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DDW: Telaprevir Improves HCV Clearance in Resistant Patients

June 03, 2009

By Todd Neale

CHICAGO, June 3 -- The investigational protease inhibitor telaprevir, added to standard hepatitis C (HCV) treatment, produced a sustained virologic response in about half of patients who had previously failed with conventional therapy, a phase IIb trial showed.

The group of patients who received telaprevir and peginterferon, but not ribavirin had less of a benefit than those who received all three drugs, he reported at Digestive Disease Week here.

Because there is no existing standard of care for patients who fail to respond to standard treatment for HCV, he said, "I personally believe this . . . represents a new paradigm for how we will treat nonresponders in the future."

About three million people in the U.S. are infected with HCV, and about half will be able to clear the virus with peginterferon and ribavirin, according to Dr. Di Bisceglie.

Conducted at 53 centers, the PROVE3 (Protease Inhibition for Viral Evaluation) study follows the PROVE1 and PROVE2 studies, which evaluated the effect of telaprevir in treatment-naive patients. (See EASL: Telaprevir Shows Promise of Shortened Hepatitis C Therapy and AASLD: Telaprevir Yields Good Response in Combo Therapy for HCV)

PROVE3 involved 453 patients with HCV genotype 1, the most common in the U.S. All had failed prior courses of treatment, either by having no virologic response, by relapsing after completing successful treatment, or by having the virus re-emerge before the end of treatment.

The patients were randomized to four treatment arms with varying duration of treatment with telaprevir, peginterferon, and ribavirin:

  • 12 weeks of all three drugs followed by 12 weeks of standard treatment
  • 24 weeks of all three drugs followed by 24 weeks of standard treatment
  • 24 weeks of telaprevir and peginterferon, but no ribavirin
  • 24 weeks of placebo plus standard treatment followed by 24 weeks of standard treatment (control)

The median age of the patients was 51 and about two-thirds were male. All four groups were well-matched according to baseline characteristics.

The primary endpoint was sustained virologic response 24 weeks after the end of each treatment regimen.

All three telaprevir groups were superior to placebo in the percentage of patients who had a sustained virologic response at follow-up:

  • 51% in patients who received 12 weeks of telaprevir (P<0.001)
  • 52% in those who received telaprevir for 24 weeks along with standard treatment (P<0.001)
  • 23% in those who did not receive ribavirin (P=0.035)
  • 14% in the controls

Similar benefits were seen at four weeks, indicating a rapid virologic response, and immediately at the end of treatment.

Some patients relapsed between the end of treatment and the follow-up, 24 weeks later. The relapse rates were 30% and 13% in the two groups that received telaprevir plus standard treatment and 53% in both the group that did not receive ribavirin and the controls.

Notably, almost 40% of patients who had not responded to treatment at all before the study showed a sustained virologic response at follow-up in the two groups that received all three drugs (P<0.001 for both). That compared with only 9% of the controls.

Response rates of 69% and 76% were seen among prior relapsers (P<0.001 for both), with the higher rate occurring in those who received 48 weeks of standard treatment in addition to 24 weeks of telaprevir.

There was no difference in response rates between patients with and without cirrhosis.

"It appears that telaprevir is able to overcome this and other traditional poor response factors," Dr. Di Bisceglie said.

The most common adverse events in groups receiving telaprevir were fatigue, nausea, headache, rash, itching, anemia, and gastrointestinal side effects, only some of which were severe enough to result in discontinuation.

The dosing regimen involving 24 weeks of all three drugs, followed by 24 weeks of peginterferon and ribavirin, is currently being evaluated in a phase III trial dubbed REALIZE.

Dr. Di Bisceglie said FDA approval for telaprevir is about two years away. Telaprevir and a similar drug, boceprevir, appear to be the closest to approval.

Patients with significant liver disease should receive treatment with peginterferon and ribavirin right away, he said, but patients who have previously failed a course of treatment might think about waiting for these drugs to hit the market.

"These drugs are coming and not that far away, and it may be better to be waiting with our nonresponders for better treatment," he said.

Digestive Disease Week

Di Bisceglie A, et al "SVR results of PROVE3, a phase 2b clinical trial assessing safety and efficacy of telaprevir in hepatitis C genotype-1-infected patients with prior non-response, viral breakthrough or relapse to peginterferon-alfa-2a/b and ribavirin therapy" DDW 2009; Abstract 751d

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