Pegylated Interferon Lambda Boosts Response with Few Side Effects

Current standard therapy for chronic hepatitis C virus (HCV) infection, pegylated interferon alfa (Pegasys or PegIntron) plus ribavirin, cures only about half of people with hard-to-treat HCV genotype 1 and can cause difficult side effects including flu-like symptoms, depression, and loss of red and white blood cells (anemia and neutropenia, respectively).

Interferon lambda is a cytokine (chemical messenger) produced by immune cells in response to viral infection; as a type III interferon, it uses a different signalling pathway than type I interferons such as interferon alfa. Because interferon lambda uses a receptor present on fewer types of cells, it is predicted to have better tolerability.

At the European Association for the Study of the Liver's International Liver Congress (EASL 2011) last week in Berlin researchers presented findings from a Phase 2b trial comparing pegylated interferon lambda vs pegyalted interferon alfa in more than 500 chronic hepatitis C patients with various HCV genotypes.

Below is an edited excerpt from a press release issued by interferon lambda develop Bristol-Myers Squibb describing the study and its findings.

Investigational Compound PEG-Interferon Lambda Achieved Higher Response Rates with Fewer Flu-Like and Musculoskeletal Symptoms and Cytopenias Than PEG-Interferon Alfa in Phase IIb Study of 526 Treatment-Naive Hepatitis C Patients

	Higher virologic response rates achieved at 4 weeks (RVR) and maintained through 12 weeks of treatment (cEVR) across all genotypes studied
	Data presented at The International Liver Congress in Berlin

Princeton, N.J. -- April 2, 2011 -- Bristol-Myers Squibb Company (NYSE: BMY) today announced results from the Phase IIb EMERGE clinical trial, in which treatment with the investigational compound PEG-Interferon lambda and ribavirin achieved higher rates of rapid virologic response (RVR) [undetectable viral load (HCV RNA <25 IU/mL) at week 4] in genotypes 1, 2, 3, and 4, and complete early virologic response (cEVR) [undetectable viral load at week 12] in genotypes 1 and 4 than the standard regimen of PEG-Interferon alfa and ribavirin in treatment-naive patients chronically infected with hepatitis C (HCV).

In this study, there were fewer flu-like and musculoskeletal symptoms and cytopenia [blood cell deficiency], as well as fewer interferon and ribavirin dose reductions for anemia in the PEG-Interferon lambda arms up to 12 weeks. Rates of serious adverse events, depression and other common adverse events (incidence > 10%) were similar across treatment arms up to week 12.

The EMERGE study findings were presented in a late-breaker oral session at the International Liver Congress (ILC), the 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany.

"There is a significant unmet medical need for more therapies that can benefit more hepatitis C patients. This is especially true for patients with HCV genotypes 1 and 4, who generally have lower response rates to treatment with PEG-Interferon alfa and ribavirin than patients with other genotypes," said Stefan Zeuzem, MD, chief of the department of medicine and professor of medicine at the Johann Wolfgang Goethe University Hospital in Frankfurt, Germany. "The EMERGE study results demonstrate that PEG-Interferon lambda may have the potential to help address this unmet need, and support further studies of this new type of investigational interferon."

PEG-Interferon lambda is the first investigational type III interferon. Interferon lambda mediates antiviral activity through a receptor that is distinct from that used by interferon alfa and is present on fewer cell types within the tissues of the body. This restricted distribution of the interferon lambda receptor offers the potential for more targeted delivery of interferon therapy.

Study Results

Viral Response: HCV Genotypes 1 and 4

In this study, HCV genotype 1 and 4 patients treated with PEG-Interferon lambda achieved statistically significant (p<0.05) higher rates of cEVR (primary study endpoint) versus PEG-Interferon alfa at all doses [lambda 240 mcg: 56.3% (n=103), lambda 180 mcg: 55.9% (n=102), lambda 120 mcg: 55.0% (n=100) vs. alfa: 37.9% (n=103)]. These statistically significant (p<0.05) higher viral response rates were seen as early as four weeks of treatment, with greater rates of RVR at the two higher doses of PEG-Interferon lambda (lambda 240 mcg: 16.5%, lambda 180 mcg: 14.7%, lambda 120 mcg: 6.0% vs. alfa: 5.8%).

Viral Response: HCV Genotypes 2 and 3

In patients with HCV genotypes 2 and 3, treatment with all doses of PEG-Interferon lambda achieved cEVR rates similar to PEG-Interferon alfa [lambda 240 mcg: 83.3% (n=30), lambda 180 mcg: 96.6% (n=29), lambda 120 mcg: 90% (n=30), and alfa: 86.2%, (n=29)]. Statistically significant (p<0.05) higher rates of RVR were achieved at the two higher doses of PEG-Interferon lambda (lambda 240 mcg: 66.7%, lambda 180 mcg: 75.9%, lambda 120 mcg: 43.3% vs. alfa: 31%).

Safety

In this study, rates of adverse events commonly associated with interferon treatment were lower with PEG-Interferon lambda than with PEG-Interferon alfa. These adverse events included flu-like symptoms (lambda 240 mcg: 9.7%; lambda 180 mcg: 9.9%; lambda 120 mcg: 12.5%; alfa: 42.9%), musculoskeletal symptoms (lambda 240 mcg: 14.2%; lambda 180 mcg: 14.5%; lambda 120 mcg: 18.0%; alfa: 46.6%), neutropenia < 750/mm3 (lambda 240 mcg: 0.0%; lambda 180 mcg: 0.8%; lambda 120 mcg: 0.0%; alfa: 15.2%), anemia with hemoglobin < 10 g/dL (lambda 240 mcg: 12.9%; lambda 180 mcg: 15.4%; lambda 120 mcg: 20.5%; alfa: 43.9%.) and thrombocytopenia < 50K/mm3 (lambda 240 mcg: 0.0%; lambda 180 mcg: 0.0%; lambda 120 mcg: 0.0%; alfa: 14.4%).

The proportion of patients that required interferon dose reductions were: lambda 240 mcg: 12.7%; lambda 180 mcg: 3.8%; lambda 120 mcg: 0.8%; alfa: 18.8%, and the proportion of patients that withheld and/or reduced ribavirin were: lambda 240 mcg: 11.2%; lambda 180 mcg: 4.6%; lambda 120 mcg: 10.2%; alfa: 20.3%. The proportion of patients who required ribavirin dose reductions for anemia were: lambda 240 mcg: 0.7%; lambda 180 mcg: 1.5%; lambda 120 mcg: 2.3%; alfa: 12.8%.

Rates of serious adverse events, depression and other common adverse events (> 10%) were similar across treatment arms. Higher rates of elevated liver enzymes [AST or ALT >5x the upper limit of normal (ULN)] were seen in the highest-dose PEG-Interferon lambda treatment arm compared with PEG-Interferon alfa (lambda 240 mcg: 17.4%; lambda 180 mcg: 2.3%; lambda 120 mcg: 0.8%; alfa: 7.6%), and direct bilirubin was also elevated (>1.2 mg/dL) in the highest-dose PEG-Interferon lambda treatment arm compared with PEG-Interferon alfa (lambda 240 mcg: 7.6%; lambda 180 mcg: 3.9%; lambda 120 mcg: 0.8%; alfa: 0.8%); all resolved spontaneously without sequelae or 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 PEG-Interferon lambda in 526 treatment-naive 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 PEG-Interferon lambda vs. PEG-Interferon alfa, both in combination with ribavirin. The 526 patients were randomized into four dose groups: PEG-Interferon lambda 240 mcg (n=134), PEG-Interferon lambda 180 mcg (n=131), PEG-Interferon lambda 120 mcg (n=128) and PEG-Interferon alfa 180 mcg (n=133).

The study will continue for 48 weeks in genotype 1 and 4 patients and 24 weeks in genotype 2 and 3 patients. The primary endpoint of the study is the proportion of patients who achieve complete early virologic response (cEVR).

About PEG-Interferon lambda

PEG-Interferon lambda 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 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.

4/5/11

Reference
S Zeuzem, S Arora, B Bacon, et al. Pegylated interferon-lambda (pegIFN-[lambda]) shows superior viral response with improved safety and tolerability versus pegIFN-[alpha]-2a in HCV patients (G1/2/3/4): EMERGE phase IIb through week 12. 46th Annual Meeting of the European Association for the Study of the Liver (EASL 2011). Berlin. March 30-April 3. Abstract 422.

Other Source
Bristol-Myers Squibb. Investigational Compound PEG-Interferon Lambda Achieved Higher Response Rates with Fewer Flu-Like and Musculoskeletal Symptoms and Cytopenias Than PEG-Interferon Alfa in Phase IIb Study of 526 Treatment-Naive Hepatitis C Patients. Press release. April 2, 2011.