Investigational Hepatitis C Quad Therapy Regimen of Daclatasvir and Asunaprevir Plus Interferon Alfa and Ribavirin Achieved

  Investigational Hepatitis C Quad Therapy Regimen of Daclatasvir and
  Asunaprevir Plus Interferon Alfa and Ribavirin Achieved SVR24 in 93% of
  Difficult-to-Treat Genotype 1a/b Prior Null Responders in Expanded Phase II

  *Quad therapy treatment groups included predominantly genotype 1a patients,
    a patient population with limited treatment options
  *Findings support the ongoing development of multiple daclatasvir-based
    treatment regimens to help meet the needs of diverse HCV patient

Business Wire

BOSTON -- November 11, 2012

Bristol-Myers Squibb Company (NYSE: BMY) today announced new Phase II data
demonstrating that an investigational quad therapy regimen combining the NS5A
replication complex inhibitor daclatasvir (DCV), the NS3 protease inhibitor
asunaprevir (ASV), and a backbone of alfa interferon and ribavirin (alfa/RBV)
achieved sustained virologic response rates 12- and 24-weeks post-treatment
(SVR[12 ]and SVR[24]) of 95% (39/41) and 93% (38/41), respectively, in
patients with genotype 1 (GT1) hepatitis C virus (HCV) who were prior null
responders to alfa/RBV. The DCV ASV Quad treatment groups included
predominantly GT1a patients (36/41), a patient population with limited
effective treatment options.

These data were presented today at the American Association for the Study of
Liver Diseases congress in Boston, along with safety and efficacy data on
DCV/ASV Dual therapy in GT1b prior null responders enrolled in this same

There were no serious adverse events related to study drug or discontinuations
due to adverse events in the DCV ASV Quad  therapy treatment groups of this
study. Overall, headache was the most common adverse event in the DCV ASV Quad
treatment groups (60%, 43%).

“In this study, we are encouraged to see that patients who are among the most
difficult to treat – those with genotype 1a who did not respond to previous
treatment with alfa interferon and ribavirin – demonstrated high SVR rates of
93 percent,” said Brian Daniels, MD, senior vice president, Global Development
and Medical Affairs, Research and Development, Bristol-Myers Squibb. “The
results seen with this daclatasvir-based quadruple regimen are important as we
continue to evaluate treatment approaches that improve response rates in this
challenging patient population.”

Daclatasvir is the first NS5A replication complex inhibitor to be investigated
in HCV clinical trials and is currently in Phase III development. Asunaprevir
is an oral, NS3 protease inhibitor in Phase III development with daclatasvir.

Study Design and Results

The expansion of this randomized, open-label, phase IIa study evaluated the
antiviral activity and safety of the combination of DCV and ASV with and
without alfa/RBV in 101 HCV genotype 1 prior null responders to alfa/RBV. The
primary endpoint of the study was the proportion of patients achieving
undetectable viral load (HCV RNA < LLOQ[TND]) 12 weeks post-treatment

Patients received one of five treatment regimens for 24 weeks. Genotype 1b
infected patients were randomized to receive one of four treatment regimens
for 24 weeks (two DCV/ASV Dual treatment groups, two DCV/ASV/Alfa/RBV Quad
treatment groups). Genotype 1a infected patients were randomized to receive
one of two treatment regimens for 24 weeks (two DCV/ASV/Alfa/RBV Quad
treatment groups). A fifth group (DCV/ASV/RBV Triple therapy) included both
GT1a and GT1b infected patients and enrolled separately. The DCV/ASV Quad
treatment groups received DCV 60 mg once daily and ASV 200 mg either twice
daily (Group B1) or once daily (Group B2). Both groups received a backbone of
PEG-interferon alfa-2a 180 µg once weekly and ribavirin 1000-1200 mg daily
(according to body weight) in two divided doses.

Virologic Response

DCV ASV Quad therapy resulted in high rates of sustained virologic response in
this predominantly genotype 1a prior null responder patient population. Of
patients in Groups B1 and B2, 85% (17/20) and 91% (19/21) had HCV genotype 1a.

  *Group B1 patients (ASV dosed BID), achieved SVR[12 ]and SVR[24] rates of
    95% (19/20) and 90% (18/20), respectively. One patient did not receive a
    viral load measurement at 24 weeks post-treatment.
  *Group B2 patients (ASV dosed QD) achieved SVR[12 ]and SVR[24 ]rates of 95%
  *There was no virologic breakthrough in either Group B1 or B2. Two patients
    relapsed post-treatment, one Group B1 patient at week 4 and one Group B2
    patient at week 12.

The study also found that in a GT1a prior null responder population, an
interferon-free regimen of DCV, ASV 200 mg BID and ribavirin resulted in a
high rate of viral breakthrough and did not warrant further investigation.


In the patients treated with DCV ASV Quad  therapy, there were no serious
adverse events due to study drug, no deaths, and no treatment discontinuations
due to adverse events (AEs). Most AEs were mild to moderate in severity. The
most common AEs (≥40% in any group) were:

                        Group B1                   Group B2
Adverse Event                                 
                        DCV + ASV 200 mg BID +     DCV + ASV 200 mg QD +
                        alfa/RBV                   alfa/RBV
Headache              60% (12/20)              43% (9/21)
Diarrhea              45% (9/20)               33% (7/21)
Weakness (asthenia)   30% (6/20)               57% (12/21)
Fatigue               40% (8/20)               24% (5/21)
Insomnia              45% (9/20)               14% (3/21)

Eleven patients experienced Grade 3 or 4 neutropenia. Eight patients
experienced Grade 3-4 lymphopenia (absolute). Four patients experienced Grade
3-4 leukopenia. Grade 3-4 ALT/AST elevations were infrequent. None were
accompanied by elevated total or direct bilirubin and all AST/ALT elevations
improved without intervention.

About Bristol-Myers Squibb’s Commitment to Liver Disease

Bristol-Myers Squibb is studying a portfolio of compounds that aims 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
compounds with different mechanisms of action, pursuing both biologics as well
as small molecule DAAs. These compounds are being studied as part of multiple
treatment regimens with the goal of increasing SVR rates across diverse
patient types and geographies.

Daclatasvir is an NS5A replication complex inhibitor that is being extensively
studied as a key component of potential DAA-based hepatitis C treatment
regimens. Studied in more than 3,000 patients to date, daclatasvir is in Phase
III development. Asunaprevir is an NS3 protease inhibitor in Phase III
development for hepatitis C as a component of daclatasvir-based treatment
regimens, and has been studied in more than 1,200 patients to date.

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.

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
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Bristol-Myers Squibb
Cristi Barnett, 609-252-6028
Sonia Choi, 609-252-5132
John Elicker, 609-252-4611
Ranya Dajani, 609-252-5330
Ryan Asay, 609-252-5020
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