Investigational Hepatitis C Dual DAA Regimen of Daclatasvir and Asunaprevir Achieved SVR12 in 78% of Difficult-to-Treat Genotype

  Investigational Hepatitis C Dual DAA Regimen of Daclatasvir and Asunaprevir
  Achieved SVR12 in 78% of Difficult-to-Treat Genotype 1b Prior Null
  Responders In Expanded Phase II Study

  *Interferon- and ribavirin-free dual DAA regimen is one of multiple
    daclatasvir-based regimens in development to help meet the needs of
    diverse HCV patient population

  *Findings support both the global and Japanese daclatasvir registrational

Business Wire

BOSTON -- November 11, 2012

Bristol-Myers Squibb Company (NYSE: BMY) today announced new Phase II data
demonstrating that the dual regimen of the investigational NS5A replication
complex inhibitor daclatasvir (DCV) and the investigational NS3 protease
inhibitor asunaprevir (ASV), without interferon or ribavirin, achieved high
rates of sustained virologic response 12 weeks post-treatment (SVR[12]) in
patients with genotype 1b (GT1b) hepatitis C virus (HCV) who were prior null
responders to alfa interferon and ribavirin (alfa/RBV). In this study, the
DCV/ASV Dual regimen achieved SVR[12] in 78% (14/18) and 65% (13/20) of GT1b
patients when asunaprevir was dosed twice daily (Group A1) or once daily
(Group A2), respectively.

These results were presented today at the American Association for the Study
of Liver Diseases congress in Boston, along with data from this same study on
the safety and efficacy of quadruple therapy with DCV/ASV/alfa/RBV in
predominantly GT1a prior null responders.

In the patients treated with the DCV/ASV Dual regimen therapy, there were no
serious adverse events related to study drug or discontinuations due to
adverse events. Overall, headache was the most common adverse event in the
DCV/ASV Dual regimen groups (Group A1: 44%, Group A2: 40%).

“We continue to see a significant unmet need for treatment approaches that
improve response rates in patients with hepatitis C genotype1b who have not
responded to prior therapy, with currently available treatment regimens
achieving low cure rates of 30 to 40%,” said Brian Daniels, MD, senior vice
president, Global Development and Medical Affairs, Research and Development,
Bristol-Myers Squibb. “The high response rates seen in this study with
daclatasvir and asunaprevir are encouraging as we seek interferon- and
ribavirin-free hepatitis C regimens for this difficult-to-treat patient

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.
The DCV/ASV Dual regimen is part of a global registrational program and a
registrational program specific to Japan, where the majority of HCV patients
have GT1b.

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 Dual
treatment groups received DCV 60 mg once daily and ASV 200 mg either twice
daily (Group A1) or once daily (Group A2).

Virologic Response

  *In Group A1 (DCV + ASV 200 mg BID), 78% (14/18) of patients achieved
    SVR[12]. Of the four patients who did not achieve SVR[12], one patient was
    missing a viral load measurement at 12 weeks post-treatment and one had
    transient viremia (detectable viral load). Both of these patients had
    undetectable viral load on subsequent visits.
  *In Group A2 (DCV + ASV 200 mg QD), 65% (13/20) of patients achieved
  *With DCV/ASV Dual therapy, eight total patients experienced virologic
    breakthrough1 – two Group A1 patients and six Group A2 patients. All
    received rescue therapy with the addition of alfa/RBV to their regimen.
    One Group A2 patient relapsed post-treatment at week 4.
  *An analysis of HCV sequences confirmed that five of the six Group A2
    patients with virologic breakthrough had baseline polymorphisms that
    confer DCV resistance (NS5A domain). Additionally, at breakthrough, seven
    patients had confirmed resistance to both DCV and ASV.


In the patients treated with DCV/ASV Dual 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 A1*                    Group A2*
Adverse Event                                       
                                    DCV + ASV 200                DCV + ASV 200
                                    mg BID                       mg QD
Headache                      44% (8/18)             40% (8/20)
Diarrhea                      28% (5/18)             40% (8/20)
Weakness                      28% (5/18)             30% (6/20)
Fatigue                       28% (5/18)             10% (2/20)
Insomnia                      22% (4/18)             15% (3/20)
* Adverse events in groups A1 and A2 includes patients who had alfa/RBV added
to their regimen

Grade 3-4 AEs in Group A2 included neutropenia in one patient receiving
alfa/RBV as rescue therapy. SAEs in Groups A1 and A2 included panic attack,
forearm fracture, viral gastroenteritis, and prostate cancer; all were
determined by study investigators to be unrelated to study therapy. Grade 3-4
ALT/AST elevations were infrequent and none were accompanied by elevated total
or direct bilirubin. All AST/ALT elevations improved without intervention. All
patients in groups A1/A2 with cytopenias were receiving alfa/RBV as rescue

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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^1 Virologic breakthrough defined as ≥ 1 log increase from nadir in HCV RNA,
HCV RNA ≥ LLOQ on or after Week 8, and confirmed HCV RNA < LLOQ-TD on or after
Week 8 (DUAL and TRIPLE arms only)


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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