Neil Canavan

November 18, 2011

November 18, 2011 (San Francisco, California) — Two new compounds — a protease inhibitor and a polymerase inhibitor — have the potential to replace pegylated interferon in standard treatment regimens for hepatitis C virus (HCV), according to late-breaking data reported here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting.

In an interim analysis of the open-label phase 2b SOUND-C2 study, investigators looked at the novel protease inhibitor BI 201335 (BI35, Boehringer Ingelheim) and the novel polymerase inhibitor BI 207127 (BI27, Boehringer Ingelheim).

The analysis involved 362 treatment-naïve patients with HCV genotype 1. In the cohort, 52% were male, 98% were white, 85% had an HCV RNA viral load of at least 800,000 IU/mL at baseline, 39% had HCV genotype 1a, 10% showed evidence of compensated cirrhosis, and 26% carried the interleukin (IL)28B polymorphism C/C genotype.

The 5 treatment groups, which all received BI35 120 mg once daily, were:

  • BI27 600 mg 3 times a day plus ribavirin for 16 weeks, for 28 weeks, or for 40 weeks (thrice-daily groups)

  • BI27 600 mg twice daily plus ribavirin for 28 weeks (twice-daily group)

  • BI27 600 mg 3 times daily without ribavirin for 28 weeks (no-ribavirin group).

"Having 2 investigational compounds in 1 trial is a bit unusual," noted Federico Mensa, MD, from the division of clinical research in virology at Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut.

"The idea is to take interferon out of the regimen equation. That treatment is associated with so many adverse events that many patients don't even want to start treatment," Dr. Mensa noted. It's thought that the combination of 2 of the so-called direct-acting antiviral agents will also prevent the emergence of resistance prior to sustained virologic response, he added.

The interim analysis was performed after all patients completed 12 weeks of treatment. Data for the 238 patients in the 16-week and 28-week thrice-daily groups were combined, since those patients received the same treatment for the first 12 weeks.

Results at week 4 show that response to antiviral treatment (HCV RNA viral load below the lower limit of quantification) ranged from 88% for the thrice-daily groups to 72% for the no-ribavirin group.

At week 12, responses ranged from 76% for the twice-daily group to 57% for the no-ribavirin group.

At weeks 4 and 8, virologic failure occurred in 3.4%, 1.3%, and 4.3% of patients in the thrice-daily, twice-daily, and no-ribavirin groups, respectively.

Virologic breakthrough at 12 weeks occurred in 13.4%, 20.5%, and 32.6% of patients in the twice-daily, thrice-daily, and no-ribavirin groups, respectively.

Patients infected with HCV genotype 1a had a lower response rate than others in the study, particularly those in the no-ribavirin group. The lowest rate of response was for IL28B non-C/C patients in the no-ribavirin group (22%); it was 100% in patients with the C/C genotype in the no-ribavirin group. Excellent response was seen in genotype 1b patients, regardless of IL28B status.

"Viral response rates at 12 weeks of up to 76% were comparable to complete early virologic responses achieved with first-generation protease inhibitors plus pegylated interferon," said Dr. Mensa.

How do low response rates observed for patients with HCV genotype 1a, IL28B non-C/C stack up? "This is an important question. Right now my understanding is that we have not seen that data published — the response rates for genotype 1a patients with the unfavorable C/C IL28b variant are not available, to my knowledge, for boceprevir or telaprivir. So it is hard to make a comparison," said Dr. Mensa.

There were some early discontinuations recorded for reasons other than virologic failure, including adverse events and patients lost to follow-up — 17% in the thrice-daily groups, 6% in the twice-daily group, and 13% in the no-ribavirin group. The most common adverse events were mild to moderate gastrointestinal or skin events.

Discussions are ongoing regarding the treatment protocol for a planned phase 3 study using these agents.

What Took So Long?

"Clearly, the protease inhibitors have shot ahead of the nonnukes [polymerase inhibitors], especially because the structural chemistry was understood earlier," said David R. Nelson, MD, associate dean for clinical research in the division of gastroenterology, hepatology, and nutrition at the University of Florida College of Medicine in Gainesville. "Protease inhibitors have also been much more potent than the typical nonnukes. There were some in development prior to protease inhibitors, but the potency of these drugs early on is what limited clinical trial results."

Dr. Nelson is the lead investigator of the ZENITH trial, in which the polymerase inhibitor VX-222 (Vertex Pharmaceuticals) is being combined with the recently approved protease inhibitor telaprevir in a population of treatment-naïve patients infected with HCV genotype 1.

The ZENITH trial is looking at the efficacy and tolerability of VX-222, telaprevir, and ribavirin with and without pegylated interferon. Response rates for the pegylated-interferon-free group will be reported at the 2012 meeting of the European Association of the Study of the Liver.

Dr. Mensa reports being an employee of Boehringer Ingelheim. Dr. Nelson reports being a consultant for Bayer HealthCare, Biolex, and Roche; and receiving grants and research support from Abbott, Anadys Pharmaceuticals, Bayer HealthCare, BMS, Gilead Sciences, Human Genome Sciences, Merck, Novartis, Roche, and Vertex Pharmaceuticals.

The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting. Late-breaking abstract 15, presented November 7, 2011. Abstract 14, presented November 9, 2011.

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