Phase 1b Study of Pegylated Interferon Lambda 1 With or... : Hepatology (original) (raw)

Viral Hepatitis

Phase 1b Study of Pegylated Interferon Lambda 1 With or Without Ribavirin in Patients with Chronic Genotype 1 Hepatitis C Virus Infection†

Muir, Andrew J.*,1,2,‡; Shiffman, Mitchell L.3; Zaman, Atif4; Yoffe, Boris5; de la Torre, Andrew6; Flamm, Steven7; Gordon, Stuart C.8; Marotta, Paul9; Vierling, John M.10; Carlos Lopez-Talavera, Juan11; Byrnes-Blake, Kelly12; Fontana, David12; Freeman, Jeremy12; Gray, Todd12; Hausman, Diana12; Hunder, Naomi N.12; Lawitz, Eric13

1 Division of Gastroenterology, Duke University, Durham, NC

2 Duke Clinical Research Institute, Duke University, Durham, NC

3 Liver Institute of Virginia, Newport News, VA

4 Oregon Health and Sciences University, Portland, OR

5 Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, TX

6 New Jersey Medical School, Newark, NJ

7 Northwestern University, Chicago, IL

8 Henry Ford Hospital, Detroit, MI

9 University of Western Ontario, Ontario, Canada

10 Baylor College of Medicine, Houston, TX

11 Research and Development, Bristol-Myers Squibb, Princeton, NJ

12 ZymoGenetics, Incorporated, Seattle, WA

13 Alamo Medical Research, San Antonio, TX

*Address reprint requests to: Andrew J. Muir, M.D., Division of Gastroenterology, Duke University School of Medicine, DUMC 3913, Durham, NC 27701.

E-mail:[email protected]

Received March 17, 2010; accepted April 26, 2010; previously published online May 14, 2010

†Potential conflict of interest: Dr. Byrnes-Blake owns stock in Zymogenetics. Dr. de la Torre is a consultant for and received grants from Gilead and Novartis. He is on the speakers' bureau of and received grants from Onyx-Bayer. He also received grants from Roche. Dr. Shiffman advises and received grants from Biolex, Conatus, Human Genome Sciences, Romark, Valeant, Vertex, and Zymogenetics. He also advises Anadys, Bristol-Myers Squibb, and Novartis. He received grants from GlaxoSmithKline, Globeimmune, Idenix, Johnson & Johnson, and Wyeth. He is a consultant for Pfizer. He is a consultant for, advises, is on the speakers' bureau of, and received grants from Roche. He advises, is on the speakers' bureau of, and received grants from Schering-Plough. Dr. Muir is a consultant for and received grants from Zymogenetics. He also received grants from Merck and Human Genome Science. Dr. Lopez-Talavera owns stock in and holds intellectual property rights for Bristol-Myers Squibb. Drs. Hunder, Freeman, Fontana, and Gray own stock in Zymogenetics. Dr. Gordon is on the speakers' bureau of and received grants from Roche and Schering-Plough. Dr. Lawitz is on the speakers' bureau of and received grants from Schering-Plough, Merck, and Gilead. He also received grants from Abbott, Anadys, Bristol-Myers Squibb, GlaxoSmithKline, GlobeImmune, Human Genome Sciences, Idenix, Idera, Intarcia Therapeutics, Medarex, Medtronic, Novartis, Pharmasset, Roche, Valeant, Vertex, Virochem, and Zymogenetics. Dr. Vierling received grants from Abbott, Conatus, Hyperion, Intercept, Ocera, Roche, Merck, Novartis, Sundise, Zymogenetics, GlobeImmune, Excalenz, and Pharmasset.

‡fax: 919-684-8264

Abstract

Interferon lambda 1 (IFN-λ1) is a type III IFN that produces intracellular responses similar to those of IFN-α but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open-label three-part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single-agent pegylated interferon lambda (PEG-IFN-λ) at 1.5 or 3.0 μg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN-α-based treatment. Part 2 evaluated weekly doses of PEG-IFN-λ ranging from 0.5 to 2.25 μg/kg in combination with ribavirin (RBV) for 4 weeks in treatment-relapse patients. Part 3 evaluated weekly PEG-IFN-λ at 1.5 μg/kg in combination with RBV for 4 weeks in treatment-naive patients. Fifty-six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG-IFN-λ dose levels (from 0.5 to 3.0 μg/kg). Two of seven treatment-naive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu-like symptoms and no significant hematologic changes other than RBV-associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol-defined criteria for dose-limiting toxicity (DLT) or temporarily holding therapy with PEG-IFN-λ. Most DLT occurred in patients with high PEG-IFN-λ exposure.

Conclusion:

Weekly PEG-IFN-λ with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV.