VX-222, a non-nucleoside NS5B polymerase inhibitor, in telaprevir-based regimens for genotype 1 hepatitis C virus infection

Adrian M. Di Bisceglie, Mark Sulkowski, Ed Gane, Ira M. Jacobson, David Nelson, Cynthia Desouza, Katia Alves, Shelley George, Tara Kieffer, Eileen Z. Zhang, Robert Kauffman, Mohammed Asmal, Margaret J. Koziel

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: To investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens for treatment of genotype 1 HCV. METHODS: In total, 152 treatment-naive patients received VX-222+telaprevir ('DUAL' regimen; n=47), with ribavirin ('TRIPLE' regimen; n=46), or with peginterferon+ribavirin ('QUAD' regimen; n=59) for 12 weeks. Patients with detectable HCV RNA at weeks 2 and/or 8 received peginterferon+ribavirin for 24 (DUAL and TRIPLE) or 12 (QUAD) additional weeks. RESULTS: VX-222 (100 or 400mg twice daily) was well tolerated, with an increased rate of gastrointestinal adverse events observed with the higher dose. Across VX-222 400-mg twice-daily regimens, the QUAD was associated with the highest frequency of grade 3/4 adverse events. The DUAL was discontinued because of high viral breakthrough before week 12. Sustained virologic response (SVR) 24 weeks after end of treatment (SVR24), including patients treated with 12 or 24 additional weeks of peginterferon+ribavirin, was 67% for TRIPLE (VX-222 400mg twice daily) and 79 and 90% for QUAD (VX-222 100 and 400mg twice daily, respectively). CONCLUSION: These results provide valuable information regarding the safety, tolerability, and efficacy of telaprevir combined with a non-nucleoside polymerase inhibitor, as dual therapy or with ribavirin without or with peginterferon. Telaprevir and VX-222, alone or with ribavirin without or with peginterferon, were generally well tolerated, with improved tolerability without peginterferon. SVR24 rates achieved with TRIPLE and QUAD regimens containing telaprevir and VX-222 were comparable to those observed with telaprevir-based therapy.

Original languageEnglish (US)
Pages (from-to)761-773
Number of pages13
JournalEuropean Journal of Gastroenterology and Hepatology
Volume26
Issue number7
DOIs
StatePublished - 2014

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Virus Diseases
Hepacivirus
Ribavirin
Genotype
Therapeutics
Safety
telaprevir
lomibuvir
Antiviral Agents
RNA

Keywords

  • Antiviral agent
  • Clinical trial
  • Combination drug therapy
  • Protease inhibitor

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology
  • Medicine(all)

Cite this

VX-222, a non-nucleoside NS5B polymerase inhibitor, in telaprevir-based regimens for genotype 1 hepatitis C virus infection. / Di Bisceglie, Adrian M.; Sulkowski, Mark; Gane, Ed; Jacobson, Ira M.; Nelson, David; Desouza, Cynthia; Alves, Katia; George, Shelley; Kieffer, Tara; Zhang, Eileen Z.; Kauffman, Robert; Asmal, Mohammed; Koziel, Margaret J.

In: European Journal of Gastroenterology and Hepatology, Vol. 26, No. 7, 2014, p. 761-773.

Research output: Contribution to journalArticle

Di Bisceglie, AM, Sulkowski, M, Gane, E, Jacobson, IM, Nelson, D, Desouza, C, Alves, K, George, S, Kieffer, T, Zhang, EZ, Kauffman, R, Asmal, M & Koziel, MJ 2014, 'VX-222, a non-nucleoside NS5B polymerase inhibitor, in telaprevir-based regimens for genotype 1 hepatitis C virus infection', European Journal of Gastroenterology and Hepatology, vol. 26, no. 7, pp. 761-773. https://doi.org/10.1097/MEG.0000000000000084
Di Bisceglie, Adrian M. ; Sulkowski, Mark ; Gane, Ed ; Jacobson, Ira M. ; Nelson, David ; Desouza, Cynthia ; Alves, Katia ; George, Shelley ; Kieffer, Tara ; Zhang, Eileen Z. ; Kauffman, Robert ; Asmal, Mohammed ; Koziel, Margaret J. / VX-222, a non-nucleoside NS5B polymerase inhibitor, in telaprevir-based regimens for genotype 1 hepatitis C virus infection. In: European Journal of Gastroenterology and Hepatology. 2014 ; Vol. 26, No. 7. pp. 761-773.
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abstract = "OBJECTIVE: To investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens for treatment of genotype 1 HCV. METHODS: In total, 152 treatment-naive patients received VX-222+telaprevir ('DUAL' regimen; n=47), with ribavirin ('TRIPLE' regimen; n=46), or with peginterferon+ribavirin ('QUAD' regimen; n=59) for 12 weeks. Patients with detectable HCV RNA at weeks 2 and/or 8 received peginterferon+ribavirin for 24 (DUAL and TRIPLE) or 12 (QUAD) additional weeks. RESULTS: VX-222 (100 or 400mg twice daily) was well tolerated, with an increased rate of gastrointestinal adverse events observed with the higher dose. Across VX-222 400-mg twice-daily regimens, the QUAD was associated with the highest frequency of grade 3/4 adverse events. The DUAL was discontinued because of high viral breakthrough before week 12. Sustained virologic response (SVR) 24 weeks after end of treatment (SVR24), including patients treated with 12 or 24 additional weeks of peginterferon+ribavirin, was 67{\%} for TRIPLE (VX-222 400mg twice daily) and 79 and 90{\%} for QUAD (VX-222 100 and 400mg twice daily, respectively). CONCLUSION: These results provide valuable information regarding the safety, tolerability, and efficacy of telaprevir combined with a non-nucleoside polymerase inhibitor, as dual therapy or with ribavirin without or with peginterferon. Telaprevir and VX-222, alone or with ribavirin without or with peginterferon, were generally well tolerated, with improved tolerability without peginterferon. SVR24 rates achieved with TRIPLE and QUAD regimens containing telaprevir and VX-222 were comparable to those observed with telaprevir-based therapy.",
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T1 - VX-222, a non-nucleoside NS5B polymerase inhibitor, in telaprevir-based regimens for genotype 1 hepatitis C virus infection

AU - Di Bisceglie, Adrian M.

AU - Sulkowski, Mark

AU - Gane, Ed

AU - Jacobson, Ira M.

AU - Nelson, David

AU - Desouza, Cynthia

AU - Alves, Katia

AU - George, Shelley

AU - Kieffer, Tara

AU - Zhang, Eileen Z.

AU - Kauffman, Robert

AU - Asmal, Mohammed

AU - Koziel, Margaret J.

PY - 2014

Y1 - 2014

N2 - OBJECTIVE: To investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens for treatment of genotype 1 HCV. METHODS: In total, 152 treatment-naive patients received VX-222+telaprevir ('DUAL' regimen; n=47), with ribavirin ('TRIPLE' regimen; n=46), or with peginterferon+ribavirin ('QUAD' regimen; n=59) for 12 weeks. Patients with detectable HCV RNA at weeks 2 and/or 8 received peginterferon+ribavirin for 24 (DUAL and TRIPLE) or 12 (QUAD) additional weeks. RESULTS: VX-222 (100 or 400mg twice daily) was well tolerated, with an increased rate of gastrointestinal adverse events observed with the higher dose. Across VX-222 400-mg twice-daily regimens, the QUAD was associated with the highest frequency of grade 3/4 adverse events. The DUAL was discontinued because of high viral breakthrough before week 12. Sustained virologic response (SVR) 24 weeks after end of treatment (SVR24), including patients treated with 12 or 24 additional weeks of peginterferon+ribavirin, was 67% for TRIPLE (VX-222 400mg twice daily) and 79 and 90% for QUAD (VX-222 100 and 400mg twice daily, respectively). CONCLUSION: These results provide valuable information regarding the safety, tolerability, and efficacy of telaprevir combined with a non-nucleoside polymerase inhibitor, as dual therapy or with ribavirin without or with peginterferon. Telaprevir and VX-222, alone or with ribavirin without or with peginterferon, were generally well tolerated, with improved tolerability without peginterferon. SVR24 rates achieved with TRIPLE and QUAD regimens containing telaprevir and VX-222 were comparable to those observed with telaprevir-based therapy.

AB - OBJECTIVE: To investigate in this phase 2a study (ZENITH) the safety, tolerability, and antiviral activity of VX-222, a selective, non-nucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase, combined with various telaprevir-based regimens for treatment of genotype 1 HCV. METHODS: In total, 152 treatment-naive patients received VX-222+telaprevir ('DUAL' regimen; n=47), with ribavirin ('TRIPLE' regimen; n=46), or with peginterferon+ribavirin ('QUAD' regimen; n=59) for 12 weeks. Patients with detectable HCV RNA at weeks 2 and/or 8 received peginterferon+ribavirin for 24 (DUAL and TRIPLE) or 12 (QUAD) additional weeks. RESULTS: VX-222 (100 or 400mg twice daily) was well tolerated, with an increased rate of gastrointestinal adverse events observed with the higher dose. Across VX-222 400-mg twice-daily regimens, the QUAD was associated with the highest frequency of grade 3/4 adverse events. The DUAL was discontinued because of high viral breakthrough before week 12. Sustained virologic response (SVR) 24 weeks after end of treatment (SVR24), including patients treated with 12 or 24 additional weeks of peginterferon+ribavirin, was 67% for TRIPLE (VX-222 400mg twice daily) and 79 and 90% for QUAD (VX-222 100 and 400mg twice daily, respectively). CONCLUSION: These results provide valuable information regarding the safety, tolerability, and efficacy of telaprevir combined with a non-nucleoside polymerase inhibitor, as dual therapy or with ribavirin without or with peginterferon. Telaprevir and VX-222, alone or with ribavirin without or with peginterferon, were generally well tolerated, with improved tolerability without peginterferon. SVR24 rates achieved with TRIPLE and QUAD regimens containing telaprevir and VX-222 were comparable to those observed with telaprevir-based therapy.

KW - Antiviral agent

KW - Clinical trial

KW - Combination drug therapy

KW - Protease inhibitor

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