Bob Roehr

November 09, 2010

November 9, 2010 (Boston, Massachusetts) — Boceprevir is a protease inhibitor that targets the hepatitis C virus (HCV). When added to the standard of care (pegylated-interferon alfa-2b and ribavirin), boceprevir improved the sustained viral response (SVR) rate approximately 70% over standard of care alone, according to the final results from the SPRINT-2 trial, reported here at The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting.

The SPRINT-1 findings were published in August, as reported by Medscape Medical News at that time.

Principal investigator Fred Poordad, MD, chief of hepatology at Cedars-Sinai Hospital in Los Angeles, California, presented the SPRINT-2 final results. The researchers evaluated the effect of the triple-drug regimen on patients with HCV genotype 1, and conducted a separate analysis of the treatment effect in black patients. SVR rates have been below 50% in HCV genotype 1 patients, especially in those of African descent, Dr. Poordad noted.

The study had a 3-group design that included a 4-week lead-in of standard of care before adding boceprevir, and response-guided therapy to determine the overall duration of therapy for responders. After the initial lead-in period, the control group received standard of care plus placebo for 44 weeks; the 44-week boceprevir group received boceprevir plus standard of care for 44 weeks; and the response-guided therapy group received boceprevir plus standard of care for 24 weeks, with an additional 20 weeks of standard of care only if HCV RNA was detectable during weeks 8 to 24. Patients with detectable HCV RNA at week 24 were withdrawn from the study.

The pegylated-interferon alfa-2b dose was 1.5 μg/kg subcutaneously once a week; ribavirin dose was weight-based (600 to 1400 mg/day) twice daily, orally; boceprevir dose was 800 mg orally 3 times a day.

The SVR in nonblack patients was 40% in the control group, 67% in the response-guided therapy group, and 68% in the 44-week boceprevir group.

Dr. Poordad said that although "the relapse rate in the control arm was 23%, it was less than 10% for patients receiving boceprevir."

The SVR in the black patient cohort was 23% in the control group, 42% in the response-guided therapy group, and 53% in the 44-week boceprevir group. "Relapse rates were slightly higher than [in nonblacks], roughly the same across all 3 arms, ranging from 12% to 17%," Dr. Poordad said.

"At the end of lead-in [week 4], the viral load measurement predicted quite well who would ultimately respond. Patients who had greater than a 1 log decline at the end of the lead-in phase, if they received boceprevir, ultimately had over an 80% SVR. The control arm had a 52% SVR," he reported.

"Conversely, patients who did not achieve a 1 log decline in the control arm had a 5% SVR; [it was] 29% to 39% in those receiving boceprevir."

Resistance mutations to boceprevir developed in 4% of the more rapid responders. Dr. Poordad said that "patients who had less than a 1 log decline at the end of lead-in ended up with 35% to 47% resistance using population sequencing. This is likely an underestimate of the overall development of resistance associated variants."

Adverse events were higher in the boceprevir groups than in the control group — most notably anemia (20% more likely) and dysgeusia (19% to 25% more likely). Discontinuation because of anemia was less than 2%, but erythropoetin (EPO) use was 19% more in the boceprevir groups than in the control group.

When pressed, Dr. Poordad noted that "this is a problem with all of the protease inhibitors." He said the sponsor provided EPO for use at the discretion of the physician, and acknowledged that most insurance carriers do not cover such use, which could affect clinical practice. He added that "there is an ongoing studying looking at SVR with and without EPO use."

Boceprevir has a low barrier to the emergence of resistance by the virus. The sponsor has adopted the strategy of a 4-week lead-in of standard of care to knock down levels of viremia before boceprevir is added, to minimize the risk of resistance emerging. Boceprevir and telaprevir share resistance points and cannot be rescued by the other, the researcher noted.

Medscape Medical News asked Michael Fried, MD, from the University of North Carolina at Chapel Hill, if it might make sense to re-evaluate patients at this point on whether those with a rapid virological response (HCV RNA <50 IU/mL at week 4) and undetectable HCV RNA level on standard of care really need a third drug.

He hedged a bit in responding: "The problem is that such a small percentage of patients have [rapid virological responses]. With genotype 1 in the United States, it might be 5%. But you have to wait and see what happens with the final results. Then you can adapt with your patient. I don't think it is appropriate to make blanket statements."

Scott L. Friedman, MD, a hepatologist at Mount Sinai School of Medicine in New York City, and immediate past president of AASLD, believes that third-party payers will play a role in determining the staging of therapy through what they are willing to cover. They will ask: "Do you really need to incorporate a very expensive new drug when you have a marker that tells you your standard of care is going to be highly effective?"

SPRINT-2 investigators are predicting that boceprevir will likely to be approved by the US Food and Drug Administration in 2011.

The SPRINT trials were sponsored by Schering-Plough, now part of Merck. Dr. Poordad and Dr. Fried report extensive financial ties with most of the major companies involved in HCV research. Dr. Friedman has disclosed no relevant financial relationships.

The Liver Meeting 2010: American Association for the Study of Liver Diseases (AASLD) 61st Annual Meeting: Abstract LB-4. Presented November 1, 2010.

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