AASLD - Peginterferon lambda-1a decreases viral load more quickly, safely than alfa-2a in HCV patients

Peginterferon lambda-1a decreases viral load more quickly, safely than alfa-2a in HCV patients

November 14, 2012

BOSTON — Noncirrhotic patients with chronic HCV experienced a more rapid decrease in HCV RNA and fewer side effects when treated with pegylated interferon lambda-1a compared with alfa-2a in a study presented at The Liver Meeting.

In phase 2b of the EMERGE trial, researchers administered ribavirin and 120 mcg peginterferon lambda-1a, 180mcg peginterferon lambda-1a or 240 mcg peginterferon lambda-1a or 180 mcg peginterferon alfa-2a for up to 48 weeks to 407 noncirrhotic, treatment-naive patients with chronic HCV. They included 384 patients with genotype 1 and 23 patients with genotype 4. Ninety-eight patients received 120 mcg, 102 received 180 mcg, 104 received 240 mcg of lambda, and 103 patients received alfa. The impact of lambda on HCV RNA levels was evaluated, along with safety, through 72 weeks.

Approximately 60% of patients completed treatment and follow-up for each group. Treatment response, defined as undetectable RNA levels, occurred as follows:

• After 4 weeks of treatment (RVR): 6.1% of 120 mcg lambda group; 14.7%, 180 mcg lambda; 16.3%, 240 mcg lambda; 5.8%, alfa.
• After 12 weeks (cEVR): 55.1%, 120 mcg lambda; 55.9%, 180 mcg lambda; 56.7%, 240 mcg lambda; 36.9%, alfa.
• After 48 weeks (ETR): 58.2%, 120 mcg lambda; 57.8%, 180 mcg lambda; 55.8%, 240 mcg lambda; 56.3%, alfa.
• After 72 weeks (SVR24): 45.9%, 120 mcg lambda group; 37.3%, 180 mcg lambda; 39.4%, 240 mcg lambda; 36.9%, alfa.

Investigators noted that treatment with lambda led to a more rapid decrease in HCV RNA than treatment with alfa. Incidence of viral breakthrough and relapse were similar among all four groups. Of the three evaluated lambda doses, 180 mcg was selected for use in phase 3 of the study. Patients in the 240 mcg group experienced hepatic laboratory abnormalities and were reduced to a 180-mcg dose during the trial.

Among patients receiving 180 mcg lambda, incidence of serious adverse events were fewer (2.9% compared with 6.8% in the alfa group), as were incidence of interferon dose reductions (7.8% vs. 28.2%), reduction or withholding of ribavirin (10.8% of patients compared with 33.0%), and flu-like (12.7% vs. 45.6%) and musculoskeletal symptoms (15.7% vs. 46.6%). Patients receiving lambda had fewer increases to ALT and more incidence of direct bilirubin greater than 1.2 mg/dL, and were less likely to experience abnormal hemoglobin levels, low neutrophils and low platelet counts than alfa-treated patients.

“At the 180-mcg dose selected for phase 3, lambda was associated with rapid reduction of viral load, with significantly higher RVR and eVR rates, similar SVR24 rates and low relapse rates following end of treatment,” researcher Andrew J. Muir, MD, MHS, Duke University Medical Center, said. “The improved tolerability, together with the faster time to virologic response, supports the further assessment of lambda … in patients chronically infected with genotypes 1 and 4.”
Disclosure: The researchers report numerous financial disclosures.

For more information:
Muir AJ. P214: Peginterferon Lambda-1a (Lambda) Compared to Peginterferon Alfa-2a (Alfa) in Treatment-Naïve Patients with HCV Genotypes (GT) 1 or 4: SVR24 Results From EMERGE Phase 2b. Presented at: The Liver Meeting 2012; Nov. 9-13, Boston.

http://www.healio.com/hepatology/chronic-hepatitis/news/online/%7B22B7A971-3E96-460C-A5E0-69DFA24BD950%7D/Peginterferon-lambda-1a-decreases-viral-load-more-quickly-safely-than-alfa-2a-in-HCV-patients

AASLD-Lambda and Daclatasvir Plus Ribavirin Achieved SVR12 in 93% of Genotype 1b Treatment-Naive Patients

Bristol-Myers Squibb’s Investigational Hepatitis C Compounds Lambda and Daclatasvir Plus Ribavirin Achieved SVR12 in 93% of Genotype 1b Treatment-Naive Patients In Phase IIb Study

First presentation of interim data on Lambda in combination with the direct-acting antiviral (DAA) daclatasvir, from the global D-LITE study of genotype 1 patients

Data from a separate Phase IIb study, EMERGE, continue to demonstrate comparable SVR24 rates and further illustrate the safety and tolerability profile of Lambda vs. alfa interferon in genotype 1 and 4 patients

Phase III development of Lambda in combination with other antivirals underway, and in combination with daclatasvir and ribavirin to initiate in 2013

BOSTON--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced for the first time interim results from the global, D-LITE Phase IIb study, in which a 24-week regimen combining the investigational compound Peginterferon lambda-1a (Lambda) with the investigational direct-acting antiviral (DAA) daclatasvir (DCV) and ribavirin (RBV), achieved sustained virologic response 12 weeks post-treatment (SVR₁₂) in 93% (13/14) of treatment-naïve, genotype 1b chronic hepatitis C patients who achieved a protocol-defined response (PDR)¹. The SVR12 rate for all genotype 1 infected patients in the Lambda/RBV/DCV group was 76% (28/37). These study findings were presented in a late breaker presentation at the American Association for the Study of Liver Diseases (AASLD) congress in Boston. The Company also presented SVR₄ results from the D-LITE Japanese sub-study, where all subjects were infected with HCV genotype 1b and SVR₁₂ was 100%. SVR results from the EMERGE Phase IIb study of Lambda versus alfa interferon (alfa) in treatment-naïve genotype 1 or 4 patients were also presented.

In the D-LITE study, adverse events were mostly low grade and self-limiting. In the Lambda/RBV/DCV treatment group, only one of 37 patients experienced a serious adverse event (breast cancer), which was unrelated to study drug.
  
“Despite the desire for all-oral regimens without alfa interferons for the treatment of chronic hepatitis C, it is likely that certain patient populations will require interferon-based therapies to eradicate hepatitis C. Development of lambda interferon is an important goal for such patients, especially those who cannot tolerate or refuse to use alfa interferon,” said D-LITE lead investigator John M. Vierling, M.D., FACP, Professor of Medicine and Surgery, Director of Baylor Liver Health, and Chief of Hepatology at the Baylor College of Medicine in Houston, TX. “Treatment with lambda interferon combined with daclatasvir and ribavirin achieved high rates of sustained virologic response, and the data support further study of regimens using lambda interferon to address the medical needs of hepatitis C patients who cannot use alfa interferons.”
  
PEGinterferon lambda-1a is the first investigational type III interferon in Phase III development for the treatment of hepatitis C. Daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in Phase III development

D-LITE Study Results
D-LITE is a randomized, double-blind, global phase IIb study designed to evaluate for the first time the safety and efficacy of Lambda 180 μg s.c. weekly in combination with an investigational direct-acting antiviral daclatasvir (DCV) dosed 60 mg orally once daily or asunaprevir (ASV) dosed 200 mg orally twice daily plus ribavirin (RBV), compared to alfa 180 μg s.c. weekly plus RBV in 119 treatment-naïve patients with chronic HCV genotype 1 infection. RBV was dosed based on weight twice daily in all three treatment groups. The primary endpoint of the study is the proportion of patients who achieve SVR₂₄. The interim SVR₁₂ results in patients who achieved a PDR (protocol defined response, based on viral suppression at weeks 4 and 12, qualified patients to complete therapy at 24 weeks), were presented.
  
Virologic Response

In the Lambda/RBV/DCV treatment group, 90% (37/41) of patients achieved a protocol-defined response (PDR). Of these patients, 76% (28/37) achieved SVR₁₂ after 24 weeks of treatment. Response rates were higher in genotype 1b patients, with 93% (13/14) of genotype 1b patients achieving SVR₁₂ and 65% (15/23) of genotype 1a patients achieving SVR₁₂.
The Company also presented SVR₁₂ data from the D-LITE study Japanese cohort of genotype 1b patients in an oral presentation. In the Japanese cohort, 100% of patients in the Lambda/RBV/DCV arm (8/8) achieved a PDR and went on to achieve SVR₄ and SVR₁₂.
Based on these study results, the combination regimen of Lambda/RBV/DCV will move into Phase III development.
  
Safety Data

In the Lambda/RBV/DCV treatment group, one of 37 patients experienced a serious adverse event (breast cancer), which was unrelated to study drug, and six patients experienced grade 3-4 adverse events. There were no adverse event-related treatment discontinuations. No patients in this treatment group experienced ALT elevation and two patients experienced AST elevation that were manageable. One patient who received Lambda/RBV/DCV experienced elevated total bilirubin, manageable with dose modification.
  
In the D-LITE study Japanese cohort, one patient experienced a grade 3-4 AE (transient leukopenia).
Safety and efficacy data for the Lambda/RBV/ASV treatment group were also presented at the AASLD annual meeting.

EMERGE Study Results
The EMERGE 2B study is a randomized, controlled, multicenter, Phase IIb study designed to evaluate the safety, efficacy, and pharmacokinetics of Lambda/RBV versus alfa/RBV, in 526 non-cirrhotic, treatment-naïve patients with chronic hepatitis C genotype 1, 2, 3 or 4 with 407 patients with genotype 1 or 4 chronic hepatitis C randomized into four dose groups: Lambda 240 µg (n=104), Lambda 180 µg (n=102), Lambda 120 µg (n=98) and alfa 180 µg (n=103), each administered weekly 48 weeks in combination with daily oral RBV. As of April 2011, all subjects who remained on 240 µg Lambda were reduced to 180 µg, the dose selected for further development. The primary endpoint of the study is the proportion of patients who achieved complete early virologic response (cEVR). HCV viral load and safety were assessed through 72 weeks (48-weeks on-treatment and 24-weeks post-treatment or to SVR₂₄). Results in patients with HCV genotype 2 or 3 were previously reported.

Virologic Response

In this study, at the dose selected for further development (180µg), Lambda/RBV achieved SVR₂₄ rates that were comparable to alfa/RBV, with a greater early virologic response as demonstrated by RVR and cEVR rates.

		Lambda 180 µg		Alfa 180 µg
RVR (undetectable viral load at week 4 on treatment)		14.7% (p<0.05)		5.8%
cEVR (undetectable viral load at week 12 on treatment)		55.9% (p<0.05)		36.9%
EOT (undetectable viral load at end of 48 weeks of treatment)		57.8%		56.3%
SVR24 (undetectable viral load 24 weeks post-treatment)		37.3%		36.9%

Safety Data

Treatment-related serious adverse events were reported in three patients who received Lambda at the 180 µg dose (one case each of hyperbilirubinemia, nausea/vomiting and anemia) and seven patients who received alfa (two cases of sarcoidosis and one case each of hyperbilirubinemia, depression/suicidal ideation, pneumonia, appendicitis and neutropenia). Compared to alfa, Lambda was associated with a reduced rate of interferon dose reductions (Lambda: 7.8%, 8/102 vs. alfa: 28.2%, 29/103) and ribavirin dose reductions (Lambda: 10.8%, 11/102 vs. alfa: 33.0%, 34/103 patients).
  
The most commonly reported adverse events at the Lambda 180 µg dose were fatigue (46.1%), headache (27.5%) and nausea (21.6%). Certain adverse events commonly associated with interferon alfa treatment were less frequently seen with Lambda than with alfa in this study. There was a greater than 2-fold difference in frequency between Lambda and alfa in the rate of flu-like symptoms and musculoskeletal symptoms.
  

Adverse Events of Special Interest		Lambda 180 µg n=102		Alfa 180 µg n=103
Musculoskeletal symptoms		15.7%		46.6%
Flu-like symptoms		12.7%		45.6%
Neurologic		33.3%		45.6%
Constitutional		46.1%		42.7%
Psychiatric		32.4 %		40.8%

Lambda was also associated with fewer hematologic abnormalities than alfa, and similar rates of elevated liver enzyme and total bilirubin levels.
  

Laboratory Abnormalities		Lambda 180 µg n=102		Alfa 180 µg n=103
Hematologics
Anemia (hemoglobin <9 g/dL or Δ ≥4.5 g/dL)		5.9%		31.1%
Hemoglobin-associated ribavirin reduction		0.0%		23.3%
Neutropenia (neutrophils <750/mm3)		1.0%		20.4%
Thrombocytopenia (platelets <50,000/ mm3)		0.0%		1.9%
Hematologic abnormality-associated interferon reduction		0.0%		20.4%
Liver-Related
AST and/or ALT > 5.0-10 x ULN		3.0%		6.8%
AST and/or ALT > 10 x ULN		0.0%		1.0%
Total bilirubin 2.6 - 5.0 x ULN		5.0%		3.9%
Total bilirubin > 5.0 x ULN		2.0%		1.0%

Efficacy and safety results for the Lambda 120 µg and 240 µg treatment groups were also presented at the AASLD annual meeting.

About Bristol-Myers Squibb’s Commitment to Liver Disease
Bristol-Myers Squibb is researching 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 compounds with different mechanisms of action, pursuing both biologics as well as small molecule direct-acting antivirals. These compounds are being studied as part of multiple treatment regimens with the goal of increasing SVR rates across diverse patient types and geographies.
  
Peginterferon lambda-1a is the first investigational type III interferon in Phase III development for the treatment of hepatitis C. Native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than native human interferon alfa proteins. Lambda receptors are present on fewer cell types within the human body than alfa receptors. This restricted distribution of the interferon lambda receptor offers the potential for more targeted delivery of interferon therapy. Lambda is in Phase III development for the treatment of chronic hepatitis C and in Phase II development for the treatment of chronic hepatitis B. The Company has studied Lambda in more than 950 people for the treatment of chronic hepatitis C and B.

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. 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 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 move from exploratory development into full product development, 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, 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 Defined as viral load below the lower limit of quantitation (HCV RNA < 25 IU/mL) at week 4 and undetectable viral load (HCV RNA <10 IU/mL) at week 12.

Contacts

Bristol-Myers Squibb Company

Media:
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AASLD-Bristol-Myers Squibb to Present New Data

Bristol-Myers Squibb to Present New Data Demonstrating Company’s Continuing Commitment to Research and Development in Liver Disease at The American Association for the Study of Liver Diseases (AASLD) Annual Meeting

• Late breaker oral presentation will feature first report of SVR₄ results from an interferon- and ribavirin-free, 12-week, triple DAA, investigational regimen of daclatasvir, asunaprevir and BMS-791325 in hepatitis C (HCV)

• Oral presentations on HCV investigational compounds daclatasvir, asunaprevir and peginterferon lambda-1a (Lambda) demonstrate diversity of portfolio
• Late breaker poster presentations will report Phase II data on Lambda in the treatment of HCV and chronic hepatitis B

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) announced today that 27 abstracts on the Company’s research in liver disease have been accepted for presentation at The Liver Meeting^® 2012, the 63^rd annual meeting of The American Association for the Study of Liver Diseases (AASLD), in Boston, November 9 – 13.

Bristol-Myers Squibb is studying a portfolio of compounds with the potential to address unmet medical needs for patients with liver disease, including the investigational compounds daclatasvir, asunaprevir, Lambda and BMS-791325 being studied in hepatitis C (HCV), Lambda being studied in hepatitis B (HBV), and BARACLUDE^® (entecavir). BARACLUDE is currently indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in aminotransferases (ALT or AST), or histologically active disease.

Key presentations include:

• A late breaker oral presentation of SVR₄ results with an interferon- and ribavirin (RBV)-free, 12-week regimen of daclatasvir, asunaprevir and BMS-791325 in a Phase II study of treatment-naïve patients with chronic HCV genotype 1

• An oral presentation of SVR₁₂ results with a regimen of daclatasvir and asunaprevir, with or without alfa interferon (alfa)/RBV, in a Phase II study of chronic HCV genotype 1 null responders
• A late breaker oral presentation on the first report of SVR₄ results from 12-week treatment arms of a Phase II study of daclatasvir and GS-7977, with or without RBV, in treatment-naïve patients with chronic HCV genotype 1, 2 or 3
• A late breaker poster presentation on SVR₁₂ results from the D-LITE Phase II study of Lambda in combination with RBV and either daclatasvir or asunaprevir in patients with chronic HCV genotype 1
• A late breaker poster presentation on Lambda versus alfa in a Phase II study of patients with chronic hepatitis B

“Bristol-Myers Squibb has a long-term commitment to viral hepatitis and has been at the forefront of the evolving science in both hepatitis B and C, where there remains considerable unmet medical need,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “In hepatitis C, we believe improving treatment outcomes requires a personalized approach to meet the needs of the diverse patient population. The data we are presenting at AASLD help expand our understanding of the potential efficacy and safety profiles of our investigational hepatitis C compounds and support our ongoing Phase III development programs.”
The Company will also show three presentations of outcomes research/real-world data that add to the understanding of the prevalence of and current treatment patterns in HBV, HCV and hepatocellular carcinoma (HCC).
The complete list of Bristol-Myers Squibb data presentations is below. Abstracts can be accessed on the AASLD website at http://aasld2012.abstractcentral.com/.

Title		Date/Time
Chronic Hepatitis B: BARACLUDE (entecavir) Clinical Data
Entecavir + Adefovir Versus Lamivudine + Adefovir Or Entecavir Alone In Lamivudine-Resistant Chronic Hepatitis B: 96-Week Data From The DEFINE Study		November 10, 2:00 – 7:30 p.m.
Antiviral Efficacy of Entecavir in Black/African American and Hispanic patients with Chronic Hepatitis B who are nucleos(t)ide-naïve		November 10, 2:00 – 7:30 p.m.
Randomized, observational study of long-term entecavir treatment versus other standard of care nucleos(t)ide analog therapy in nucleos(t)ide-naïve patients with chronic hepatitis B from a ‘real-world’ clinical practice setting in China		November 10, 2:00 – 7:30 p.m.
Disease and Treatment Perceptions Among Asian Americans Diagnosed with Chronic Hepatitis B Infection		November 10, 2:00 – 7:30 p.m.
Hepatitis C: Direct-Acting Antiviral Data
Sustained Virologic Response in Chronic HCV Genotype (GT) 1-Infected Null Responders With Combination of Daclatasvir (DCV; NS5A Inhibitor) and Asunaprevir (ASV; NS3 Inhibitor) With or Without Peginterferon Alfa- 2a/Ribavirin (PEG/RBV)		November 11, 4:45 – 5:00 p.m.
First Ever Successful Use of Daclatasvir and GS-7977, an Interferon-Free Oral Regimen, in a Liver Transplant Recipient with Severe Recurrent Hepatitis C		November 10, 2:00 – 7:30 p.m.
Comparison of Pre-Existing and Emerging Resistance-Associated Variants in US, EU and Japanese HCV Genotype 1b Prior Interferon Alfa (IFN-α) Non Responders and IFN-α Ineligible Patients Treated with Daclatasvir and Asunaprevir		November 11, 8:00 a.m. – 5:30 p.m.
Characterization of HCV NS5A Resistance Variants in Naive Patients Infected with Genotypes 2 and 3 Receiving Short-Term Treatment of Daclatasvir in Combination with Pegylated Interferon-Alfa and Ribavirin		November 11, 8:00 a.m. – 5:30 p.m.
Characterization of HCV Genotype 1 NS5A Resistance Variants From the Phase 2b COMMAND-1 Study: Daclatasvir Plus Peginterferon-alfa /ribavirin in Treatment-naive Patients		November 11, 8:00 a.m. – 5:30 p.m.
Twelve- or 16-Week Treatment With Daclatasvir Combined With Peginterferon Alfa and Ribavirin for Hepatitis C Virus Genotype 2 or 3 Infection: Command GT2/3 Study		November 11, 8:00 a.m. – 5:30 p.m.
Daclatasvir, an NS5A Replication Complex Inhibitor, Combined With Peginterferon Alfa-2a and Ribavirin in Treatment-Naive HCV-Genotype 1 or 4 Subjects: Phase 2b COMMAND-1 SVR12 Results		November 11, 8:00 a.m. – 5:30 p.m.
High Rate of Sustained Virologic Response with the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B inhibitor), With or Without Ribavirin, in Treatment-Naïve Patients Chronically Infected With HCV Genotype 1, 2, or 3		November 12, 3:15 – 3:30 p.m.
An Interferon-free, Ribavirin-free 12-Week Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 Yielded SVR4 of 94% in Treatment- Naïve Patients with Genotype (GT) 1 Chronic Hepatitis C Virus (HCV) Infection		November 12, 3:30 – 3:45 p.m.
Asunaprevir in Japanese Subjects in Phase 2: Exposure-Safety Versus US/EU-Based Subjects and Preliminary Assessment of Correlation with Single Nucleotide Polymorphisms (SNPs) in Liver Uptake Transporters		November 13, 8:00 a.m. – Noon
Effect of Hepatic Impairment on the Pharmacokinetics of Asunaprevir (BMS-650032, ASV)		November 13, 8:00 a.m. – Noon
Hepatitis C and B: PEG-Interferon Lambda Data
Peginterferon Lambda-1a (Lambda) is less likely to induce clinically significant neuropsychiatric symptoms during the treatment of chronic hepatitis C virus (HCV) infection, compared to Peginterferon alfa-2a (Alfa)		November 11, 8:00 a.m. – 5:30 p.m.
Peginterferon Lambda-1a (Lambda) is Associated With Less Autoimmune Thyroid Disease and Serious Autoimmune Disease Than Peginterferon Alfa- 2a (Alfa) When Used in Combination With Ribavirin (RBV) for the Treatment of Chronic Hepatitis C Virus Infection		November 11, 8:00 a.m. – 5:30 p.m.
Peginterferon Lambda, a New Potential Therapeutic Option for the Treatment of Chronic Hepatitis B: A Phase 2B Comparison with Peginterferon Alfa in Patients with HBeAg-Positive Disease		November 12, 8:00 a.m. – 5:30 p.m.
Sustained Virologic Response (SVR12) in HCV Genotype 1 Patients Receiving Peginterferon Lambda in Combination With Ribavirin and Either Daclatasvir or Asunaprevir: Interim Results From the D-LITE Study		November 12, 8:00 a.m. – 5:30 p.m.
Peginterferon Lambda–1a (Lambda) Compared to Peginterferon Alfa–2a (Alfa) in Treatment–Naïve Patients With HCV Genotypes (GT) 1 or 4: SVR24 Results From EMERGE Phase 2b		November 13, 8:45 – 9:00 a.m.
First Report of Peginterferon Lambda/Ribavirin in Combination With Either Daclatasvir or Asunaprevir in HCV Genotype 1 Japanese Subjects: Early Sustained Virologic Response (SVR4) Results From the D-LITE Japanese Sub-Study		November 13, Noon – 12:15 p.m.
Baseline CXCR3 Ligand Levels are Associated With Early Virologic Response to Treatment With Peginterferon Lambda-1a in Chronic Hepatitis C Patients in a Phase 2b Study		November 13, 8:00 a.m. – Noon
Pegylated Interferons Lambda-1a and Alfa-2a Display Different Gene Induction and Cytokine Release Profiles in Both Human Hepatocytes and Peripheral Blood Mononuclear Cells		November 13, 8:00 a.m. – Noon
Hepatitis C: Outcomes Research / Real-World Data
Genome-Wide Association Study to Identify Potential Single Nucleotide Polymorphisms Associated with Hepatocellular Carcinoma among Chronic Hepatitis C Patients		November 11, 8:00 a.m. – 5:30 p.m.
Reasons for Treatment (Tx) Discontinuation Among Hepatitis C (HCV) Patients Treated in Clinical Practice		November 13, 8:00 a.m.- Noon
Hepatocellular Carcinoma: Brivanib Data
Brivanib (BRI) versus Sorafenib (SOR) as First-line Therapy in Patients with Unresectable, Advanced Hepatocellular Carcinoma (HCC): Results from the Phase 3 BRISK-FL Study		November 12, 4:15 – 4:30 p.m.
Hepatocellular Carcinoma: Outcomes Research
Observations of Hepatocellular Carcinoma (HCC) Management Patterns from the Global HCC BRIDGE Study: Global Comparison of Outcomes by Locoregional Therapy		November 13, 8:00 a.m. – Noon

INDICATION and IMPORTANT SAFETY INFORMATION about BARACLUDE (entecavir) Tablets:

INDICATION BARACLUDE (entecavir) 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 (entecavir):

• 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 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 (entecavir) 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 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 (entecavir) 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.
• The safety and efficacy of BARACLUDE in liver transplant recipients are unknown. 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 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 (entecavir) 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.
BARACLUDE^® (entecavir) is a registered trademark of Bristol-Myers Squibb.

Bristol-Myers Squibb
Media:
Cristi Barnett, 609-252-6028
cristi.barnett@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com

Geno 1-4: Hepatitis C Drug Development Goes from Pony Ride to Rocket Launch

2012 pipeline report launched in Washington: HIV, HCV, TB, PEP, cure and vaccine research.

On July 21- 2012 HIV i-Base (U.K.) and Treatment Action Group (TAG) (U.S.) released their new comprehensive "2012 Pipeline Report"

The report is ready to view at the new website launched today by "TAG"

For the HCV community, there is a particular article in the report written by Tracy Swan and Karyn Kaplan you won't want to miss;

Hepatitis C Drug Development Goes from Pony Ride to Rocket Launch.
The in depth report includes some of the following topics; HCV drug resistance, DAA drug-drug interactions, nucleosides and nucleotide polymerase inhibitors, HCV protease inhibitors, the next generation of drugs, HCV quad therapy, SVR-4 ,SVR-12, interferon free therapy, ABT-450/r, ACH-1625, BI 201335, bms-650032, bms-790052, Danoprevir, genotypes 1-4, GS-7977 Formally/PSI-7977, GS-9256, Lambda, MK-7009, TMC435 and much more....

The 2012 Pipeline Report: HIV, Hepatitis C Virus (HCV), and Tuberculosis (TB) Drugs, Diagnostics, Vaccines, and Preventive Technologies in Development by Polly Clayden, Simon Collins, Colleen Daniels, Nathan Geffen, Mark Harrington, Richard Jefferys, Coco Jervis, Karyn Kaplan, Erica Lessem, and Tracy Swan is available online at:
http://www.treatmentactiongroup.org/pipeline-report/2012
and as an interactive web report at:
http://www.pipelinereport.org.

EASL-Interferon Lambda Beats Alfa in Clearing HCV Genotype 2 or 3

From Medscape Medical News

Interferon Lambda Beats Alfa in Clearing HCV Genotype 2 or 3
Daniel M. Keller, PhD

April 27, 2012 (Barcelona, Spain) — In a phase 2b study of treatment-naive adults with chronic hepatitis C virus (HCV) infection, pegylated interferon-lambda was more effective and safer than interferon-alfa in eliminating the virus in patients infected with HCV genotypes 2 or 3. The study is the first report of sustained virologic response with lambda.

Stefan Zeuzem, MD, professor of medicine and chief of the Department of Medicine I at the J.W. Goethe University Hospital in Frankfurt, Germany, who presented the results here at the International Liver Congress 2012, showed data demonstrating that 180 μg of lambda, compared with alfa, produced a more rapid virologic response and a greater sustained virologic response at 24 weeks (SVR24), and was associated with fewer adverse events and less need for a dose reduction of lambda and of the accompanying ribavirin.

Treatment of chronic HCV with alfa interferons and ribavirin is limited by hematologic toxicity and other adverse effects. Lambda has marked activity against HCV and a restricted distribution of receptors in the body, which could make organ systems outside the liver less susceptible to its effects.

Dr. Zeuzem and colleagues performed a blinded randomized study of 526 noncirrhotic treatment-naive HCV-infected adults, 18 to 70 years of age, 118 of whom were chronically infected with genotype 2 or 3 and had HCV RNA levels of at least 100,000 IU/mL. The genotype 2/3 patients received daily ribavirin and weekly doses of lambda 120 μg (n = 29), 180 μg (n = 29), or 240 μg (n = 30) for 24 weeks. Other patients (n = 30) received daily ribavirin plus alfa 180 μg weekly for 24 weeks.
At baseline, the 4 groups were similar in age (range, 48.1 to 50.6 years), sex (range, 52% to 70% male), body mass index (range, 27.8 to 29.0 kg/m²), and viral load (range, 6.42 to 6.66 log₁₀ IU/mL). Most participants were white (range, 76.7% to 89.7%). The proportion of genotype 2 patients was 41.4% in the 120 μg group, 58.6% in the 180 μg group, 53.3% in the 240 μg group, and 50% in the alfa group. A large majority of patients in each group had low liver fibrosis scores.

Lambda Effective With Fewer Adverse Events
Lambda/ribavirin treatment was associated with an early and rapid drop in HCV RNA in a dose-dependent manner. After 2 weeks of treatment, the greatest reductions were seen with the 180 μg and 240 μg doses. All 3 doses of lambda produced more rapid decreases in virus level than alfa/ribavirin. The 180 μg dose will be used going forward in phase 3 trials.

HCV RNA was undetectable at week 4 in 75.9% of patients in the 180 μg group and in 30.0% in the alfa group (P < .05). Complete early virologic response (meaning HVC RNA was detectable at week 4 but not at week 12) and SVR24 were somewhat better with lambda than with alfa, but the difference was not statistically significance. In the lambda groups, 96.6% of patients achieved a complete early virologic response and 75.9% achieved SVR24.

With lambda 180 μg, 70.6% of genotype 2 patients achieved SVR24, as did 83.3% of genotype 3 patients.

Relapse rates, defined as an HCV RNA level of 25 IU/mL or greater during the follow-up period, were low, at about 21% in the lambda 180 μg group and about 25% in the alfa group.
Although all groups experienced a high level of adverse events (in the range of about 95%), some long associated with alfa therapy — "in particular, flu-like symptoms...such as myalgia, arthralgia, pyrexia, and chills" — were significantly lower in the lambda groups (7% to 17% in the 180 μg group) than in the alfa group (20% to 33%). Flu-like symptoms were definitely lower in all 3 lambda groups (20.7% for 180 μg) than in the alfa group (40%), Dr. Zeuzem said, as were musculoskeletal symptoms (20.7% vs 63.3%).

However, the prevalence of psychiatric adverse events (e.g., depression, irritability, or insomnia) was greater in the lambda groups than in the alfa group (41.4% vs 33.3%).
There were no discontinuations because of adverse events in the 180 μg group, but 6.7% dropped out of the alfa group. In the lambda groups, there were dose reductions in lambda or ribavirin at a rate of 6.9% for each; in the alfa group, there were dose reductions at rates of 26.7% for alfa and 43.3% for ribavirin.

Serious adverse events affected less than 4% of patients in the 180 μg and alfa groups. There were no serious adverse events directly related to treatment in the lambda groups.
It has been reported that lambda causes elevations in serum bilirubin, but in this trial at the 180 μg dose, there was only 1 patient (3.4%) with bilirubin elevation (in the range of 1.6 to 2.5 times the upper limit of normal).

There were no reductions in neutrophil or platelet counts associated with any dose of lambda. There were drops in both in the alfa group as long as therapy continued. Low hemoglobin (below 10 g/dL, or a drop of at least 3.4 g/dL), often associated with alfa/ribavirin, occurred in 44.8% of the alfa group and necessitated a ribavirin dose reduction in 23.3% of patients. Hemoglobin levels did not drop as much in the 180 μg group; only 6.9% were classified as having low hemoglobin, and none required a ribavirin dose reduction.

Session moderator George Papatheodoridis, MD, associate professor of medicine and gastroenterology at the Medical School of Athens University and Hippokration General Hospital in Greece, and a member of the Governing Board Scientific Committee of the European Association for the Study of the Liver (EASL), summarized the findings for Medscape Medical News.

"It seems that the efficacy of interferon lambda might be slightly higher [than alfa], but definitely we can say that the safety profile is better.... The only side effect that was higher, and we cannot explain that, is the psychiatric side effects," he said.

In light of a robust pipeline of oral drugs now in development, Dr. Papatheodoridis said the use of interferons could be fairly limited in the treatment of HCV in the future. "I don't know what role interferon lambda may find when and if it gets licensed. After 2 or 3 years, it is possible that most of the patients will be treated with interferon-free regimens," he explained.

Mark Thursz, MD, professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, and secretary general of the EASL, alluded to this point during a news conference, drawing attention to the safety profile of lambda. Patients receiving ribavirin typically show a drop in hemoglobin, "but there's a smaller drop...in the lambda- than in the alfa-treated patients," he said. "More important are these data on neutrophils and platelets.... You can see no drop in patients who were treated with the lambda interferon.... For patients who still need an interferon and in whom problems with cell counts are going to be an issue, this is a solution."

Dr. Papatheodoridis noted that the bilirubin increase seen with lambda probably does not indicate any damage to the liver, but is perhaps the effect of "this interferon on the enzymes that are involved in the metabolism of bilirubin, which is not very dangerous; it's a lab finding without major clinical significance."

Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX, Janssen, Merck, Novartis, Presidio Pharmaceuticals, Roche, Santaris, and Vertx Pharmaceuticals. Dr. Papatheodoridis and Dr. Thursz have disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 10. Presented April 19, 2012.

EASL-Peginterferon Lambda Achieved SVR24 Rates Comparable to Peginterferon Alfa with Fewer Side-Effects

Investigational Compound Peginterferon Lambda Achieved SVR24 Rates Comparable to Peginterferon Alfa with Fewer Flu-Like and Musculoskeletal Symptoms in Phase IIb Study in Treatment-Naïve Genotype 2 or 3 Hepatitis C Patients

.

• First report of sustained virologic response (SVR) results for Lambda interferon
• Numerically greater virologic response rates consistent at 4 weeks (RVR*), throughout treatment, and maintained through SVR₂₄ in Lambda 180 µg dose versus alfa

• Data presented at The International Liver Congress in Barcelona

.

PRINCETON, N.J.--(BUSINESS WIRE)--Apr 19, 2012 - Bristol-Myers Squibb Company (NYSE: BMY) today announced results from the Phase IIb EMERGE clinical trial in 118 treatment-naïve patients chronically infected with genotype 2 or 3 hepatitis C virus (HCV). In this study, the investigational compound peginterferon lambda-1a (Lambda) plus ribavirin (RBV) achieved sustained virologic response rates 24 weeks post-treatment (SVR₂₄) that were comparable to peginterferon alfa-2a (alfa) plus ribavirin. Rates of SVR₂₄ ranged from 60.0% to 75.9% in the Lambda/RBV arms versus 53.3% in the alfa/RBV arm (n=30). The 180 µg dose arm of Lambda/RBV achieved SVR₂₄ in 75.9% (n=29) and was the dose selected for phase III clinical trials.

In this study, adverse events were mostly low grade and self-limited. Overall, rates of serious adverse events and adverse events were similar across treatment arms up to SVR₂₄. There were fewer flu-like and musculoskeletal symptoms in the Lambda/RBV arms. Additionally, lower rates of anemia, neutropenia, and thrombocytopenia were observed and there were fewer interferon and ribavirin dose reductions for anemia in the Lambda/RBV arms. Two (2) cases of hyperbilirubinemia >5x the upper limit of normal (ULN) were observed in the Lambda 240 µg dose arm and zero (0) cases of hyperbilirubinemia >5x the upper limit of normal (ULN) were observed in the Lambda 180 µg, Lambda 120 µg, and alfa arms.

These EMERGE study findings in hepatitis C genotype 2 and 3 patients were presented in an oral session at the International Liver Congress (ILC), the 47^th annual meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain.

“There is a significant unmet medical need for antiviral therapies that can benefit more hepatitis C patients with a goal of decreasing treatment-related adverse events and potentially reducing treatment duration," said Stefan Zeuzem, MD, chief of the department of medicine and professor of medicine at the Goethe University Hospital in Frankfurt, Germany. "The EMERGE study results of peginterferon lambda versus peginterferon alfa in patients infected with HCV genotype 2 or 3 demonstrate that peginterferon lambda, in combination with ribavirin, may have the potential to help address these unmet needs, and these data support further studies of this investigational Lambda interferon.”

Study Results
Viral Response
The primary endpoint of the study was the proportion of patients with complete early virologic response (cEVR^¡). Treatment with all doses of Lambda achieved cEVR rates similar to alfa (Lambda 240 µg: 86.7%, Lambda 180 µg: 96.6%, Lambda 120 µg: 89.7%, and alfa: 86.7%). Higher rates of RVR were achieved in the Lambda arms [Lambda 240 µg: 66.7% (p<0.05), Lambda 180 µg: 75.9% (p<0.05), Lambda 120 µg: 44.8% vs. alfa: 30%]. In patients with HCV genotypes 2 and 3, treatment with all doses of Lambda achieved SVR₂₄ rates similar to PEG-Interferon alfa [Lambda 240 µg: 60.0% (n=30), Lambda 180 µg: 75.9% (n=29), Lambda 120 µg: 65.5% (n=29), and alfa: 53.3%, (n=30)].

Safety
Overall, the rates of serious adverse events and adverse events were similar across treatment arms up to SVR₂₄. In this study, there were some differences seen in the relative frequency of adverse events between lambda and alfa. Some of the adverse events commonly associated with interferon treatment such as flu-like symptoms (Lambda 240 µg: 23.3%; Lambda 180 µg: 20.7%; Lambda 120 µg: 17.2%; alfa: 40.0%), musculoskeletal symptoms (Lambda 240 µg: 16.7%; Lambda 180 µg: 20.7%; Lambda 120 µg: 27.6%; alfa: 63.3%), constitutional symptoms such as fatigue (Lambda 240 µg: 50.0%; Lambda 180 µg: 27.6%; Lambda 120 µg: 41.4%; alfa: 53.3%), neutropenia < 750/mm³ (Lambda 180 µg: 0.0%, n=29; alfa: 27.5%, n=30), anemia with hemoglobin < 10 g/dL or a decline of > 3.4g/dL (Lambda 180 µg: 6.9%, n=29; alfa: 44.8%, n=30), and thrombocytopenia < 100,000/mm³ (Lambda 180 µg: 0.0%, n=29; alfa: 24.1%, n=30) were less frequently seen with Lambda than with alfa. Some others such as psychiatric (Lambda 240 µg: 40.0%; Lambda 180 µg: 41.4%; Lambda 120 µg: 44.8%; alfa: 33.3%) and neurologic (Lambda 240 µg: 36.7%; Lambda 180 µg: 24.1%; Lambda 120 µg: 27.6%; alfa: 33.3%) adverse events were similar across groups.
The proportion of patients that required interferon dose reductions were: Lambda 240 µg: 13.3%; Lambda 180 µg: 6.9%; Lambda 120 µg: 6.9%; alfa: 26.7%, and the proportion of patients that required withheld and/or reduced ribavirin were: Lambda 240 µg: 23.3%; Lambda 180 µg: 6.9%; Lambda 120 µg: 24.1%; alfa: 43.3%. The proportion of patients who required ribavirin dose reductions for low hemoglobin were: Lambda 240 µg: 0.0%; Lambda 180 µg: 0.0%; Lambda 120 µg: 0.0%; alfa: 23.3%.

The proportion of patients with elevated liver enzymes [AST or ALT > 10x the upper limit of normal (ULN)] were: Lambda 240 µg: 3.3%; Lambda 180 µg: 0.0%; Lambda 120 µg: 0.0%; alfa: 0.0%. Total bilirubin was also elevated > 5.0x ULN in the highest-dose Lambda treatment arm compared with PEG-Interferon alfa (Lambda 240 µg: 6.7%; Lambda 180 µg: 0.0%; Lambda 120 µg: 0.0%; alfa: 0.0%); all resolved following interferon dose modification and/or discontinuation.

About the EMERGE Phase IIb Study
The EMERGE study is a two-part, randomized, controlled, multicenter, phase II study of peginterferon lambda-1a in treatment-naïve patients with chronic hepatitis C genotype 1, 2, 3 or 4. Part one of EMERGE was a Phase IIa study, and results were previously presented at The American Association for the Study of Liver Diseases (AASLD) 2010 Liver Meeting.

Part two of EMERGE is an ongoing, blinded Phase IIb study designed to evaluate the safety, efficacy, and pharmacokinetics of Lambda versus alfa, both in combination with ribavirin. In the study, the 526 non-cirrhotic patients were randomized into four dose groups: Lambda 240 µg, Lambda 180 µg, Lambda 120 µg, and alfa 180 µg. Of the 526 patients, 118 patients with genotype 2 or 3 chronic hepatitis C were randomized into four dose groups: Lambda 240 µg (n=30), Lambda 180 µg (n=29), Lambda 120 µg (n=29) and alfa 180 µg (n=30). The results for these 118 patients were presented today at The International Liver Congress 2012.

Phase IIb RVR and cEVR results for genotypes 1, 2, 3, and 4 were previously presented at The International Liver Congress in 2011. The study continued for 24 weeks in genotype 2 and 3 patients and will continue for 48 weeks in genotype 1 and 4 patients. The primary endpoint of the study is the proportion of patients who achieve complete early virologic response (cEVR). HCV RNA and safety were assessed through 48 weeks (24-weeks on-treatment and 24-weeks post-treatment or to SVR₂₄).

About Bristol-Myers Squibb's Commitment to Liver Disease
Bristol-Myers Squibb is researching 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. Peginterferon lambda-1a is the first investigational type III interferon in Phase IIb development for the treatment of hepatitis C. Native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than native human interferon alfa proteins. Lambda receptors are present on fewer cell types within the human body than alfa receptors. This restricted distribution of the interferon lambda receptor offers the potential for more targeted delivery of interferon therapy.

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. 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 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 move from exploratory development into full product development, 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, 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.

^* Rapid virologic response (RVR): undetectable viral load (HCV RNA <25 IU/mL) at week 4
Sustained Virologic Response 24 or SVR₂₄: undetectable viral load 24 weeks post-treatment, demonstrative of cure

^¡ Complete Early Virologic Response or cEVR: undetectable viral load at week 12

Contact: Bristol-Myers Squibb

Media:
Cristi Barnett, 609-252-6028
cristi.barnett@bms.com
or
Investors:
John Elicker, 609-252-4611
john.elicker@bms.com

PEG-Interferon Lambda Phase 2a Interim Clinical Trial Results at AASLD 2010

ZymoGenetics and Bristol-Myers Squibb to Present PEG-Interferon Lambda Phase 2a Interim Clinical Trial Results at AASLD 2010

SEATTLE & PRINCETON, N.J.--

(BUSINESS WIRE)--

ZymoGenetics, Inc. and Bristol-Myers Squibb Company announced that interim results from Phase 2a of the EMERGE clinical trial of PEG-Interferon lambda administered with ribavirin in treatment-naïve hepatitis C virus patients, will be presented at the American Association for the Study of Liver Diseases (AASLD) annual meeting in Boston, October 29 – November 2, 2010.

PEG-Interferon lambda abstracts, including clinical, pharmacokinetic and viral kinetic data along with in vitro data in combination with direct-acting antiviral agents, were published today and are available on the AASLD website at http://www.aasld.org/ .


AASLD 2010 PEG-Interferon lambda Poster Presentations

Title: Pegylated Interferon Lambda (PEG-IFN-λ) Phase 2 Dose-Ranging, Active-Controlled Study in Combination with Ribavirin (RBV) for Treatment-Naïve HCV Patients (Genotypes 1, 2, 3, or 4): Safety, Viral Response, and Impact of IL-28B Host Genotype through Week 12
Abstract: 821
Presenter: A.J. Muir
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM

Title: Pharmacokinetics of PEG-Interferon lambda (PEG-IFN-λ) Following Fixed Dosing in Treatment-Naïve Hepatitis C Subjects (Single Dose Interim Data from a Dose-Ranging Phase 2A Study)
Abstract: 830
Presenter: K.A. Byrnes-Blake
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM

Title: The Effect of Treatment Group, HCV Genotype, and IL28B Genotype on Early HCV Viral Kinetics in a Phase 2A Study of PEG-Interferon lambda (PEG-IFN-λ) in Hepatitis C Patients
Abstract: 831
Presenter: J.A. Freeman
Date: Sunday, October 31, 2010
Time: 8:00 AM – 5:30 PM

Title: In vitro activity of the combination of pegylated interferon lambda (PEG-IFN-λ) with direct-acting antivirals in the HCV replicon model
Abstract: 1854
Presenter: F. McPhee
Date: Tuesday, November 2, 2010
Time: 7:00 AM - 12:00 PM

About PEG-Interferon lambda

PEG-Interferon lambda (IL-29) is a novel and first in class interferon in development for hepatitis C. The native human interferon lambda proteins are generated by the immune system in response to viral infection, and signal through a different receptor than type I interferons, such as interferon alpha. Because this receptor is present on fewer cell types within the human body, it is hypothesized that PEG-Interferon lambda may be able to demonstrate an improved safety and tolerability profile compared to alpha interferons.

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 www.bms.com or follow us on Twitter at http://twitter.com/bmsnews .

About ZymoGenetics

ZymoGenetics is a biopharmaceutical company focused on the development and commercialization of therapeutic proteins for the treatment of human diseases. The company developed and is marketing RECOTHROM® Thrombin, topical (Recombinant) in the United States. ZymoGenetics has two product candidates in Phase 2 clinical development: PEG-Interferon lambda, being studied in collaboration with Bristol-Myers Squibb for treatment of hepatitis C virus infection, and IL-21, being tested as a potential treatment for metastatic melanoma. In addition, ZymoGenetics has an anti-IL-31 monoclonal antibody in preclinical development, which it expects to test initially as a treatment for atopic dermatitis. Several of the product candidates previously identified through ZymoGenetics’ discovery research efforts have been licensed to and are being developed by third parties, including Merck Serono and Novo Nordisk. ZymoGenetics is eligible to receive milestone payments and royalties related to these assets. For further information, visit www.zymogenetics.com.

Bristol-Myers Squibb Forward-Looking Statements

This press release contains "forward-looking statements" relating to the acquisition of ZymoGenetics by Bristol-Myers Squibb. 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 acquisition will be completed, or if it is completed, that it will close within the anticipated time period. Forward-looking statements in the 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, 2009, its Quarterly Reports on Form 10-Q, and 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.

Except for the historical information presented herein, matters discussed herein may constitute forward-looking statements that are subject to certain risks and uncertainties that could cause actual results to differ materially from any future results, performance or achievements expressed or implied by such statements. Statements that are not historical facts, including statements preceded by, followed by, or that include the words “future”; “anticipate”; “potential”; “believe”; or similar statements are forward-looking statements. Risks and uncertainties include uncertainties as to the timing of the tender offer and merger; uncertainties as to how many of the ZymoGenetics shareholders will tender their shares in the offer; the risk that competing offers will be made; the possibility that various closing conditions for the transaction may not be satisfied or waived, including that a governmental entity may prohibit, delay or refuse to grant approval for the consummation of the transaction; the effects of disruption from the transaction making it more difficult to maintain relationships with employees, licensees, other business partners or governmental entities; as well as risks detailed from time to time in ZymoGenetics’ public disclosure filings with the SEC, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2009, subsequent quarterly filings on Form 10-Q and the Solicitation/Recommendation Statement filed in connection with the tender offer. The information contained in this release is as of September 28, 2010.

This press release is neither an offer to purchase nor a solicitation of an offer to sell shares of ZymoGenetics. Bristol-Myers Squibb Company and Zeus Acquisition Corporation have filed a tender offer statement with the SEC, and have mailed an offer to purchase, forms of letter or transmittal and related documents to ZymoGenetics shareholders. ZymoGenetics has filed with the SEC, and has mailed to ZymoGenetics shareholders a solicitation/recommendation statement on Schedule 14D-9. These documents contain important information about the tender offer and stockholders of ZymoGenetics are urged to read them carefully when they become available.

These documents will be available at no charge at the SEC's website at www.sec.gov. The tender offer statement and the related materials may be obtained for free by directing a request by mail to Georgeson Inc., 199 Water Street, 26th Floor, New York, New York 10038 or by calling toll-free 800-491-3096. In addition, a copy of the offer to purchase, letter or transmittal and certain other related tender offer documents (once they become available) may also be obtained free of charge from Bristol-Myers Squibb by directing a request to: Public Affairs, Telephone No.: 609-252-6579; E-Mail: jennifer.mauer@bms.com.

ZymoGenetics Forward-Looking Statement

This press release contains forward-looking statements, including statements related to conducting and analyzing the results of clinical trials. Phrases such as “look forward” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon ZymoGenetics’ current expectations and involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, risks related to ZymoGenetics’ ability to design and conduct clinical trials, the possibility that clinical trial results may vary between different arms of a clinical trial and the difficulty of using prior clinical trial results to predict future outcomes, as well as those other risks detailed in ZymoGenetics’ filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the year ended December 31, 2009 and periodic reports on Form 10-Q and current reports on Form 8-K. Do not place undue reliance on these forward-looking statements, which speak only as of the date of this press release. All forward-looking statements are qualified in their entirety by this cautionary statement, and, except where required by law, ZymoGenetics undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this press release.

PEGASYS® (Peginterferon alfa-2a) is a registered trademark of Hoffmann-La Roche

Contact:
Bristol-Myers SquibbMediaCristi Barnett, 609-252-6028cristi.barnett@bms.comorInvestors

John Elicker, 609-252-4611john.elicker@bms.com orZymoGeneticsMedia and InvestorsSusan W. Specht 206-442-6592spechts@zymogenetics.com