SUMMARY: Combinations of directing-acting oral drugs are effective against hepatitis C virus (HCV) and may enable patients to avoid interferon and its side effects -- or at least shorten the length of standard treatment -- according to studies presented at the recent American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston. Researchers reported that 3 HCV protease/polymerase combinations -- Bristol-Myers Squibb's BMS-650032 + BMS-790052, Gilead's GS-9256 + GS-9190, and Boerhinger Ingelheim's BI 201335 + BI 207127 -- showed potent early anti-HCV activity, but more than 2 drugs will likely be needed to hold off resistance. Ribavirin without pegylated interferon may fulfill this role.

By Liz Highleyman

Current standard therapy for genotype 1 chronic hepatitis C consists of pegylated interferon plus ribavirin for 48 weeks. Interferon-based therapy can cause difficult side effects, however, and only about half of people with this hard-to-treat genotype achieve a cure.

The first oral drugs that directly target steps of the viral lifecycle -- such as HCV protease and polymerase inhibitors -- are in the final stages of development. Most studies to date have looked at these agents used alone in regimens with pegylated interferon/ribavirin, but new research shows that dual or triple combinations may allow selected patients to achieve sustained response without interferon.

BMS-650032 + BMS-790052

At a late breaker session, Anna Lok from the University of Michigan at Ann Arbor and colleagues presented data on Bristol-Myers Squibb's combination regimen consisting of the HCV NS3 protease inhibitor BMS-650032 and the NS5A inhibitor BMS-790052. NS5A is a non-structural protein adjacent to the NS5B polymerase; its function is not fully understood, but it appears to play a crucial role in HCV replication.

In the Phase 2a Study AI447011, genotype 1 (mostly 1a) chronic hepatitis C patients who were null responders to previous interferon-based therapy (< 2 log decline in HCV RNA) were randomly assigned to received 600 mg twice-daily BMS-650032 plus 60 mg once-daily BMS-790052, either alone (Group A) or in combination with 180 mcg/week pegylated interferon alfa-2a (Pegasys) and 1000-1200 mg/day weight-adjusted ribavirin (Group B) for 24 weeks.

After 2 weeks of therapy, participants in both the 2-drug and 4-drug groups saw median HCV RNA viral load decreases of about -5 log. At week 4, about two-thirds of patients in both groups (64% vs 60%, respectively) experienced rapid virological response (RVR), or undetectable viral load (< 10 IU/mL).

After this point, however, the 4-drug combo with interferon began to show an advantage. In an intent-to-treat analysis, 45% of patients (5 out of 11) in the 2-drug oral-only group achieved complete early virological response (EVR) or undetectable HCV RNA at 12 weeks, compared with 90% (9 out of 10) in the 4-drug group.

Just over half of people (55%) receiving only the oral drugs experienced virological breakthrough, while everyone taking the 4-drug combo maintained viral suppression through week 12. Viral breakthrough occurred exclusively in people with genotype 1a; the 2 participants with genotype 1b in the 2-drug group maintained viral suppression. Breakthrough occurred as early as week 3 and as late as week 12. Genotyping identified drug-resistance mutations in the NS3 protease and NS5A regions. Patients who experienced viral breakthrough in Group A added pegylated interferon/ribavirin, and most then achieved undetectable viral load.

BMS-650032 and BMS-790052 were generally well-tolerated. The most common side effect was diarrhea, usually mild-to-moderate, affecting about 70% of patients in both groups. Nausea was more common in the 4-drug group, but otherwise side effects were statistically similar in the 2 arms. There were no serious adverse events, treatment discontinuations due to adverse events, or deaths in either group during the study period.

These findings indicate that these 2 oral drugs alone are not potent enough to maintain long-term viral suppression for genotype 1a patients, likely due to development of drug resistance. But the BMS-650032/BMS-790052 combination increased the likelihood of response to standard therapy at 12 weeks, and may ultimately allow for shorter interferon-based treatment.

GS-9256 + GS-9190

At the same session, Stefan Zeuzem from J.W. Goethe University Hospital in Frankfurt and colleagues presented data from a study of Gilead Sciences' NS3 protease inhibitor GS-9256 and NS5B polymerase inhibitor GS-9190, now named tegobuvir. Study 196-0112 is a Phase 2a trial looking at treatment-naive genotype 1 patients -- an easier-to-treat population than the null responders in the Bristol-Myers Squibb study described above.

In this novel study design, 16 patients were randomly assigned to receive dual therapy with the 2 direct-acting agents alone (75 mg GS-9256 and 40 mg GS-9190, both twice-daily), 15 received triple therapy with these drugs plus 1000-1200 mg/day weight-adjusted ribavirin, and 15 were to be treated with quadruple therapy using the same 3 drugs plus 180 mcg/week pegylated interferon alfa-2a for up to 28 days. Participants with suboptimal response or viral breakthrough in the 2-drug or 3-drug arms added standard therapy.

Median maximum HCV viral load declines at day 28 were -4.1 log in the 2-drug group and -5.1 log in the 3-drug group, indicating that ribavirin enhanced the antiviral activity of GS-9256 plus GS-9190, even without interferon. Here too, some participants experienced virological breakthrough. Further analysis showed that most patients who did so had HCV isolates with NS3 plus NS5B resistance mutations.
At the time of analysis, all 14 participants who had taken the 4-drug regimen of GS-9256/GS-9190 plus standard therapy for 28 days achieved RVR (HCV RNA < 25 IU/mL) without viral breakthrough. With 4-drug therapy the median maximum viral load decline was -5.7 log.

Again, treatment was generally well-tolerated. Most adverse events were mild-to-moderate and resolved with ongoing therapy. The most common side effects in each of the 3 arms were headache, diarrhea, and nausea. Some patients taking the 3-drug combination also experienced fatigue and insomnia, and some taking the 4-drug regimen experienced flu-like symptoms. Nearly one-third of patients in all arms saw an increase in indirect bilirubin levels, which typically resolved with continued dosing and did not lead to treatment discontinuation.

This study also showed that the combination of direct-acting agents had potent antiviral activity, but worked better with the addition of ribavirin and even more so with interferon. These findings suggest some patients may be able to use HCV protease and polymerase inhibitors with ribavirin in interferon-sparing regimens.

BI 201335 + BI 207127

Finally, Zeuzem also presented the latest data on Boehringer Ingelheim's direct-acting dual combination, the NS3/4A protease inhibitor BI 201335 plus the NS5B polymerase inhibitor BI 207127, also used with ribavirin.

In this Phase 1b trial, 32 treatment-naive patients with genotype 1 chronic hepatitis C were randomly assigned to receive either 400 or 600 mg 3-times-daily BI 207127, plus 120 mg once-daily BI 201335, plus 1000-1200 mg/day weight-adjusted ribavirin for 28 days. At that point all switched to BI 201335 plus pegylated interferon/ribavirin.

All participants experienced a "rapid and sharp" decline in HCV viral load during the first 2 days of treatment, followed by a slower second-phase decline in all but 2 patients. At 28 days, 11 of 15 patients (73%) in the 400 mg BI 201335 dose arm and all 17 (100%) in the 600 mg arm achieved HCV RNA suppression < 25 IU/mL.

Two hard-to-treat patients with genotype 1a and high baseline viral load in the lower BI 201335 dose arm experienced virological breakthrough (0.7 and > 1 log increase). At the higher BI 201335 dose level, there was no difference in response between patients with genotype 1a and 1b, but in the 400 mg dose arm genotype 1a patients had a lower response rate.

Once again, BI 201335/BI 207127 plus ribavirin was generally well-tolerated. The most common adverse events were mild-to-moderate gastrointestinal symptoms including diarrhea and nausea, as well as skin rash, and photosensitivity. There were no severe adverse events or treatment discontinuations during the 28-day study period. Unconjugated bilirubin levels also increased in this study.

Investigators concluded that interferon-sparing treatment with BI 201335, BI 207127, and ribavirin demonstrated strong early antiviral activity against HCV genotype 1 with good safety and tolerability.

Overview

Taken together, these studies indicate that combinations of direct-acting agents have potent activity against HCV, but require additional drugs to maintain viral suppression long enough to achieve sustained virological response, or continued undetectable HCV viral load 24 weeks after completion of therapy.

Addition of ribavirin alone -- creating an all-oral, interferon-sparing regimen -- may be a viable option for some patients. Harder-to-treat individuals, including those with genotype 1a, may also require pegylated interferon, but the direct-acting drugs will shorten total treatment time.

In addition to the combinations described here, Vertex Pharmaceuticals recently announced that it will modify an ongoing Phase 2 trial evaluating the HCV protease inhibitor telaprevir plus the polymerase inhibitor VX-222 so that some participants will also receive ribavirin (without pegylated interferon).

Investigator affiliations:
Abstract LB-8: Research & Development, Bristol-Myers Squibb, Hopewell, NJ, Princeton, NJ, and Wallingford, CT; University of Michigan, Ann Arbor, MI; Alamo Medical Research, San Antonio, TX; The Research Institute, Springfield, MA; University of Colorado-Denver, Aurora, CO; Liver Institute at Methodist, Dallas, TX; Carolinas Center for Liver Disease, Statesville, NC; Metropolitan Research, Fairfax, VA

Abstract LB-1: J.W. Goethe University Hospital, Frankfurt, Germany; ifi-Studien und Projekte GmbH an der Asklepios Klinik St, Georg Haus K, Hamburg, Germany; Institute of Liver Studies, London, UK; Medizinische Hochschule Hannover, Hannover, Germany; Hospital Beaujon, Clichy, France; Barts and London NHS Trust, London, UK; Hôspital Saint-Louis, Paris, France; Universitatsklinikum Würzburg, Würzburg, Germany; Hôspital Erasme, Bruxelles, Belgium; CHU de Grenoble - Hospital Michallon, La Tronche, France; Gilead Sciences, Foster City, CA.

Abstract LB-7: J.W. Goethe University Hospital, Frankfurt, Germany; Hôpital Beaujon, Paris, 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; Johannes Gutenberg University Mainz, Mainz, Germany; University Hospital Hamburg-Eppendorf, Hamburg, Germany; Hôpital Cochin, Paris, France; Hôpital Pitié-Salpêtrière, Paris, France; Hôpital de Brabois, Nancy, France; Alfred Hospital, Melbourne, VIC, Australia; Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany; Hôpital Hotel-Dieu , Lyon, France; University Hospital Basel, Basel, Switzerland; Boehringer Ingelheim, Ridgefield, CT; Boehringer Ingelheim (Canada) Ltd, Laval, QC, Canada; Boehringer-Ingelheim GmbH, Biberach, Germany.

11/16/10

References

A Lok, D Gardiner, E Lawitz, and others. Combination Therapy With BMS-790052 and BMS-650032 Alone or With PegylatedInterferon and Ribavirin (pegIFN/RBV) Results in Undetectable HCV RNA Through 12 Weeks of Therapy in HCV Genotype 1 Null Responders. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract LB-8.

M Bifano, H Sevinsky, BR Bedford, and others. Co-administration of BMS-790052 and BMS-650032 does not result in a clinically meaningful pharmacokinetic interaction in healthy subjects. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 827.

S Zeuzem, P Buggisch, K Agarwal, and others. Dual, Triple, and Quadruple Combination Treatment with a Protease Inhibitor (GS-9256) and a Polymerase Inhibitor (GS-9190) alone and in Combination with Ribavirin (RBV) or PegIFN/RBV for up to 28 days in Treatment Naïve, Genotype 1 HCV Subjects. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract LB-1.

S Zeuzem, T Asselah, PW Angus, and others. Strong antiviral activity and safety of IFN-sparing treatment with the protease inhibitor BI 201335, the HCV polymerase inhibitor BI 207127 and ribavirin in patients with chronic hepatitis C. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract LB-7.

Other Sources

Bristol-Myers Squibb. Bristol-Myers Squibb Posts New Data on Combination of Investigational Compounds BMS-790052 and BMS-650032 for the Treatment of Chronic Hepatitis C. Press release. November 1, 2010; Pipeline Asset Update for BMS-790052 (NS5A inhibitor) and BMS-650032 (NS3 inhibitor) (undated).

Gilead Sciences. Gilead's Investigational Hepatitis C Compounds GS 9190 and GS 9256 in Combination with Standard of Care Therapies Achieve Substantial Viral Suppression in Phase II Study. Press release. October 30, 2010.

Boehringer Ingelheim. Boehringer Ingelheim's oral hepatitis C protease inhibitor and polymerase inhibitor combination shows rapid viral response without use of pegylated interferon. Press release. October 30, 2010.

Vertex Pharmaceuticals. Vertex Announces Plans to Enroll Additional Treatment Arm in Ongoing Phase 2 Combination Study of Telaprevir and VX-222 for the Treatment of People with Hepatitis C. Press release. November 10, 2010.