Sustained Response Seen with New Hepatitis C Drug

WHEELING, W.Va., April 24 -- An investigational protease inhibitor for hepatitis C virus (HCV) infection showed promise in a phase II trial as add-on therapy, a researcher said.

Twice as many patients receiving boceprevir in addition to PEG-interferon-alfa2b (Pegintron) and ribavirin (Rebetol) achieved sustained virologic responses in a 48-week trial, compared with those receiving PEG-interferon and ribavirin alone (75% versus 38%, P<0.0001), reported Paul Kwo, M.D., of the Indiana University School of Medicine in Indianapolis.

The three-drug combination was most effective when boceprevir was added to the regimen four weeks after patients started on PEG-interferon and ribavirin.

Dr. Kwo presented updated results of the 595-patient randomized trial at the European Association for the Study of the Liver's annual meeting in Copenhagen.

He had reported preliminary results last November at a U.S. meeting. (See AASLD: Hepatologists Eye Protease Inhibitors for Hepatitis C)

Boceprevir is one of several investigational products in development that target the HCV NS3 protease enzyme.

The SPRINT-1 trial reported by Dr. Kwo tested six regimens containing boceprevir against PEG-interferon and ribavirin as the control in patients infected with HCV genotype 1.

PEG-interferon was given weekly at 1.5 mcg/kg.

Ribavirin doses ranged from 800 to 1,400 mg/day in all but one of the treatment arms; the study also included a low-dose ribavirin regimen in which doses ranged from 400 to 1,000 mg/day.

Boceprevir was given at 800 mg three times a day.

Treatment lasted 28 weeks in two of the boceprevir arms and 48 weeks in the other four.

Patients had high viral loads at baseline, above 600,000 IU/mL in 89%. Slightly more than half had genotype 1a HCV and 7% had evidence of cirrhosis.

The researchers found that "rapid" (undetectable HCV RNA within four weeks) and "early" (HCV undetectable within 12 weeks) virologic responses to treatment were highly predictive of responses maintained to the end the treatment.

From 74% to 100% of patients showing rapid responses also had sustained responses; 60% to 91% of those with rapid responses maintained them successfully.

Overall, the best results were seen with the 48-week regimen that included the four-week PEG-interferon and ribavirin lead-in.

Of 103 patients receiving this regimen, 77 achieved sustained virologic responses.

Other key results in this group included:

• Relapse rate: 3%
• Discontinuation rate from adverse events: 9%
• Viral breakthrough rate: 5%

In contrast, the relapse rate in the control group was 24% and the discontinuation rate was 8%.

Dr. Kwo also reported that the boceprevir regimen that included low-dose ribavirin was relatively ineffective. Sustained virologic responses were seen in only 36% of patients, with relapses in 23%, and viral breakthrough in 27%.

With the boceprevir regimen including full-dose ribavirin and no lead-in period, 67% of patients had sustained virologic responses, but 19% discontinued because of adverse events.

The two 28-week treatment regimens -- one with a four-week lead-in period before boceprevir was started, the other without -- led to sustained responses in 56% and 55% of patients, respectively, with relapse rates of 25% and 30%.

Fatigue, anemia, nausea, and headache were the most common adverse events reported in the boceprevir arms.

Treatment-emergent anemia was associated with sustained virologic responses, according to a press release issued by the study's sponsor, Schering-Plough.

The company said anemia occurred in about half of patients receiving boceprevir and more than one-third of the control group.

Erythropoietin was given to 26% of control patients and 39% to 51% of those in the boceprevir arms who also received standard-dose ribavirin.

Boceprevir is now being studied in two randomized phase III trials intended as registration studies, according to Schering-Plough.

Both include a lead-in with PEG-interferon and ribavirin before boceprevir is introduced.

The investigators believe the lead-in allows time to reach steady-state blood levels of the standard drug and for the interferon drug to prime the patient's immune system.

According to Schering-Plough, this approach may head off development of resistance to boceprevir.

The study was funded by Schering-Plough.

Some of the study investigators were employees of Schering-Plough. No other potential conflicts of interest were reported.




Primary source: European Association for the Study of the Liver
Source reference:
Kwo P, et al "HCV sprint-1 final results : SVR 24 from a phase 2 study of boceprevir plus pegintronTM (PEG-interferon alfa-2b)/ribavirin in treatment-naïve subjects with genotype-1 chronic hepatitis C" EASL 2009; Abstract 12