By Liz Highleyman

About half of all people with chronic hepatitis C virus (HCV) infection achieve a cure, or sustained virological response (SVR), with the standard treatment of pegylated interferon plus ribavirin; rates are even lower for patients with difficult-to-treat HCV genotype 1. Thus, researchers have studies various antiviral agents that directly target various stages of the HCV lifecycle.

At the 43rd annual meeting of the European Association for the Study of the Liver (EASL) last week in Milan, researchers presented data on Schering-Plough's investigational oral HCV NS3 serine protease inhibitor boceprevir (formerly known as SCH503034).

Triple Combination Therapy

In a late-breaker session, Paul Kwo of Indiana University School of Medicine and colleagues presented interim results from HCV SPRINT-1, a Phase 2 study assessing the safety and efficacy of boceprevir in combination with pegylated interferon and ribavirin in 595 treatment-naive patients with genotype 1 chronic hepatitis C treated in the U.S. (77%), Canada, and Europe; 16% were black (a group that responds less well to interferon-based therapy) and 7% had liver cirrhosis at baseline.

Participants were randomly allocated to various regimens containing 800 mg twice-daily boceprevir, 1.5 mcg/kg/week pegylated interferon alfa-2b (PegIntron), and weight-based ribavirin (Rebetol):

• 4 weeks of pegylated interferon plus 800-1400 mg/day ribavirin, followed by boceprevir/pegylated interferon/ribavirin at the same doses for 24 or 44 weeks (lead-in arm).

• Boceprevir plus pegylated interferon plus 800-1400 mg/day ribavirin for 28 or 48 weeks (no lead-in arm);

• Boceprevir plus pegylated interferon plus 400-1000 mg/day ribavirin for 48 weeks (low-dose ribavirin arm);

• Pegylated interferon plus ribavirin for 48 weeks (standard therapy control arm).

The rationale for this novel approach, according to Schering-Plough, is that both pegylated interferon and ribavirin reach steady-state concentrations by week 4; therefore, patients in the lead-in arm would have boceprevir added after the other drugs have already reached optimal levels. Further, pegylated interferon will have activated the immune system by the time boceprevir is added. Researchers hope this strategy might minimize "functional monotherapy" with the protease inhibitor before high enough levels of pegylated interferon and ribavirin are achieved, which may reduce the risk of drug resistance.

The primary study endpoint of the study will be SVR, or undetectable HCV RNA (below 15 IU/mL) 24 weeks after completion of treatment. For the interim analysis, researchers presented response rates 12 weeks after completion of therapy -- or "SVR12" -- in the 28-week arms. This data was not yet available for participants treated for 48 weeks.

Results

• Proportions of patients achieving undetectable HCV RNA in the various arms are shown in the table below.

• In an intent-to-treat analysis, the SVR rate in the lead-in, 28-week, full-dose ribavirin arm was 57%, compared with 55% in the arm that received triple therapy from the outset.

• Response rates at week 4 of boceprevir treatment were higher for patients in the pegylated interferon/ribavirin lead-in arm (62%) compared with those who started on triple therapy (38%) or the control arm (8%).

• Similar results were seen at week 12 (79%, 69%, and 34%, respectively).

• In the 28-week boceprevir arms, lead-in patients had a lower rate of viral breakthrough compared with the initial triple therapy arm (4% vs 7%, respectively).

• RVR, or undetectable HCV RNA after 4 weeks of boceprevir, was a good predictor of sustained response.

• Response rates were higher in the full-dose compared with the low-dose ribavirin boceprevir-containing arms.

• 11%-15% of patients discontinued treatment in the boceprevir arms, compared with 8% in the control arm.

• The most common adverse events leading to treatment discontinuation in the boceprevir-containing arms were fatigue (2%), nausea (2%), headache, and anemia (<1% each).

• The incidence of rash-related adverse events was similar in the boceprevir-containing arms and the pegylated interferon/ribavirin control arm.

Conclusion

Based on these findings, the investigators concluded, "Four weeks of treatment with [pegylated interferon/ribavirin] prior to boceprevir administration markedly increased RVR and EVR and reduced viral breakthrough by 50%."

"This new treatment paradigm has the potential to maximize efficacy of multi-drug combinations and minimize the risk of resistance by identifying responders to [pegylated interferon/ribavirin]," they continued. "Interim results also demonstrate that full dose ribavirin is optimal."

"These interim results are very encouraging, especially given the response seen with a shorter course of therapy in a difficult-to-treat patient population," said Dr. Kwo in a press release issued by Shering-Plough. "Boceprevir has been well tolerated by patients in this study, including in the longer duration treatment arms, and we look forward to further results from this ongoing study."

Final results from SPRINT-1 are expected to be available in early 2009.

Indiana University School Of Medicine, Indianapolis, IN; Alamo Medical Research, San Antonio, TX; Mount Vernon Endoscopy Center, Alexandria, VA; University of Miami Center for Liver Diseases, Miami, FL; Baylor College of Medicine, Houston, TX; Indianapolis Gastroenterology Research Foundation, Indianapolis, IN; South Florida Center of Gastroenterology, Wellington, FL; Liver Specialists of Texas, Houston, TX; Henry Ford Hospital, Detroit, MI; Digestive Disease Associates, Baltimore, MD; Univ Of California-Davis, Sacramento, CA; Liver and Intestinal Research Center, Vancouver, Canada; Weill Medical College Of Cornell Univ, New York NY; Digestive Healthcare Of Georgia, Atlanta, GA; Schering-Plough Research.

Null Responders

In a related study, researchers looked at response to boceprevir combination therapy in 357 "null responders" with genotype 1 HCV who had less than a 2 log10 drop in HCV RNA after 12 weeks of prior treatment with pegylated interferon/ribavirin, or failure to achieve undetectable viral load if treated longer than 12 weeks.

Participants received 1.5 mcg/kg/week pegylated interferon (PegIntron) plus boceprevir at doses of 100, 200, 400, or 800 mg, some with ribavirin. The control arm received standard therapy, adding boceprevir if HCV remained detectable. Early data showed that the lower doses of boceprevir were less effective, so all patients who demonstrated virological response to boceprevir switched to triple combination therapy using 800 mg boceprevir for an additional 24 weeks.

SVR rates ranged from 2% in the control group to 14% using the boceprevir regimens studied, though no patients received triple therapy with the highest dose of boceprevir for the full treatment period. Individuals who experienced a viral load decrease greater than 2 log10 at week 12 were most likely to achieve undetectable HCV RNA on triple therapy. Boceprevir resistance mutations were detected in a majority of subjects who did not achieve SVR.

The investigators concluded that, "Some 'null' responders to [pegylated interferon/ribavirin] can achieve an SVR with [pegylated interferon/ribavirin/800 mg boceprevir], but response is dependent on residual interferon responsiveness." They added that, "Treatment failures to [pegylated interferon/ribavirin] with > 2 log10 viral drop at [week 12] may be good candidates" for triple therapy.

University of Miami School of Medicine, Miami, FL; Cedars-Sinai Medical Center, Los Angeles, CA; Weill Medical College of Cornell University, New York, NY; Northwestern University, Chicago, IL; St. Louis University, St. Louis, MO; Alamo Medical Research, San Antonio, TX; Henry Ford Hospital, Detroit, MI; Duke University Medical Center, Durham, NC; Liver Institute at Methodist Dallas, Dallas, TX; A.P.H. Paris, Hopital Pitie-Salpetriere, Paris, France; Johns Hopkins Univ, Baltimore MD; Hospices Civils De Lyon Hotel Dieu, Lyon, France; Opedale Molinette, Torino, Italy; Univsitaetsklinikum Des Saarlandes, Homburg/Saar, Germany.

Boceprevir Resistance Mutations

Finally, researchers presented results from a clonal analysis of mutations in the HCV NS3 protease domain in non-responders treated with boceprevir.

HCV RNA was assessed at baseline, day 14 (end-of-treatment), and day 28 (end-of-follow-up) in samples collected from 22 patients treated with 400 mg boceprevir 2 or 3 times daily.

Mutations were detected at 51 different amino acid positions within the NS3 protease, with a frequency greater than 5% by the end of treatment. Mutations at 5 amino acid positions (V36, T54, R155, A156, V170) previously shown to confer resistance to boceprevir in vitro were detected in 14 patients. However, no mutations at position A156 were detected at the end-of-follow-up.

J W Goethe University Hospital, Medizinische Klinik I, 60590 Frankfurt am Main, Germany; Saarland University Hospital, Klinik für Innere Medizin II, Homburg, Germany; Schering Plough, Kenilworth, NJ.

4/29/08

References

P Kwo, E Lawitz, J McCone, and others. Interim Results from HCV SPRINT-1: RVR/EVR from Phase 2 Study of Boceprevir Plus PegINTRON (Peginterferon Alfa-2b)/Ribavirin in Treatment-Naïve Subjects with Genotype-1 CHC. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

E Schiff, F Poordad, I Jacobson, and others. Boceprevir (B) Combination Therapy in Null Responders (NR): Response Dependent on Interferon Responsiveness. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

S Susser, MW Welker, M Zettler, and others. Clonal Analysis of Mutations Selected in the HCV NS3 Protease Domain of Genotype 1 Non-Responders Treated with Boceprevir (SCH503034). 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

Additional Source

Schering-Plough Corporation. Interim Results from Boceprevir Phase II Study in Genotype 1 Treatment-Naive Hepatitis C Patients Presented At EASL. Press release. April 26, 2008.