IFN-lambda and type 1 IFNs induce antiviral activity through STAT1/STAT2 Pathway

PEG-Interferon lambda (PEG-IFN-λ, PEG-IL-29)

PEG-IFN lambda is a unique, novel Interferon with the potential to become the new treatment of choice for patients with Hepatitis C

PEG-Interferon lambda induces antiviral activity against Hepatitis C virus (HCV) through a unique receptor that activates the same signaling pathway as Interferon alpha (the current standard of care for patients with hepatitis C), but with a more restricted distribution than the Interferon alpha receptor. PEG-Interferon lambda is currently being tested as a single agent and in combination with ribavirin in a Phase 1b study in patients with genotype 1 who have relapsed after treatment with IFN alpha. Results from the Phase 1b trial showed that PEG-Interferon lambda as single agent reduced viral load without side effects typically seen with Interferon alpha.

On January 12, 2009, ZymoGenetics and Bristol-Myers Squibb Company (NYSE:BMY) announced a global collaboration for PEG-Interferon lambda.

Background

Native Interferon lambda is a member of the Type III Interferon family and is generated by the immune system in response to viral infection. Interferon lambda induces antiviral activity through the same intracellular signaling pathway as Interferon alpha and should consequently have similar anti-viral activity as Interferon alpha. The receptor for Interferon lambda, however, is distinct from the receptor used by Interferon alpha and is present on fewer cell types within the tissues of the body that are important sites of viral infection, including hepatocytes in the liver. The receptor for Interferon lambda is expressed at low levels on hematopoietic cells compared to the receptor for Interferon alpha. This restricted receptor distribution pattern has the potential to result in a more favorable safety profile for Interferon lambda than for Interferon alpha with fewer and less severe side effects. ZymoGenetics is developing a pegylated recombinant version of Interferon lambda (PEG-IFN lambda) for the treatment of patients with HCV.

Clinical Trials

ZymoGenetics completed and presented data from a Phase 1a single-dose, single-agent study designed to evaluate the safety and tolerability of PEG-IFN lambda in healthy subjects. Fever, fatigue, insomnia, and irritability were not observed at any dose level. No significant hematologic changes, including neutropenia, were observed. Liver enzyme increases were noted at higher doses. Injection site pain or reactions were not observed. These data demonstrated that PEG-IFN lambda was well-tolerated at pharmacologically active doses, supporting the decision to go forward and initiate studies in patients with HCV.

In November 2009, the company presented final results from a Phase 1b repeat dose study of PEG-IFN lambda as a single agent and in combination with ribavirin to assess safety and antiviral activity in patients with chronic genotype 1 HCV infection. In the study, PEG-Interferon lambda demonstrated anti-viral activity at all dose levels tested in both relapse and treatment naïve HCV patients. A majority of patients across all treatment arms achieved a greater than 2 log reduction in HCV RNA.  Minimal constitutional symptoms or hematologic effects were observed with PEG-Interferon lambda given as a single agent or in combination with ribavirin. The majority of adverse events and laboratory changes were grade 1 or 2. Dose-limiting elevations in ALT or AST, with or without an increase in bilirubin, were dose-dependent and reversible. Overall, the results of the study supported moving to dose-ranging Phase 2 studies in treatment-naïve HCV patients.

A Phase 2 study designated “EMERGE” is ongoing, in which PEG-IFN lambda and ribavirin are administered to treatment-naïve patients with chronic hepatitis C virus (HCV) infection. The EMERGE study is an international, randomized multi-center clinical trial that will enroll approximately 50 patients in the first, open label portion that will explore a wide range of doses to be tested in the second part of the study. The second part of the study is designed to enroll approximately 600 patients. Weekly subcutaneous doses of PEG-Interferon lambda will be administered for up to 48 weeks. The study will assess the safety and antiviral efficacy of PEG-Interferon lambda compared to PEGASYS®. All patients will also receive daily ribavirin. The primary endpoint of the trial is the proportion of patients who achieve undetectable levels of HCV RNA after 12 weeks of therapy (cEVR). Sustained virological response (SVR) defined as undetectable levels of HCV 24 weeks after treatment will also be assessed.

PEG-IFN lambda Phase 2 EMERGE Two-Part Study Design

  • Part A: open-label, dose selection for Part B (approx. 55 patients)

    • 4 fixed doses of PEG-IFN lambda, 1 PEGASYS

  • Part B: blinded (approx. 600 patients)

    • 3 doses of PEG-IFN lambda, 1 PEGASYS
    • cEVRprimary endpoint
    • Started May 2010

PEG-IFN lambda EMERGE Phase 2b Design

Market Opportunity

Hepatitis C

Hepatitis C is an established, high-growth commercial market with an unmet medical need. Chronic HCV infection is a leading cause of cirrhosis, liver failure and hepatocellular carcinoma worldwide. In the United States, it is estimated that HCV is associated with up to 20,000 deaths per year, and is the main reason for liver transplantation. An estimated 4 million people in the U.S. and 11 million people worldwide have HCV.

The current standard of care for HCV involves weekly injections for 48-weeks with pegylated Interferon alpha and oral administration of ribavirin. The response rates for the most common form of HCV in the United States to standard treatment are approximately 50%. The majority of patients treated with Interferon alpha products develop side effects early in therapy that include fever, chills and flu-like symptoms, as well as hematopoietic side effects such as neutropenia, thrombocytopenia, and leukopenia. Later side effects may include fatigue, irritability and depression. As a result of side effects, a reduction in Interferon alpha dosage is required in 10 to 40 percent of patients and, for 5 to 15 percent, treatment is discontinued. For those who continue therapy, additional supportive medications and treatments are often needed, increasing the overall cost of therapy for patients, doctors, and insurance companies. Without effective intervention, the National Institutes of Health project that the number of deaths from chronic HCV infection may triple in the next 10-20 years.

Direct antiviral agents are being developed and tested in combination with Interferon alpha. Initial studies indicate that adding direct antiviral agents to standard of care can be potent, but direct antiviral agents are likely to exacerbate known side effects and or introduce new side effects. Because HCV mutates rapidly and can remain dormant for many years, direct antiviral agents could unintentionally select for drug resistant quasi-species, particularly in the event of a drug holiday. Patient lack of adherence to dose schedule regimens could impact the efficacy and use of these drugs. Direct antiviral agents are expected to be used as adjunct therapy, and Interferon therapy will likely remain the backbone of standard of care.

Based on early clinical data demonstrating encouraging antiviral activity and the potential for fewer and more tolerable side effects, PEG-IFN lambda has the potential to provide a desirable alternative to treatment with Interferon alpha for patients with Hepatitis C.

Scientific Publications

Phase 1b

  • Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection: Hepatology, Epub 2010 May 14

  • EASL 2010: Pharmacokinetics of PEG-IFN lambda in a dose-ranging Phase 1B study in Hepatitis C patients (PDF)
  • AASLD 2009: Final Phase 1b PEG-IFN lambda AASLD Results (PDF)
  • EASL 2009: PEG-IFN-λ Antiviral Activity and Safety Profile in a 4-Week Phase 1b Study in Relapsed Genotype 1 Hepatitis C Infection (PDF)
  • EASL 2009: Viral Kinetic Modeling During Treatment with Interferon Lambda-1a in Genotype 1 Chronic Hepatitis C (PDF)
  • AASLD 2008: Phase 1b dose-escalation study of PEG-Interferon-λ (PEG-rIL-29) in relapsed chronic hepatitis C patients (PDF)

Phase 1a

  • EASL 2008: PEG-Interferon lambda (PEG-rIL-29): Translation of in vitro preclinical data to clinical results (PDF)
  • HEP DART 2007: A Phase 1, randomized, blinded, placebo-controlled, single-dose, dose-escalation study of PEG-Interferon lambda (PEG-rIL-29) in healthy subjects (PDF)

Preclinical

Press Releases