A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection

Andrew J. Muir, Sanjeev Arora, Gregory Everson, Robert Flisiak, Jacob George, Reem Ghalib, Stuart C. Gordon, Todd Gray, Susan Greenbloom, Tarek Hassanein, Jan Hillson, Maria Arantxa Horga, Ira M. Jacobson, Lennox Jeffers, Kris V. Kowdley, Eric Lawitz, Stefan Lueth, Maribel Rodriguez-Torres, Vinod Rustgi, Lynn ShemanskiMitchell L. Shiffman, Subasree Srinivasan, Hugo E Vargas, John M. Vierling, Dong Xu, Juan C. Lopez-Talavera, Stefan Zeuzem

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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 languageEnglish (US)
Pages (from-to)1238-1246
Number of pages9
JournalJournal of Hepatology
Volume61
Issue number6
DOIs
StatePublished - Dec 1 2014

Fingerprint

Ribavirin
Infection
Genotype
RNA
Therapeutics
Transaminases
Bilirubin
Interferon-alpha
Interferons
Human Influenza
Antiviral Agents
Hemoglobins
Neutrophils
Blood Platelets
peginterferon lambda-1a
Sustained Virologic Response
peginterferon alfa-2a

Keywords

  • Efficacy
  • Safety
  • SVR
  • Treatment-naive
  • Type III interferon

ASJC Scopus subject areas

  • Hepatology

Cite this

Muir, A. J., Arora, S., Everson, G., Flisiak, R., George, J., Ghalib, R., ... Zeuzem, S. (2014). A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection. Journal of Hepatology, 61(6), 1238-1246. https://doi.org/10.1016/j.jhep.2014.07.022

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 journalArticle

Muir, AJ, Arora, S, Everson, G, Flisiak, R, George, J, Ghalib, R, Gordon, SC, Gray, T, Greenbloom, S, Hassanein, T, Hillson, J, Horga, MA, Jacobson, IM, Jeffers, L, Kowdley, KV, Lawitz, E, Lueth, S, Rodriguez-Torres, M, Rustgi, V, Shemanski, L, Shiffman, ML, Srinivasan, S, Vargas, HE, Vierling, JM, Xu, D, Lopez-Talavera, JC & Zeuzem, S 2014, 'A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection', Journal of Hepatology, vol. 61, no. 6, pp. 1238-1246. https://doi.org/10.1016/j.jhep.2014.07.022
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. / A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection. In: Journal of Hepatology. 2014 ; Vol. 61, No. 6. pp. 1238-1246.
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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.",
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author = "Muir, {Andrew J.} and Sanjeev Arora and Gregory Everson and Robert Flisiak and Jacob George and Reem Ghalib and Gordon, {Stuart C.} and Todd Gray and Susan Greenbloom and Tarek Hassanein and Jan Hillson and Horga, {Maria Arantxa} and Jacobson, {Ira M.} and Lennox Jeffers and Kowdley, {Kris V.} and Eric Lawitz and Stefan Lueth and Maribel Rodriguez-Torres and Vinod Rustgi and Lynn Shemanski and Shiffman, {Mitchell L.} and Subasree Srinivasan and Vargas, {Hugo E} and Vierling, {John M.} and Dong Xu and Lopez-Talavera, {Juan C.} and Stefan Zeuzem",
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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

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 - Safety

KW - SVR

KW - Treatment-naive

KW - Type III interferon

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