Abstract
Background & Aims Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. Methods This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 μg) or peginterferon alfa-2a (alfa; 180 μg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. Results Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 μg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 μg dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. Conclusion Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1238-1246 |
| Number of pages | 9 |
| Journal | Journal of Hepatology |
| Volume | 61 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 1 2014 |
Keywords
- Efficacy
- SVR
- Safety
- Treatment-naive
- Type III interferon
ASJC Scopus subject areas
- Hepatology
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A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection. / Muir, Andrew J.; Arora, Sanjeev; Everson, Gregory; Flisiak, Robert; George, Jacob; Ghalib, Reem; Gordon, Stuart C.; Gray, Todd; Greenbloom, Susan; Hassanein, Tarek; Hillson, Jan; Horga, Maria Arantxa; Jacobson, Ira M.; Jeffers, Lennox; Kowdley, Kris V.; Lawitz, Eric; Lueth, Stefan; Rodriguez-Torres, Maribel; Rustgi, Vinod; Shemanski, Lynn; Shiffman, Mitchell L.; Srinivasan, Subasree; Vargas, Hugo E.; Vierling, John M.; Xu, Dong; Lopez-Talavera, Juan C.; Zeuzem, Stefan.
In: Journal of Hepatology, Vol. 61, No. 6, 01.12.2014, p. 1238-1246.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection
AU - Muir, Andrew J.
AU - Arora, Sanjeev
AU - Everson, Gregory
AU - Flisiak, Robert
AU - George, Jacob
AU - Ghalib, Reem
AU - Gordon, Stuart C.
AU - Gray, Todd
AU - Greenbloom, Susan
AU - Hassanein, Tarek
AU - Hillson, Jan
AU - Horga, Maria Arantxa
AU - Jacobson, Ira M.
AU - Jeffers, Lennox
AU - Kowdley, Kris V.
AU - Lawitz, Eric
AU - Lueth, Stefan
AU - Rodriguez-Torres, Maribel
AU - Rustgi, Vinod
AU - Shemanski, Lynn
AU - Shiffman, Mitchell L.
AU - Srinivasan, Subasree
AU - Vargas, Hugo E.
AU - Vierling, John M.
AU - Xu, Dong
AU - Lopez-Talavera, Juan C.
AU - Zeuzem, Stefan
N1 - Funding Information: This study was fully funded by Bristol-Myers Squibb . Funding Information: A. Muir has received advisory board/review panel honoraria from Merck, Vertex, Gilead, Bristol-Myers Squibb, Abbott and Achillion; has consulted for Profectus and GSK; and has received grants and research support from Merck, Vertex, Roche, Bristol-Myers Squibb, Gilead, Achillion, Abbott, Pfizer, Salix and GSK. S. Arora has received research grants from Genentech, Gilead, Beckman Coulter and AbbVie. G . Everson has received research grants from Bristol-Myers Squibb, AbbVie, Gilead, Janssen and NIH-NIDDK; has received advisory board honoraria from Bristol-Myers Squibb, Gilead, Janssen, Eisai and Novartis, and received no compensation from participation on an advisory board for BioTest. Dr. Everson is the inventor of the technology; holds the patent with the University of Colorado Denver; and is manager of HepQuant LLC which has exclusive licensing rights to the technology filed in patents US 11/814,793, EP1845840, US 12/557,916, WO2011031667, AU2010292409, CA2773824, EP2475399, US20120329161, WO2012166802, AU2012262329 and US 14/078,058. R. Flisiak has received consulting and lecture fees and advisory board honoraria from Bristol-Myers Squibb, Gilead, Merck, Roche and Janssen; and an advisory board honoraria from AbbVie. J. George has received lecture fees and advisory board honoraria from Bristol-Myers Squibb, MSD, Roche, AbbVie, Boehringer Ingelheim, Janssen and Gilead. R. Ghalib has received grants and research support from Bristol-Myers Squibb, Vertex Pharmaceuticals, Merck, Genentech, ZymoGenetics, Pharmasset, Anadys, Duke Clinical Research Institute, Achillion, Boehringer Ingelheim, Gilead, ViroChem Pharmaceuticals, Abbott, Medtronic Inc, Novartis, Roche, Schering Plough, Tibotec and Inhibitex; and has received speaking fees and honoraria for teaching from Merck, Genentech and Vertex Pharmaceuticals. S.C. Gordon has received grants and research support from AbbVie, Bristol-Myers Squibb, Gilead, GSK, Intercept Pharmaceuticals, Merck and Vertex Pharmaceuticals; has been a consultant and advisor for Bristol-Myers Squibb, Amgen, CVS Caremark, Gilead, Merck, Novartis and Vertex Pharmaceuticals; and appeared on a Data Monitoring Board for Tibotec/Janssen. TT. Gray was an employee of Bristol-Myers Squibb during the time of the study and writing of the manuscript. T. Hassanein has received consulting fees from Bristol-Myers Squibb, Gilead, Genentech and Salix Pharmaceuticals; has received grants and research support from Janssen, Boehringer-Ingelheim, Gilead, Salix Pharmaceuticals, Bristol-Myers Squibb, Vertex, Abbvie, Eisai, Idenix, Ikaria, Roche, Tacheda and Sundise; and has received speaking fees and honoraria for teaching from Bristol-Myers Squibb, Gilead, Genentech and Salix Pharmaceuticals. J. Hillson was an employee of ZymoGenetics/Bristol-Myers Squibb during the time of the study and writing of the manuscript. M.A. Horga was an employee of Bristol-Myers Squibb at the time of the study. I.M. Jacobson has received research grants from or served as a consultant/advisor to Bristol-Myers Squibb, Abbott, Achillion, Boehringer Ingelheim, Enanta, Gilead, GSK, Idenix, Kadmon, Novartis, Presidio, Roche/Genentech, Schering/Merck, Tibotec/Janssen and Vertex. K.V. Kowdley has received research grants from ZymoGenetics/Bristol-Myers Squibb, AbbVie, Beckman, Bristol-Myers Squibb, Boehringer Ingelheim, Conatus, Genentech, Gilead, GSK, Ikaria, Intercept, Janssen, Merck, Mochida, Pharmasset, Vertex, Novartis and Trio Health outside the submitted work; and received honoraria for advisory boards and scientific consulting from AbbVie, Boehringer Ingelheim, Gilead, Ikaria, Janssen, Merck, Pharmasset, Vertex, Novartis and Trio Health. E. Lawitz has received grants and research support from AbbVie, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GSK, Idenix, Intercept Pharmaceuticals, Janssen, Medtronic, Merck & Co., Novartis, Presidio, Roche, Santaris Pharmaceuticals and Vertex; has received speaking fees from Gilead, GSK, Kadmon, Merck and Vertex; and participated on advisory boards for AbbVie, Achillion, BioCryst, Biotica, Enanta, Idenix, Janssen, Merck & Co., Novartis, Santaris Pharmaceuticals, Theravance and Vertex. S. Lueth has received speaker fees and honoraria for participation on advisory boards for Bristol-Myers Squibb, and sponsorship for educational activities in viral hepatitis. M. Rodriguez-Torres has received grants and research support from Abbott, Akros Pharma, Anadys, Beckman Coulter, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Pharmaceuticals, GSK, Hoffmann-La Roche, Human Genome Sciences, Idenix, Idera Pharmaceuticals, Inhibitex, Johnson & Johnson, Merck Sharp & Dohme Corp., Mochida Pharmaceutical, Novartis, Pfizer, Pharmasset, Santaris, Scynexis, Inc., Siemens Healthcare Diagnostics, Vertex and ZymoGenetics; and has been a consultant for Akros Pharma, Bristol-Myers Squibb, Genentech, Hoffmann-La Roche, Inhibitex, Janssen R&D Ireland, MSD, Pharmasset, Santaris and Vertex. V. Rustgi has received grants and research support from Gilead, Bristol-Myers Squibb, Abbott, Achillion; and has received speaking fees and honoraria for teaching from Merck, Genentech and Vertex. L. Shemanski was an employee of Bristol-Myers Squibb during the time of the study and writing of the manuscript. M.L. Shiffman has received grants and/or fees for speaking and Advisor meetings from Bristol-Myers Squibb, AbbVie, Achillion, Bayer, Beckman-Coulter, Gen-Probe, Gilead, GSK, Globeimmune, Intercept, Janssen, Lumena, Merck, Novartis, Roche/Genentech and Vertex. S. Srinivasan is an employee of Bristol-Myers Squibb. H.E. Vargas has received research grants from Bristol-Myers Squibb, Gilead, AbbVie, Janssen, Merck and Novartis. J.M. Vierling has received grants and research support from Abbott, Bristol-Meyers-Squibb, Conatus, Excalenz, Genfit, Gilead, Globeimmune, Hyperion, Idenix-Novartis, Ikaria, Intercept, Merck, Mochida, Novartis, Ocera, Pfizer, Pharmasset, Roche, Sundise, Tranzyme, Vertex and ZymoGenetics; has worked on Speaker Bureaus for the Chronic Liver Diseases Foundation and GALA; and has appeared on advisory boards and review panels for the NIH, NIDDK, FDA, CDER, CDC, Abbott, Bristol-Myers-Squibb, Excalenz, Gilead, GSK, Globeimmune, HepQuant, Hyperion, Idenix, Immuron, Janssen, Novartis, Roche, Schering, Salix, Sundise, Tranzyme, Vertex, HepaLife Technologies, Herbalife, Ocera and SciGen. D. Xu is an employee of Bristol-Myers Squibb. J.C. Lopez-Talavera was a Bristol-Myers Squibb employee during the time of the study and writing of the manuscript, is now employed by AbbVie, and is a Bristol-Myers Squibb shareholder. S. Zeuzem has received fees for consultancy and lectures from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Janssen, Merck, Novartis, Roche, Santaris and Vertex. L. Jeffers and S. Greenbloom have nothing to disclose. Funding Information: The authors would like to thank David Fontana, Jeremy Freeman, and Laura Ishak for their significant contribution to the success of the study. Editorial assistance was provided by Dr. Stephen Griffiths and Dr. Nicholas Fitch at ArticulateScience (London, UK) and was funded by Bristol-Myers Squibb.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - Background & Aims Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. Methods This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 μg) or peginterferon alfa-2a (alfa; 180 μg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. Results Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 μg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 μg dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. Conclusion Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.
AB - Background & Aims Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. Methods This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 μg) or peginterferon alfa-2a (alfa; 180 μg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. Results Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 μg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 μg dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. Conclusion Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.
KW - Efficacy
KW - SVR
KW - Safety
KW - Treatment-naive
KW - Type III interferon
UR - http://www.scopus.com/inward/record.url?scp=84922813934&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922813934&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2014.07.022
DO - 10.1016/j.jhep.2014.07.022
M3 - Article
C2 - 25064437
AN - SCOPUS:84922813934
VL - 61
SP - 1238
EP - 1246
JO - Journal of Hepatology
JF - Journal of Hepatology
SN - 0168-8278
IS - 6
ER -