AASLD-Daclatasvir and Asunaprevir Achieved SVR12 in 78% of Difficult-to-Treat Genotype 1b Prior Null Responders

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 programs 

Sunday, November 11, 2012 4:45 pm EST

BOSTON--(BUSINESS WIRE)--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 (SVR₁₂) 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 SVR₁₂ 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 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. 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 (SVR₁₂).
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 SVR₁₂. Of the four patients who did not achieve SVR₁₂, 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 SVR₁₂
• 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.

Safety

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:

Adverse Event

Group A1* DCV + ASV 200 mg BID

Group A2* DCV + ASV 200 mg QD

Headache

44% (8/18)

40% (8/20)

Diarrhea

28% (5/18)

40% (8/20)

Weakness (asthenia)

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 therapy.

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 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 compounds described in this release will support regulatory filings, or that the compounds will receive regulatory approvals or, if approved, 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, 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.

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)

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