Daniel M. Keller, PhD

April 13, 2011

April 13, 2011 (Berlin, Germany) — The addition of boceprevir, an investigational oral viral protease inhibitor, to pegylated interferon alfa-2a and ribavirin (Peg-IFN/RBV) was associated with significantly higher sustained viral responses (SVR) among patients with hepatitis C virus (HCV) infection for whom Peg-IFN/RBV had failed in the past, compared with retreatment with Peg-IFN/RBV alone.

Reporting the final results of a phase 3 randomized double-blind placebo-controlled trial during a late-breaking poster session here at the European Association for the Study of the Liver (EASL) 46th Annual Meeting, Steven Flamm, MD, professor of medicine and surgery at the Feinberg School of Medicine of Northwestern University in Chicago, Illinois, noted that 64% (86 of 134) of patients receiving boceprevir achieved an SVR, compared with 21% (14 of 67) of patients in the control group (P < .0001). The relapse rate for the boceprevir group was 12% and for the control group was 33%.

The trial randomly assigned 201 adult patients infected with genotype 1 HCV to boceprevir 800 mg 3 times daily plus Peg-IFN/RBV (n = 134) or to placebo plus Peg-IFN/RBV (n = 67) for 44 weeks. Genotype 1 HCV is particularly difficult to eradicate, Dr. Flamm noted.

Each group had an initial 4-week lead-in period with Peg-IFN/RBV alone. The primary end point of the trial was an SVR 24 weeks after the end of therapy. In the study population, 70% were men, 10% were black, and 16% had cirrhosis.

Discontinuations from the trial because of adverse events were more frequent in the boceprevir group than in the control group (17% vs 4%). The rates of serious adverse events were similar between groups (13% vs 10%). Anemia (hemoglobin less than 10 g/dL) occurred more often in the boceprevir group (49% vs 27%), as did grade 3/4 neutropenia (43% vs 21%). There was only 1 discontinuation (in the boceprevir group) because of anemia. Erythropoietin was allowed at the discretion of the investigator for the management of anemia.

Dr. Flamm concluded that "the addition of boceprevir to peginterferon alfa-2a and ribavirin resulted in approximately a 3-fold increase in sustained virologic response in patients who were previous nonresponders or relapsers to standard hepatitis C therapy." He noted that these results are similar to those seen in a 48-week trial of boceprevir added to Peg-interferon alfa-2b and RBV in the HCV RESPOND-2 trial (N Engl J Med. 2011;364:1207-1217). Therefore, boceprevir appears to be equally effective with either form of Peg-INF.

SILEN-C2 Trial Shows Promise for Another Protease Inhibitor

Mark Thursz, MD, FRCP, EASL vice secretary and professor of hepatology at Imperial College, London, United Kingdom, who was not involved in the study, noted that with "just over a 60% sustained viral response," boceprevir produced "excellent results in prior relapsers and actually quite respectable results . . . in prior nonresponders."

During a news conference, Dr. Thursz briefly described the major findings of the phase 2b SILEN-C2 trial of BI 201335, a once-daily oral HCV protease inhibitor, in patients with genotype 1 HCV who did not achieve an SVR with previous therapy. With BI 201335 240 mg once daily plus Peg-IFN/RBV, more than 40% of the patients achieved an SVR; with 240 mg twice daily, the SVR was almost 70%. "In this twice-daily arm, you've got some very encouraging sustained viral response rates," Dr. Thursz said.

Drug Resistance Develops Readily

Antonio Craxi, MD, director of gastroenterology and hepatology, University of Palermo, Italy, warned that resistance develops quickly to all the protease inhibitors currently in the near-term developmental pipeline, and that the resistance is a class phenomenon, meaning that resistance to 1 drug will confer resistance to all. Assuming these drugs reach clinical practice, there is a question of who will be qualified to prescribe them and monitor therapy.

"Whoever knows enough about the problem of resistance" Dr. Craxi said. "These drugs need some very careful follow-up during the first phases of treatment, strict adherence to stopping rules and futility rules, because keeping patients exposed to a protease [inhibitor] when they have not rapidly become nonviremic is quite stupid."

He advised that clinicians will require access to a laboratory with very sensitive RNA testing technology, possibly with facilities to characterize resistance mutations, "because we need to know more once a drug goes into a real-life situation." He said many of these skills are more in the realm of infectious disease specialists, but hepatologists with experience treating hepatitis B "should be qualified enough to reason on mutations. The others will have to learn," he said.

The boceprevir study was supported by Schering-Plough (now Merck). The SILEN-C2 study was funded by Boehringer Ingelheim. Dr. Flamm reports financial relationships with Amgen, Genzyme, and Schering-Plough (now Merck). Dr. Thursz has disclosed no relevant financial relationship. Dr. Craxi reports receiving research support and lecture fees and taking part in clinical trials for Roche, MSD, Siemens, and Abbott.

European Association for the Study of the Liver (EASL) 46th Annual Meeting: Late-breaker session. Presented April 3, 2011.

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