All-Oral Combination of Investigational Hepatitis C (HCV) Compounds Daclatasvir and GS-7977 Achieved Sustained Virologic Response (SVR4) in 100% of Genotype 1 and 91% of Genotype 2 and 3 Treatment-Naïve Patients in Phase II Study

  • First demonstration of 100% SVR with once-daily, interferon- and ribavirin-free regimen in treatment-naïve genotype 1 HCV patients
  • First report of a study designed to assess antiviral efficacy of a NS5A replication complex inhibitor and a NS5B nucleotide polymerase inhibitor as potential combination HCV therapy
  • All-oral investigational treatment regimen suppressed viral load through 4 weeks post-treatment (SVR4) in genotypes 1, 2 and 3, with or without ribavirin
  • Data presented at The International Liver Congress in Barcelona

PRINCETON, N.J.--(BUSINESS WIRE)--Apr 19, 2012 - Bristol-Myers Squibb Company (NYSE: BMY) announced today interim results from a Phase II open-label study of daclatasvir, Bristol-Myers Squibb's NS5A replication complex inhibitor, and GS-7977, a nucleotide NS5B polymerase inhibitor, in treatment-naïve patients with hepatitis C genotypes 1, 2 and 3. In this interim analysis, a combination of the two oral, once-daily investigational compounds taken for 24 weeks, with or without ribavirin, achieved a rapid and sustained viral response. Overall, 100% of patients with genotype 1, 2, or 3 HCV achieved viral load below the lower limit of quantification at Week 4 on treatment. In the genotype 1 HCV treatment groups, 100% of patients achieved sustained virologic response through four weeks off-treatment (SVR4). In the genotypes 2 and 3 treatment groups, 91% (40/44) of patients achieved SVR4. The data were presented today at the International Liver Congress (ILC), the 47th annual meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain.

The most frequent (‰¥25% overall) adverse events (AE) on treatment, based upon the most recent 12-week interim safety analysis, were fatigue, headache and nausea. Drug-related AEs were generally mild and did not lead to treatment discontinuation. Grade 3-4 laboratory abnormalities occurring in patients in the ribavirin treatment groups included anemia, elevated glucose, elevated fasting glucose, lymphopenia and low serum phosphorus, and the grade 3-4 laboratory abnormalities reported in the ribavirin-sparing treatment groups were low phosphorus and elevated cholesterol.

“The achievement of high SVR rates with a once-daily, pan-genotypic oral combination regimen has emerged as a key goal in HCV research,” said Mark Sulkowski, MD, Professor of Medicine, Medical Director, Viral Hepatitis Center, Johns Hopkins University School of Medicine. “The interim results of this study indicate that combining the potent antiviral activity of daclatasvir with a nucleotide analogue polymerase inhibitor has the potential to address this goal for the treatment of HCV genotypes 1, 2 and 3, and warrants further study to more fully evaluate this combination.”

Daclatasvir has demonstrated potent antiviral activity against HCV genotypes 1, 2, 3, and 4 in vitro.

Study Results

In the study, 88 treatment-naïve patients were divided into six treatment groups. The proportions of patients achieving viral load below the lower limit of quantification (HCV RNA <25 IU/mL) were:

           
Dose HCV
Genotype

 

Week 4 On-Treatment

 

Week 12 On-Treatment

 

Week 24 On-Treatment

 

Week 4 Post-Treatment (SVR4)a

 

7-day lead-in dose of GS-7977, then DCV + GS-7977 for 23 weeks

 

GT 1 100% (15/15)

 

100% (15/15)

 

87% (13/15)

 

100% (15/15)

 

GT 2/3 100% (16/16)

 

88% (14/16)

 

94% (15/16)

 

88% (14/16)b

 

DCV + GS-7977 for 24 weeks GT 1 100% (14/14)

 

93% (13/14)

 

86% (12/14)

 

100% (14/14)

 

GT 2/3 100% (14/14)

 

93% (13/14)

 

100% (14/14)

 

100% (14/14)

 

DCV + GS-7977 + ribavirin for 24 weeks GT 1 100% (15/15)

 

100% (15/15)

 

93% (14/15)

 

100% (15/15)

 

GT 2/3 100% (14/14)

 

100% (14/14)

 

86% (12/14)

 

86% (12/14)c

 

a In this study, SVR4 was defined as viral load below the lower limit of quantification. All but one patient who achieved SVR4 also had undetectable viral load (HCV RNA <10 IU/mL); this patient had undetectable viral load when retested eight days later.
b One patient experienced viral relapse and one patient experienced viral breakthrough.
c Two patients were lost to follow-up.
 
Safety data from this ongoing study are available through 12 weeks on-treatment. The most frequent (‰¥25% overall) adverse events (AEs) on treatment were fatigue, headache and nausea. AEs were generally mild to moderate intensity and did not lead to treatment discontinuation. Grade 3-4 laboratory abnormalities included anemia, elevated glucose, elevated fasting glucose, lymphopenia and low serum phosphorus– all of which occurred in patients who received ribavirin. Grade 3-4 laboratory abnormalities reported in the ribavirin-sparing treatment groups were low phosphorus and elevated cholesterol. Two patients discontinued treatment for non-drug related AEs and both achieved SVR4. An additional two patients with genotype 2 who received daclatasvir, GS-7977 and ribavirin discontinued the study for non-AE-related reasons and were lost to follow-up. No patients discontinued therapy due to treatment-related AEs. Of the 88 patients treated, one patient with genotype 3 HCV who received GS-7977 and daclatasvir without ribavirin experienced viral relapse, and one patient met the protocol definition of viral breakthrough – HCV RNA below the lower limit of quantification on or after Week 8, confirmed by immediate retesting. This definition of viral breakthrough is not widely accepted and has since been removed from the protocol.

About the Study

This Phase II study (AI444-040) was designed to evaluate the potential to achieve sustained virologic response with an oral, pan-genotypic, once-daily treatment regimen combining daclatasvir (DCV) and Gilead Sciences Inc.'s GS-7977, with or without ribavirin, in patients chronically infected with HCV genotypes 1, 2 and 3. In the initial phase of this study, patients were randomized into six groups, evaluating three different dosing schedules in patients with HCV genotype 1 (n=44) and in patients with HCV genotype 2 or 3 (n=44).

 

  • GS-7977 400 mg QD for 7 days then DCV 60 mg QD + GS-7977 400 mg QD for 23 weeks
  • DCV 60 mg QD + GS-7977 400 mg QD for 24 weeks
  • DCV 60 mg QD + GS-7977 400 mg QD + ribavirin for 24 weeks

The study was subsequently expanded to include four new treatment arms that evaluate HCV genotype 1 patients who have previously failed telaprevir or boceprevir treatment, and shorter duration of therapy in treatment-naïve HCV genotype 1 patients. These treatment groups are currently under study.

The primary endpoint of the study is sustained virologic response 12 weeks post-treatment (SVR12). An interim analysis for safety and antiviral activity was conducted at 12 weeks on-treatment. An additional interim analysis for antiviral efficacy was conducted four weeks post-treatment. Final study results will be presented at a future medical meeting.

About Hepatitis C

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

About Bristol-Myers Squibb

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

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

Bristol-Myers Squibb Forward Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the compound described in this release will move from exploratory development into full product development, that the clinical trials of this compound will support regulatory filings, or that the compound will receive regulatory approvals or, if approved, that the compound will become a commercially successful product. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2011, in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

 

Contact: Bristol-Myers Squibb:
Media:
Sonia Choi, 609-252-5132
sonia.choi@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com

 

Posted: April 2012

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