Daniel M. Keller, PhD

May 08, 2013

AMSTERDAM, the Netherlands — In this era of developing interferon-free treatment for chronic hepatitis C virus infection, faldaprevir looks good in combination with pegylated interferon and ribavirin, according to a new study.

The regimen cleared the virus with a short course of treatment and was well tolerated, Peter Ferenci, MD, from the Medical University of Vienna in Austria, told delegates here at the International Liver Congress 2013.

Faldaprevir is a potent selective inhibitor of hepatitis C virus NS3/4A protease, and has antiviral activity against hepatitis C genotypes 1, 2, 4, 5, and 6 in vitro. It can be administered orally once a day.

The phase 3 placebo-controlled trial, called STARTVerso 1, enrolled treatment-naive patients from Europe and Japan with genotype 1 infection and platelet counts above 90,000/mm³. Investigators randomized participants to 1 of 3 groups in a 1:2:2 ratio.

One group took placebo plus interferon alfa-2a 180 μg/week plus weight-based ribavirin for 24 weeks, with an additional 24 weeks of interferon and ribavirin (control group; n = 132). Another group took faldaprevir 120 mg daily for 12 or 24 weeks (guided by response) plus interferon and ribavirin (low-dose group; n = 259). The third group took faldaprevir 240 mg daily for 12 weeks with interferon and ribavirin for the entire 24 weeks (high-dose group; n = 261).

In the 2 faldaprevir groups, patients with early treatment success, defined as a hepatitis C RNA level below 25 IU/mL at week 4 and undetectable at week 8, stopped all treatment at week 24. If there was no early treatment success, patients in the control and low-dose groups continued on interferon and ribavirin out to week 48. The primary end point was a sustained virologic response 12 weeks after the end of therapy.

At baseline, the groups were well balanced; randomization had been stratified by genotype 1 subtype and race. About half the patients were men, about 78% were white, and mean age was about 47 years. In each group, 35% to 41% of the participants were infected with IL28B genotype CC.

Baseline median hepatitis C RNA level was 6.4 log10 IU/mL in each group. About 35% of participants were infected with genotype 1a virus; the rest were infected with genotype 1b. In each group, 6% had cirrhosis and 16% to 19% had fibrosis of stage F3 or higher.

Patients in the 2 faldaprevir groups had significantly better virologic responses 12 weeks after the end of therapy than those in the control group. As has been seen in many other studies, patients with genotype 1b virus had better responses than those with genotype 1a. This effect was most pronounced in the control group.

Table. Sustained Virologic Response 12 Weeks After Therapy

Group Response, % P Value vs Placebo Response in Genotype 1a Patients, % Response in Genotype 1b Patients, %
Control 52 36 60
Low-dose faldaprevir 79 <.001 69 84
High-dose faldaprevir 80 <.001 76 83


The 2 doses of faldaprevir were associated with very similar response rates. "You can get the same effect with the lower dose, thereby limiting potential side effects," Dr. Ferenci told Medscape Medical News.

In the 2 faldaprevir groups, 75% of the patients achieved early treatment success with undetectable virus by week 4, and another 13% had undetectable virus at week 8. Only 12% did not achieve early treatment success. The effect was fairly durable. Of the 88% achieving early success, 86% in the low-dose group and 89% in the high-dose group had a sustained virologic response at 24 weeks.

The Q80K mutation, a resistance mutation in the NS3 protease gene, was found in 23% of the genotype 1a patients. However, in the faldaprevir groups, there was no appreciable difference in the 12-week sustained virologic response between patients with genotype 1a and those with wild-type virus.

The sustained virologic responses in the 2 faldaprevir groups were similar, regardless of the host IL28B genotype. In the control group, response was better in patients with the CC genotype than in those with other IL28B genotypes. "This is not surprising because [the CC genotype] predicts response to interferon, and since this is an interferon-containing regimen, clearly the CC genotype is good," Dr. Ferenci said.

In all subgroup analyses based on virus genotype, patient race, IL28B genotype, fibrosis stage, or baseline hepatitis C RNA level, the effects of low- and high-dose faldaprevir were equivalent.

Excellent Safety and Tolerability

More than 90% of patients in each group experienced an adverse event, but only 4% to 5% in each group discontinued all medication. Serious adverse events affected only 6% to 7%. Anemia was the most frequent adverse event, affecting 11% to 13% of patients in each group. Rash was also common, affecting 6% to 9% of patients.

Rash of at least grade 2, affecting 7% to 9% of patients, was related to ribavirin; besides anemia, there were no hematologic adverse effects related to ribavirin. "This is in sharp contrast to both telaprevir and boceprevir," Dr. Ferenci said, noting that a lot of supportive treatment is needed to keep patients on those drugs.

"The only real side effect unique to this drug and to this whole group of drugs, which includes simeprevir, is the increase in bilirubin." However, this increase is not associated with an increase in liver values, so it is not a liver disease. It is just an inhibition of bilirubin transport without any clinical significance, Dr. Ferenci explained.

In this study, bilirubin elevations, mostly seen with the higher dose, had returned to baseline at 18 weeks. The problem of photosensitivity seen in previous studies was solved by giving subjects a strong sunscreen.

Dr. Ferenci pointed out 2 unique characteristics of this study. First, it involved patients from East Asia as well as Europe. "It's the very first study with triple therapy targeting East Asian patients. And in this short period, they're doing much better," he reported. Second, this study and a previous phase 2 study of faldaprevir involved patients with cirrhosis, whereas most studies exclude these patients. "It worked very well in cirrhotic patients without any safety signals," he explained. Patients with cirrhosis and hepatitis C genotype 1b got a big benefit from this regimen, he noted.

This trial was started in the era before interferon-free regimens had gained traction. Dr. Ferenci said the sponsor will now pursue studies of faldaprevir in combination with other drugs in interferon-free regimens, but this study shows "that this drug is safe and can be used for combination therapy without interferon," although it is not yet approved for any use.

Mark Thursz, MD, from Imperial College London in the United Kingdom, who was not involved in the study, told Medscape Medical News that the criterion of early treatment success is "slightly different" from the usual extended rapid virologic response used in other studies, "and you can see that they met that criterion extremely well."

He also pointed out the very good safety profile exhibited in this trial. "The adverse-event frequency is low in this trial. This is going to be far better tolerated by our patients than the existing protease inhibitors," he predicted.

The study was sponsored by Boehringer Ingelheim. Dr. Ferenci reports being an advisory board member for Boehringer Ingelheim, Roche, MSD, Gilead, Vertex/Tibotec, Idenix, Achillion, Rottapharma-Madaus, and GSK, and receiving unrestricted research grants from Roche Austria and MSD Austria. Dr. Thursz reports relationships with Abbott and Gilead.

International Liver Congress 2013: 48th Annual Meeting of the European Association for the Study of the Liver (EASL). Abstract 1416. Presented April 27, 2013.