04 am by Berkrot, Bill

MedCity News

(Reuters) - A combination of three experimental Bristol-Myers Squibb hepatitis C drugs appeared to be highly effective, according to data from a mid-stage clinical trial, keeping the company in the race for developing an all-oral treatment regimen for the serious liver disease.

The combination therapy, which involves three direct acting antiviral drugs that each attack different targets needed for replication of the hepatitis virus, achieved cure rates as high as 94 percent when given for either 12 weeks or 24 weeks, according to results of the small study.

Current treatment regimens for the disease still include the older, difficult-to-tolerate drugs interferon and ribavirin and are typically taken for either 24 weeks or 48 weeks. When used with newer drugs, they have cure rates as high as about 80 percent.

Several companies are developing hepatitis C regimens that do not include interferon - which is given intravenously and often causes miserable flu-like symptoms - while also pursuing much shorter treatment durations.

Gilead Sciences Inc and Abbvie Inc are widely seen as ahead of the pack with treatments that could reach the market as soon as next year. But those will likely, at least initially, include ribavirin, which many patients also have difficulty tolerating.

Data from the Bristol-Myers combination, to be presented this week at the European Association for the Study of the Liver (EASL) meeting in Amsterdam, does not include ribavirin, potentially giving the company a competitive advantage. Bristol-Myers said it expects to begin Phase III testing of its combination by late 2013, so it is still playing catch-up.

"The speed of drug development is moving quicker than any of us would have thought and the potency of these regimens with high (cures) is very good for the field and for patients," Dr. Eric Lawitz, one of the investigators who worked on the trial, said in a telephone interview from Amsterdam.

The multi-pronged study included 66 patients with the most common and difficult to treat genotype 1 form of the disease who had not previously been treated. It tested a combination of daclatasvir, from a promising new class of drugs called NS5A inhibitors, a protease inhibitor called asunaprevir, and either 75 milligrams or 150 milligrams of BMS-791325 ('325), a non-nucleoside polymerase inhibitor. The combinations were tested for either 24 weeks or 12 weeks of treatment.

With the lower dose of '325, the sustained virologic response 12 weeks after completing treatment (SVR 12) was 94 percent, and that was essentially maintained through 24 weeks. Patients in whom the virus is undetectable 24 weeks after completing treatment (SVR 24) are considered to be cured.
If data was excluded from the few patients who either missed a planned doctor visit and could not be tested or withdrew consent to participate, then all 28 patients in the lower dose arms of the trial were cured, Bristol-Myers said.

"It looks overall very promising," said Lawitz, medical director of the Texas Liver Institute in San Antonio. "Anytime we can hit 90 percent SVR, we're very interested."
There was less available data ready in time for the EASL meeting from patients who got the 150 mgs of '325, but that dose appeared to be a bit less promising than the lower dose.

The SVR 12 rate for those who received 12 weeks of treatment was 89 percent. But there was one patient who had viral breakthrough, in which the virus comes back during treatment after initially responding, and one patient who relapsed after completing treatment. There was also one viral breakthrough reported in the 24-week treatment group.

There were no patient discontinuations due to intolerance to the drugs or adverse events and no serious elevations in liver enzymes reported, the company said.

Two serious adverse events were reported. One patient suffered from kidney stones, which was deemed unrelated to the Bristol-Myers drugs by researchers, and one case of cerebral vasoconstriction (a narrowing of blood vessels in the brain) in a patient taking interferon and ribavirin following viral breakthrough.

The most commonly reported side effects were headache, diarrhea, muscle weakness and nausea, the company said.

"There hasn't been any safety signal that has been concerning from what's been reported to date," said Lawitz, adding that much larger studies with more diverse patient populations, such as those with cirrhosis, must be conducted to confirm the findings.
An estimated 170 million people worldwide are infected with hepatitis C. If untreated it can lead to cirrhosis, liver cancer or the need for a liver transplant.
(Reporting by Bill Berkrot; Editing by Tim Dobbyn)

Copyright (2013) Thomson Reuters. Click for restrictions

Bristol Says Results of Hepatitis C Drug Trial are Positive 

 

By Peter Loftus

An experimental drug cocktail from Bristol-Myers Squibb Co. (BMY) cleared the hepatitis C virus in most patients in a mid-stage clinical trial--results that could keep the company in the race to develop the next generation of treatments for the liver disease. The company had to shift gears after a major setback last year, when another hepatitis C drug in development was linked to serious safety concerns. Bristol scrapped development of that drug, dubbed a "nuke" because it was known as a nucleotide polymerase inhibitor. Now, Bristol is moving ahead with a combination of three drugs that use different mechanisms to combat the hepatitis C virus: daclatasvir, asunaprevir and BMS-791325. Based on positive results in mid-stage studies so far, Bristol expects to begin late-stage, or phase 3, clinical testing of the triple combination in late 2013 or early 2014, which could support filing for regulatory approval if results remain positive.

Douglas J. Manion, a Bristol-Myers senior vice president of development of virology drugs, said the company remains in the hunt for the next generation of hepatitis C drugs, despite dropping its "nuke" from development. "We think we're highly competitive," said Dr. Manion. Bristol's triple therapy is all oral, stripping out two elements of the current standard treatment for hepatitis C: the injected interferon and orally administered ribavirin, both of which have side effects that can be difficult for patients to tolerate. Bristol is jockeying with Gilead Sciences Inc. (GILD) and AbbVie (ABBV) to develop an all-oral treatment that would at least eliminate interferon from the mix.

The hope is that the new treatments will be easier to tolerate, shorter in duration and potentially more effective than the current standard of care. Analysts say a multi-billion-dollar market opportunity awaits the next generation of hepatitis C drugs. Bristol tested its three drugs in a mid-stage, or phase 2, study in patients with the most common form of hepatitis C, known as genotype 1. Patients were given the combination for either 12 or 24 weeks. Some were given lower doses of BMS-791325 while others were given higher doses. Bristol previously presented partial results from the study, showing that 94% of patients receiving the lower dose of BMS-791325 had sustained virologic response four weeks after the completion of 12- and 24-week treatment regimens. Sustained virologic response, or SVR, is a marker that liver specialists say closely correlates to a cure. For those receiving the higher dose of BMS-791325, some 94% achieved SVR4 after a 24-week treatment regimen, while 89% achieved SVR4 after a 12-week regimen, according to data set to be presented this week at the annual meeting of the European Association for the Study of the Liver in Amsterdam.

Two serious adverse events were reported in the study: a kidney stone that was determined to be unrelated to treatment, and a cerebral condition associated with interferon and ribavirin treatment that were given to a study patient who experienced a viral breakthrough, or a return of viral levels following treatment. Most adverse events were mild to moderate, Bristol said, with headache and diarrhea among the most common.

Write to Peter Loftus at peter.loftus@dowjones.com  Subscribe to WSJ: http://online.wsj.com?mod=djnwires

EASL-Bristol-Myers Squibb to Present New Data on Hepatitis C and Hepatitis B Compounds

Bristol-Myers Squibb to Present New Data on Hepatitis C and Hepatitis B Compounds at The International Liver Congress^TM (ILC) 2013

   

• New data on an investigational, all-oral, triple DAA regimen of daclatasvir, asunaprevir and BMS-791325 to be included in official ILC Press Conference on April 24
• New ALT flare data further characterize profile of peginterferon lambda-1a (Lambda) as investigational treatment for Chronic Hepatitis B (CHB)
• Breadth of data underscores Company’s commitment to advancing the treatment of liver disease

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that 14 abstracts on the Company’s research in liver disease have been accepted for presentation at The International Liver Congress^TM 2013, the 48th annual meeting of the European Association for the Study of the Liver (EASL), in Amsterdam, April 24 – 28.
   

“The data we are presenting at the International Liver Congress demonstrate our continued advancement of research to address unmet medical needs, through the development of regimens for personalized hepatitis C treatment and increasing options to treat hepatitis B.”

Key presentations include:

• New Phase 2 data on an investigational triple direct-acting antiviral (DAA) regimen of daclatasvir (NS5A replication complex inhibitor), asunaprevir (NS3 protease inhibitor) and BMS-791325 (NS5B non-nucleotide polymerase inhibitor) in patients with hepatitis C (HCV) genotypes 1a and 1b. The regimen is being studied as a potential interferon alfa-, ribavirin- and ritonavir-free treatment option to avoid the tolerability and drug-drug interaction profiles of these medicines. These triple DAA data will be highlighted in the official ILC Press Conference on April 24.
• An analysis of all available safety data on 1,100 patients who received daclatasvir plus interferon alfa and ribavirin in Phase 2 studies. These data support the ongoing Phase 3 development program for daclatasvir and further studies of daclatasvir as a component of DAA-based HCV treatment regimens.
• A characterization of ALT flares observed in hepatitis B (HBV) treatment with the investigational interferon Lambda vs. alfa interferon, reflecting differing profiles for the two compounds. Lambda is being developed as a potential alternative for alfa wherever interferon is used in the treatment of either HCV or HBV.
• An analysis of sustained virologic response with daclatasvir plus sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 who previously failed telaprevir or boceprevir.

“Bristol-Myers Squibb has a longstanding commitment to viral hepatitis and has been at the forefront of the evolving science in both hepatitis B and C,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “The data we are presenting at the International Liver Congress demonstrate our continued advancement of research to address unmet medical needs, through the development of regimens for personalized hepatitis C treatment and increasing options to treat hepatitis B.”

Bristol-Myers Squibb is studying a portfolio of compounds that has the potential to address unmet medical needs for patients with liver disease, including the investigational compounds daclatasvir, asunaprevir and BMS-791325 for HCV, and Lambda for HCV and HBV. In addition to these compounds, the Company’s medicine BARACLUDE^® (entecavir) is approved for the treatment of chronic hepatitis B (CHB) in adults with evidence of active viral replication and either evidence of persistent elevations in aminotransferases (ALT or AST), or histologically active disease.
The complete list of Bristol-Myers Squibb data presentations is below. Abstracts can be accessed on the ILC/EASL website at http://www.easl.eu/_the-international-liver-congress/general-information.
   

Title		Date/Time
Hepatitis C: Direct-Acting Antiviral Data
Synergistic Interactions of HCV NS5A replication Complex Inhibitors Sensitize Resistant Variants and Enhance the Efficacy of Daclatasvir (DCV, BMS-790052) In Vitro and In Vivo		April 25 12:15 – 1:30 pm
Asunaprevir with Peginterferon and Ribavirin in Treatment-Naïve Patients with Genotype –1 or -4 Chronic Hepatitis C: SVR24 Results From a Randomized Phase 2b Study (AI447016)		April 25 12:15 – 1:30 pm
Evaluation of Pharmacokinetic Drug-Drug Interaction (DDI) Between BMS-791325, an NS5B Non-Nucleotide Polymerase Inhibitor, Daclatasvir and Asunaprevir in Triple Combination in HCV Genotype 1-Infected Patients		April 25 12:15 – 1:30 pm
The Effect of Coadministration of the Proton-Pump Inhibitor Omeprazole on the Pharmacokinetics of Daclatasvir in Healthy Subjects		April 26 12:30 – 2:00 pm
Exposure-Response Analyses of Asunaprevir in Combination with Daclatasvir ± Peginterferon / Ribavirin Among Patients with Genotype 1 Chronic HCV Infection: Dose Selection for Phase 3 Clinical Trials -Response Analyses of Asunaprevir in Patients with Genotype 1, Chronic HCV Infection: Dose Selection for Phase 3 Clinical Trials		April 26 12:30 – 2:00 pm
Daclatasvir Combined With Peginterferon Alfa and Ribavirin for 12 or 16 Weeks in Patients With HCV Genotype 2 or 3 Infection: COMMAND GT2/3 Study		April 27 3:30 – 5:30 pm Oral presentation
Sustained Virologic Response with Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) In Chronic HCV Genotype (GT) 1-Infected Patients who Previously Failed Telaprevir (TVR) or Boceprevir (BOC)		April 27 3:30 – 5:30 pm Oral presentation
Safety Profile of Daclatasvir in Combination with Peginterferon Alfa and Ribavirin in 1100 Patients with Chronic HCV Infection Treated in Phase 2 Studies		April 27 12:30 – 1:30 pm
Pre-Existence, Emergence and Persistence of HCV Genotype 4 NS5A Resistance Variants from the Phase 2b COMMAND-1 Study: Daclatasvir Plus Peginterferon-Alfa/Ribavirin in Treatment-Naïve Patients		April 27 12:30 – 1:30 pm
Hepatitis C: Outcomes Research Data
Host Genetic Variants Around IL28A/IL28B Associated with HCV-Related Outcomes Based on R.E.V.E.A.L.-HCV Cohort		April 25 12:15 – 1:30 pm
Genome-Wide Association Study to Identify Potential Single Nucleotide Polymorphisms Associated with Spontaneous Hepatitis C Virus Clearance Among Chronic Hepatitis C Patients		April 25 12:15 – 1:30 pm
Hepatitis B: Peginterferon Lambda-1a Data
ALT Flares During Treatment With Peginterferon Lambda or Peginterferon Alfa in Patients with HBeAg-Positive Chronic Hepatitis B Infection (CHB)		April 26 12:30 – 2:00 pm
Hepatitis B: BARACLUDE® (entecavir) Data
Impact of Entecavir Versus Lamivudine on Hepatic Covalently Closed-Circular DNA and Total Hepatic HBV DNA in Nucleoside-Naïve HBeAg Positive Chronic Hepatitis B Patients		April 26 12:30 – 2:00 pm

INDICATION and IMPORTANT SAFETY INFORMATION about BARACLUDE^® (entecavir) Tablets:
   
INDICATION
BARACLUDE is indicated for the treatment of chronic hepatitis B virus (HBV) infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
The following points should be considered when initiating BARACLUDE:

• This indication is based on histologic, virologic, biochemical, and serologic responses in nucleoside-treatment-naïve and lamivudine-resistant adult subjects with HBeAg-positive or HBeAg-negative chronic HBV infection and compensated liver disease.
• Virologic, biochemical, serologic, and safety data are available from a controlled study in adult subjects with chronic HBV infection and decompensated liver disease.
• Virologic, biochemical, serologic, and safety data are available for a limited number of adult subjects with HIV/HBV co-infection who have received prior lamivudine therapy.

IMPORTANT SAFETY INFORMATION
WARNINGS: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY

• Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
• Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if BARACLUDE (entecavir) is used to treat chronic HBV infection in patients with HIV infection that is not being treated. Therapy with BARACLUDE is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART).
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, alone or in combination with antiretrovirals.

Warnings and Precautions

• Before initiating BARACLUDE^® (entecavir) therapy, HIV antibody testing should be offered to all patients. BARACLUDE has not been studied as a treatment for HIV infection and is not recommended for this use.
• Lactic acidosis with BARACLUDE use has been reported, often in association with hepatic decompensation, other serious medical conditions, or drug exposures. Patients with decompensated liver disease may be at higher risk for lactic acidosis. BARACLUDE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity.

Adverse Reactions

• In clinical trials in patients with compensated liver disease, the most common (≥3%) adverse reactions of any severity with at least a possible relation to study drug for BARACLUDE-treated subjects were headache, fatigue, dizziness, and nausea. In these trials, the most common adverse reactions of moderate to severe intensity (grades 2-4) were diarrhea, dyspepsia, nausea, vomiting, fatigue, headache, dizziness, somnolence, and insomnia.
• In the decompensated liver disease trial, the most common adverse reactions of any severity among patients treated with BARACLUDE, regardless of causality, included: peripheral edema (16%), ascites (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper respiratory infection (10%). In this trial, 18% (18/102) of BARACLUDE (entecavir) patients and 20% (18/89) of adefovir patients died during the first 48 weeks of therapy. The majority of those deaths were due to liver related causes.

Drug Interactions
BARACLUDE is primarily eliminated by the kidneys, therefore coadministration of BARACLUDE with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the coadministered drug. Patients should be monitored closely when receiving BARACLUDE^® (entecavir) with other renally-eliminated drugs.
   
Pregnancy and Nursing Mothers

• There are no adequate and well-controlled studies of BARACLUDE in pregnant women. BARACLUDE should be used during pregnancy only if clearly needed and after careful consideration of the risks and benefits.
• There are no studies on the effect of BARACLUDE on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
• It is not known whether BARACLUDE is excreted into human milk; however, many drugs are excreted into breast milk. Due to the potential for serious adverse reactions in nursing infants from BARACLUDE, risks and benefits should be considered when deciding whether to discontinue breast-feeding or discontinue BARACLUDE in nursing women.

Pediatric Use

• Safety and effectiveness of BARACLUDE in pediatric patients below the age of 16 years have not been established.

Renal Impairment

• Dosage adjustment of BARACLUDE is recommended for patients with a creatinine clearance <50 mL/min, including those on hemodialysis or continuous ambulatory peritoneal dialysis.

Liver Transplant Recipients

• Renal function must be carefully monitored both before and during treatment with BARACLUDE in a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus.

Dosage and Administration
BARACLUDE^® (entecavir) should be administered on an empty stomach (at least 2 hours after a meal and at least 2 hours before the next meal).
The recommended dose of BARACLUDE:

• in nucleoside-naïve adults and adolescents (16+ yrs) with compensated liver disease is 0.5 mg once daily
• in adults and adolescents (16+ yrs) with compensated liver disease, and refractory to lamivudine or with known lamivudine or telbivudine resistance mutations (rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L) is 1 mg once daily
• in adults with decompensated liver disease is 1 mg once daily

The optimal duration of treatment with BARACLUDE for patients with chronic HBV infection and the relationship between treatment and long-term outcomes such as cirrhosis and hepatocellular carcinoma are unknown.
   
Additional Information
BARACLUDE is not a cure for HBV. Patients should be advised that treatment with BARACLUDE has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.
Please see accompanying Full Prescribing Information, including Boxed WARNINGS, or click here.
    
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 product development. 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 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, 2012, 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.
BARACLUDE^® (entecavir) is a registered trademark of Bristol-Myers Squibb.

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