Twelve-Week Protease-Based Triple Therapy Results in High HCV Cure Rates

Martha Kerr

May 28, 2008

May 28, 2008 (San Diego, California) – Hepatitis C viral (HCV) response to antiviral therapy "can be dramatically improved" with the addition of the investigational protease inhibitor telaprevir (VX-950, Vertex Pharmaceuticals, Inc.) to standard treatment with ribavirin plus pegylated interferon-alpha-2a (peg-INF), investigators in the landmark PROVE1 and PROVE2 trials reported here during Digestive Disease Week 2008.

"Ribavirin plus [peg-INF] is the backbone of [HCV] treatment. That's why any new drugs are tested against this background," lead investigator Gregory T. Everson, MD, professor of medicine and director of hepatology at the University of Colorado Health Sciences Center, in Aurora, noted in an interview with Medscape Gastroenterology after announcing the results of the PROVE1 study.

PROVE1 and PROVE2 were designed to evaluate whether rapid HCV suppression translates into a sustained viral response (SVR) and whether triple therapy with telaprevir, ribavirin, and peg-INF-alpha-2a can lead to a shorter overall treatment duration.

PROVE1 was a 4-group phase 2b trial of 250 treatment-naive patients with HCV genotype 1 conducted at 37 centers in the United States. Patients randomized to the control group received the standard of care (peg-INF 180 µg weekly and ribavirin 1000 to 2000 mg daily). Patients randomized to the treatment groups received standard of care plus telaprevir 750 mg every 8 hours for 12, 24, or 48 weeks followed by standard of care for 0, 12, or 36 weeks.

The primary end point was an undetectable SVR 24 weeks after the end of treatment. Undetectable SVR was defined as less than 10 IU/mL HCV RNA copies, measured using the Roche TaqMan assay.

PROVE2 was a 28-center phase 2b European trial of 323 treatment-naive genotype 1 HCV patients who were randomized to 1 of 4 groups: standard of care (peg-INF 180 µg weekly and ribavirin 1000 to 1200 mg daily) plus placebo telaprevir; standard of care plus telaprevir 750 mg every 8 hours for 12 weeks, followed by standard of care for 12 weeks in one group and 0 weeks in another; and peg-INF 180 µg weekly plus telaprevir 750 mg every 8 hours. The primary objective was an undetectable SVR.

In PROVE1, Dr. Everson announced that the viral response to therapy at 4 weeks was greater with triple therapy (79%) than with standard treatment (11%). At week 12, viral response rates were 70% with triple therapy and 39% with dual therapy.

At 12 weeks, 91% of subjects on triple therapy and 43% of subjects on standard therapy had undetectable viral loads. At 48 weeks, SVR was 65% in patients on triple therapy and 45% in controls.

The relapse rate at 48 weeks was 2% in PROVE1 and 7% in PROVE2 (a combined relapse rate of 5%) in patients on the 24-week telaprevir-based regimen who had undetectable SVR at weeks 4 and 12.

The relapse rate for controls was 23% in PROVE1 24 weeks after the end of the 48-week standard-therapy regimen and 20% in PROVE2 at 12 weeks posttreatment.

"The take-home message is that patients may be able to get away with as little as 12 weeks of therapy using telaprevir with standard therapy," Dr. Everson told Medscape Gastroenterology. "The PROVE1 data pretty much convinced us that 24 weeks induces a sufficient and rapid viral response."

"Larger phase 3 trials will show whether or not shorter courses of treatment for a larger percentage of treatment-naive genotype 1 HCV patients can be recommended," Dr. Everson said.

Triple therapy was "generally well tolerated," with some incidence of rash, gastrointestinal symptoms, and anemia; the adverse-event rate was 20% with and 11% without telaprevir. Hemoglobin levels dropped from 12 g/dL to 11 g/dL, which is statistically significant, "but we don't know if this is clinically significant," the PROVE1 investigator noted. "Hemoglobin levels rebounded after discontinuation of treatment, indicating bone marrow recovery."

"The bottom line is we can boost antiviral response about 50% with triple therapy.... [Response] is around 40% with standard therapy, [but] another 50% with triple therapy results in overall response rates of around 70%," Dr. Everson explained.

"This telaprevir study has been long-awaited," said John M. Vierling, MD, FACP, professor of medicine and surgery and chief of hepatology at Baylor College of Medicine in Houston, Texas, who was not involved in either of the studies, in an interview with Medscape Gastroenterology.

He pointed out that telaprevir is a protease inhibitor "very specifically targeted to HCV.... With such a specific target, it can rapidly mutate and develop resistance. That's why is has to be combined with ribavirin and peg-interferon.... With 'cocktail therapy,' no real resistance develops."

"We now have proof of principle," Dr. Vierling told Medscape Gastroenterology. "I hate to use the word cure, but we appear to have a cure rate of about 41% [in both PROVE1 and PROVE2].... The problem is that with a rapid sustained viral response, there is no acquired immunity..., [instead] we prevent a host response."

"Patients are currently treated for at least 48 weeks," Dr. Vierling said. "The ultimate goal is treatment with a protease inhibitor and a polymerase inhibitor, and to eliminate interferon or ribavirin, but polymerase inhibitor trials have had some hiccups."

Dr. Everson believes that "the ideal may be 12 weeks of triple therapy [followed by] 12 weeks of ribavirin plus peg-INF; then, antiviral treatment might be able to be stopped."

Dr. Everson's study was supported by a grant from Vertex Pharmaceuticals, Inc. Dr. Vierling describes himself as having "neutralized conflicts," serving as an advisor to "all the HCV pharmaceutical companies."

Digestive Disease Week (DDW) 2008: Abstracts 160 and 223. Presented May 18 and 19, 2008.

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