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 (SVR 12) 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 SVR 4 results from the D-LITE Japanese sub-study, where all subjects were infected with HCV genotype 1b and SVR 12 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 developmentD-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 SVR 24. The interim SVR 12 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 SVR 12 after 24 weeks of treatment. Response rates were higher in genotype 1b patients, with 93% (13/14) of genotype 1b patients achieving SVR 12 and 65% (15/23) of genotype 1a patients achieving SVR 12. The Company also presented SVR 12 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 SVR 4 and SVR 12. Based on these study results, the combination regimen of Lambda/RBV/DCV will move into Phase III development.
Safety DataIn 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 SVR 24). 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 SVR 24 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%|
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|
|Laboratory Abnormalities||Lambda 180 µg n=102||Alfa 180 µg n=103|
|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%|
|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%|
About Bristol-Myers Squibb’s Commitment to Liver DiseaseBristol-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.