Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment‐naïve patients with chronic HCV genotype 1 infection (ESSENTIAL II)

• Published in: Alimentary pharmacology & therapeutics Vol. 42; no. 7; pp. 829 - 844
• Main Authors: Zeuzem, S., Flisiak, R., Vierling, J. M., Mazur, W., Thongsawat, S., Gould, M., Hsu, S.‐J., Buggisch, P., Mutimer, D., Nault, B., Merz, M., Griffel, L. H., Tanno, Hugo, Bessone, Fernando, Terg, Ruben, Frider, Bernardo, Bertuzzi, Romina, Zekry, Amany, Weltman, Martin, George, Jacob, Crawford, Darrell, Moreno, Christophe, Reynaert, Hendrik, Lee, Samuel, Ramji, Alnoor, Tam, Edward, Marotta, Paul, Yoshida, Eric, Samuel, Didier, Alric, Laurent, Goeser, Tobias, Zeuzem, Stefan, Berg, Thomas, Rasenack, Jens, Tsang, Owen, Hui, Aric Josun, Makara, Mihaly, Gervain, Judit, Varga, Marta, Horvath, Gabor, Hunyady, Bela, Vincze, Aron, Gaeta, Giovanni Battista, Alberti, Alfredo, Colombo, Massimo, Andreone, Pietro, Picciotto, Antonino, Sacchi, Paolo, Invernizzi, Pietro, Lee, Younjae, Han, Sangyoung, Lim, Youngsuk, Hwang, Seonggyu, Maldonado, Hector, Flisiak, Robert, Jablkowski, Maciej, Prelipcean, Cristina, Musa, Manuela, Manuc, Mircea, Tanasescu, Coman, Dumitrascu, Dan, Nikitin, Igor, Znoyko, Olga, Ferret, Maria Buti, Gomez, Manuel Romero, Diago, Moises, Calleja, Jose Luis, Hsu, Shih‐Jer, Hu, Tsung‐Hui, Peng, Cheng‐Yuan, Chen, Chi‐Yi, Sukeepaisarnjaroen, Wattana, Tanwandee, Tawesak, Komolmit, Piyawat, Agarwal, Kosh, Mutimer, David, Brown, Ashley, McPherson, Stuart, Poulos, John, Rustgi, Vinod, Lyche, Kip, Karnam, Umaprasanna, Person, John, O'Leary, Jacqueline, Lawitz, Eric, Pound, David, Scarsella, Anthony, Thuluvath, Paul, Mailliard, Mark, Shiffman, Mitchell, Jacobson, Ira, Bacon, Bruce, Dimitroff, James, Reindollar, Robert, Godofsky, Eliot, Van, Kinh Nguyen, Dao, Long, Huu, Hoang Bui, Minh, Yen Lam, Thanh, Ly
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.10.2015
• Subjects: Adolescent; Adult; Aged; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Chronic infection; Cirrhosis; Clinical trials; Cyclosporine - administration & dosage; Cyclosporine - adverse effects; Disease resistance; Double-Blind Method; Drug Therapy, Combination; Female; Genotype; Genotype & phenotype; Genotypes; Hepacivirus - drug effects; Hepacivirus - genetics; Hepatitis; Hepatitis C; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - virology; Humans; Infections; Interferon; Interferon-alpha - administration & dosage; Interferon-alpha - adverse effects; Liver cirrhosis; Male; Middle Aged; Pancreatitis; Patients; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - adverse effects; Randomization; Recombinant Proteins - administration & dosage; Recombinant Proteins - adverse effects; Ribavirin; Ribavirin - administration & dosage; Ribavirin - adverse effects; Thrombocytopenia; Treatment Outcome; United States; Viruses; Young Adult
• ISSN: 0269-2813; 1365-2036
• DOI: 10.1111/apt.13342

Summary Background Alisporivir (ALV) is an oral, host‐targeting agent with pangenotypic anti‐hepatitis C virus (HCV) activity and a high barrier to resistance. Aim To evaluate efficacy and safety of ALV plus peginterferon‐α2a and ribavirin (PR) in treatment‐naïve patients with chronic HCV genotype 1 infection. Methods Double‐blind, randomised, placebo‐controlled, Phase 3 study evaluating ALV 600 mg once daily [response‐guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/PR triple therapy. Results A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose‐dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. Conclusions Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment‐naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon‐free combination regimens.