Back HCV Treatment AASLD 2011: All-Oral Combination of BI 201335, BI 207127 and Ribavirin Shows Good Efficacy at 12 Weeks

AASLD 2011: All-Oral Combination of BI 201335, BI 207127 and Ribavirin Shows Good Efficacy at 12 Weeks

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An interferon-free triple regimen containing the hepatitis C virus (HCV) protease inhibitor BI 201335, the HCV polymerase inhibitor BI 207127, and ribavirin for 12 weeks suppressed viral load in three-quarters of previously untreated genotype 1 patients, according to findings from the SOUND-C trials presented at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) in San Francisco.

SOUND-C1

Stefan Zeuzem from J.W. Goethe University in Frankfurt presented findings from SOUND-C1, a small open-label study that evaluated 2 direct-acting antiviral agents (DAAs) -- 120 mg once-daily BI201335 plus 2 doses (400 and 600 mg) of BI 207127 3-times-daily -- and ribavirin in 32 treatment-naive genotype 1 chronic hepatitis C patients; people with liver cirrhosis were excluded.

After taking this oral triple combination for 4 weeks, participants stopped BI 207127 and added pegylated interferon for 20 more weeks; those with inadequate early virological response continued on pegylated interferon/ribavirin alone through 48 weeks.

Zeuzem explained that when the trial was designed more than 2 years ago, "we  didn’t have confidence whether dual DAAs would work at all," and the study was "designed to keep patients as safe as possible."

The researchers previously reported very good rapid virological response (RVR) after 4 weeks on the all-oral regimen. Here, they reported sustained response rates after addition of pegylated interferon/ribavirin.

Results

  • Participants achieved high rate of virological response at all time points:
    • RVR at week 4: 73% in the 400 mg BI 207127 arm and 100% in the 600 mg arm;
    • Extended RVR (HCV RNA < 25 IU/mL at week 4 and undetectable during weeks 5-18) and eligible for shorter therapy: 27% and 71%, respectively;
    • End-of-treatment response: 93% and 100%, respectively;
    • Sustained virological response (SVR; continued undetectable HCV RNA after completion of therapy): 73% and 94%, respectively.
  • 1 person experienced viral breakthrough and 1 had viral rebound while taking the all-oral regimen, both in the 400 mg BI 207127 arm.
  • 2 patients relapsed while on pegylated interferon/ribavirin alone (both in the 400 mg BI 207127 arm, both with HCV subtype 1a).
  • The all-oral regimen was generally well-tolerated, with no severe adverse events or discontinuations due to side effects.
  • Mild-to-moderate nausea and vomiting occurred about twice as often in the 600 mg vs 400 mg BI 207127 dose arm.

Based on these findings, the researchers concluded that BI 201335 plus BI207127 plus ribavirin, followed by triple therapy with BI 201335 and pegylated interferon/ribavirin, "demonstrated very high efficacy against HCV genotype 1."

SOUND-C2

Findings from the follow-up trial, SOUND-C2, were presented in a late-breaker poster at AASLD.

This larger study evaluated various all-oral regimens containing BI 201335 plus BI 207127, with and without ribavirin, in 362 treatment-naive genotype 1 hepatitis C patients:

  • Arm 1: 120 mg once-daily BI 201335 + 600 mg 3-times-daily BI207127 + ribavirin for 16 weeks;
  • Arm 2: 120 mg once-daily BI 201335 + 600 mg 3-times-daily BI207127 + ribavirin for 28 weeks;
  • Arm 3: 120 mg once-daily BI 201335 + 600 mg 3-times-daily BI207127 + ribavirin for 40 weeks;
  • Arm 4: 120 mg once-daily BI 201335 + 600 mg twice-daily BI207127 + ribavirin for 28 weeks;
  • Arm 5: 120 mg once-daily BI 201335 + 600 mg 3-times-daily BI207127 for 28 weeks (no ribavirin);

About half were men, almost all were white, 85% had HCV RNA > 800,000 IU/mL at baseline, 38% had HCV subtype 1a, 26% had the favorable IL28B CC gene pattern, and 10% had compensated cirrhosis.

Results

  • Week 4 RVR rates were 88% in Arms 1-3 (3-times-daily BI207127, combined), 87% in Arm 4 (twice-daily BI 207127), and 72% in Arm 5 (no ribavirin):
  • Week 12 early virological response rates were 70%, 76%, and 57%, respectively;
  • 12%, 22%, and 32%, respectively, experienced virological failure by week 12.
  • Among patients in Arm 1 followed for 12 weeks after completion of therapy, the SVR12 rate was 59% and 15% experienced virological relapse.
  • People with the favorable IL28B CC pattern had similar response rates in all arms -- and 100% achieved 12-week undetectable viral load without ribavirin -- but those with CT or TT patterns did worse without ribavirin.
  • The SVR12 rate in Arm 1 was nearly twice as high for HCV subtype 1b compared with 1a.
  • The most common side effects -- occurring in more than 25% of patients -- were asthenia (weakness), pruritis (itching), rash, photosensitivity, jaundice, nausea, vomiting, and diarrhea.
  • 6%-12% of participants in the various arms discontinued therapy due to adverse events (rash/photosensitivity or gastrointestinal symptoms).

"Interferon-free oral combination therapy with BI 201335, BI 207127 and ribavirin provides high virologic response rates in HCV genotype 1 treatment-naive patients, confirming the potent antiviral activity of this combination," the researchers concluded.

They added that, "the response rate in the ribavirin-sparing arm was substantial but lower than in other arms at week 12."

Comparing the various dose regimens, the researchers noted that the most difficult-to-treat patients -- those with non-CC IL28B patterns and HCV subtype 1a -- benefited from the higher dose of BI207127 and required ribavirin.

Follow-up is continuing to determine if participants achieve SVR 24 weeks after completion of treatment, and to compare outcomes with different durations of therapy in Arms 1-3.

Investigator affiliations:

SOUND-C1: 1: J.W. Goethe University Hospital, Frankfurt, Germany; Hôpital Beaujon, Clichy Cedex, France; Austin Hospital, Heidelberg, VIC, Australia; Hôpital Albert Michallon, Grenoble, France; Hôpital Saint-Eloi, Montpellier, France; University Hospital of Zurich, Zurich, Switzerland; Auckland City Hospital, Auckland, New Zealand; University Medical Center Mainz, Mainz, Germany; University Hospital Hamburg-Eppendorf, Hamburg, Germany; Hôpital Cochin, Paris, France; Hôpital La Pitié Salpêtrière, Paris, France; University Hospital of Nancy, Vandoeuvre-lès-Nancy, France; Alfred Hospital, Melbourne, VIC, Australia; Epimed GmbH, Berlin, Germany; Hospices Civils de Lyon, Lyon University, Lyon, France; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT; Department of Clinical Research, Boehringer-Ingelheim GmbH, Biberach an der Riss, Germany.

SOUND-C2: Klinikum der J. W. Goethe-Universität, Frankfurt, Germany; Hospital Carlos III, Madrid, Spain; Hôpital Beaujon, Clichy cedex, France; Hopital de Brabois, Vandoeuvre, France; "Dr Victor Babes" Hospital of Infectious Diseases, Bucharest, Romania; Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; “Prof. Dr.Matei Bals” Institute of Infectious Diseases, Bucharest, Romania; Hopital Pitie Salpetriere, Paris, France; Universitätsspital Zürich, Zurich, Switzerland; Johannes Gutenberg Universität, Mainz, Germany; Hopital Saint Joseph, Marseille, France; Centro Hospitalar de Lisboa Central, Lisbon, Portugal; Hospital Vall d'Hebron, Barcelona, Spain; Alfred Hospital, Melbourne, VIC, Australia; Auckland Clinical Studies, Auckland, New Zealand; Clinical Research-Virology, Boehringer Ingelheim Pharm. Inc., Ridgefield, CT; Department of Clinical Research, Boehringer-Ingelheim GmbH, Biberach, Germany. 12/2/11

References

S Zeuzem, T Asselah, PW Angus, et al. High sustained virologic response following interferon-free treatment of chronic HCV GT1 infection for 4 weeks with HCV protease inhibitor BI201335, polymerase inhibitor BI207127 and ribavirin, followed by BI201335 and PegIFN/ribavirin -- the SOUND-C1 study. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 249.

S Zeuzem, V Soriano, T Asselah, et al. Virologic response to an interferon-free regimen of BI201335 and BI207127, with and without ribavirin, in treatment-naive patients with chronic genotype-1 HCV infection: Week 12 interim results of the SOUND-C2 study. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8. 2011. Abstract LB-15.

Other Source

Boehringer Ingelheim. Positive Interim Results from Interferon-Free Phase 2b SOUND-C2 Study with Boehringer Ingelheim’s Two Investigational HCV Direct Acting Antivirals Presented at AASLD. Press release. November 7, 2011.