Friday, April 15, 2011

Boceprevir, Telaprevir to Usher in New Era of Hepatitis C Therapy

Boceprevir, Telaprevir to Usher in New Era of HCV Therapy

April 15, 2011 (Baltimore, Maryland) — Clinicians on the front line of managing patients with hepatitis C virus (HCV) infection are likely to look back on 2011 as a banner year.

"The excitement is that, in 2011, we anticipate that the US FDA [Food and Drug Administration] will review and approve 2 hepatitis C protease inhibitors — boceprevir and telaprevir — in combination with peginterferon and ribavirin," Mark S. Sulkowski, MD, from Johns Hopkins University School of Medicine, Baltimore, Maryland, noted in an interview with Medscape Medical News.

Merck and Co is developing boceprevir, and Vertex Pharmaceuticals is developing telaprevir. Both are awaiting approval in the United States.

These 2 drugs will "usher in a new era of direct antiviral therapy that will increase our ability to cure hepatitis C genotype 1," said Dr. Sulkowski, who gave the plenary talk here at the International Conference on Viral Hepatitis (ICVH) 2011 and served as course director for the conference.

The conference is sponsored jointly by the International Association of Physicians in AIDS Care (IAPAC), Johns Hopkins School of Medicine's Office of Continuing Medical Education, and the University of Bonn in Germany.

Decade-Long Dry Spell

There has not been a new HCV medication approved by the FDA since 1998, when the agency approved ribavirin in combination with standard interferon-alfa. In 2001, peginterferon was introduced, but that was just a "modification of interferon," Dr. Sulkowski noted.

"The addition of boceprevir and telaprevir to the HCV treatment armamentarium will be a major step forward for the clinical management of a disease that, to date, has left clinicians with few prescription options and patients with difficult treatment options," José M. Zuniga, PhD, MPH, president and CEO of the IAPAC, told Medscape Medical News.

Pivotal Boceprevir Data

Conference attendees heard a recap of the findings from 2 major studies (RESPOND-2 and SPRINT-2) published March 30 in the New England Journal of Medicine and reported at the time by Medscape Medical News.

Briefly, in the HCV Retreatment With HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 (RESPOND-2) trial, adding boceprevir to standard peginterferon/ribavirin therapy resulted in significantly higher rates of sustained virologic response in previously treated adults with chronic HCV genotype 1 infection than standard therapy alone.

This finding in a group of HCV genotype 1–infected patients who have experienced treatment failure "represents a significant milestone for those patients who have either not responded to or relapsed after treatment with the current standard of care (peginterferon/ribavirin)," said Dr. Zuniga.

The Serine Protease Inhibitor Therapy 2 (SPRINT-2) trial had a study design similar to that of RESPOND-2, except that participants were previously untreated adults with HCV genotype 1 infection. Again, the addition of boceprevir in this group of patients significantly increased rates of sustained virologic response, compared with standard therapy alone.

Pivotal Telaprevir Data

Attendees at the first ICVH gathering also heard data from a planned interim analysis of an ongoing phase 2a double-blind study of telaprevir in combination with standard peginterferon/ribavirin therapy in 60 patients coinfected with HIV and HCV and naïve to interferon.

In this interim analysis, which looked for a rapid viral response, substantially more patients who received telaprevir-based therapy than who received standard therapy only achieved undetectable HCV RNA at week 4 and week 12.

For HIV/HCV-coinfected interferon-naïve patients, these results "hold promise" for the potential of telaprevir, in combination with current standard therapy, "to facilitate undetectable HCV viral load at weeks 4 and 12 of treatment," said Dr. Zuniga.

"While the study continues to assess whether this combination will also facilitate sustained virological response, it does confirm in coinfected patients a similar safety and tolerability profile for this combination, as previously reported for HCV-monoinfected patients," added Dr. Zuniga, who was not involved in the RESPOND-2 or SPRINT-2 studies.

HCV Screening to Take Center Stage

With improved HCV therapy coming, identifying people infected with HCV takes on greater importance, experts at the conference agreed.

"It's fairly clear when you look at hepatitis C in the United States that many patients with hepatitis C have not been diagnosed; they are unaware of their infection," Dr. Sulkowski noted.

"We need to do a better job of educating the public, as well as physicians, about hepatitis C, developing targeted screening programs, and then getting these patients into an evaluation process. Having more effective treatments, in many ways, creates a greater public health mandate to be more aggressive in identifying patients," he told Medscape Medical News.

Dr. Sulkowski reports receiving grants and serving as a research consultant to Abbott Laboratories, Boehringer Ingelheim, Gilead Sciences, Merck & Co., Novartis, Pharmasset, Roche Laboratories, and Vertex Pharmaceuticals; and serving on the advisory board of Pfizer Inc. Dr. Zuniga reports being a consultant to Bristol-Myers Squibb.

International Conference on Viral Hepatitis (ICVH) 2011: Abstracts 71283, 71306, and 71319. Presented April 12, 2011.

Authors and Disclosures
Megan Brooks
Megan Brooks is a freelance writer for Medscape.

From Medscape Medical News

High Viral Response Rates Seen With Boceprevir for HCV

Daniel M. Keller, PhD

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.

Authors and Disclosures


Daniel M Keller, PhD

Daniel M. Keller is a freelance writer for Medscape.

Daniel M. Keller has no disclosures.

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