You have reached the legacy site. Please visit our new site at

Direct-acting Drugs Danoprevir plus RG7128 Suppress HCV without Interferon

SUMMARY: Results from the INFORM-1 trial, which evaluated 2 experimental agents that target different steps of the hepatitis C virus (HCV) lifecycle, showed that a combination of direct-acting drugs can suppress viral replication without interferon or ribavirin. As described in the October 14, 2010 advance online edition of The Lancet, the HCV protease inhibitor danoprevir (RG7227 or ITMN-191) plus the polymerase inhibitor RG7128 reduced HCV RNA by about 5 logs in both treatment-naive and previously treated patients, and caused no serious side effects in this 14-day study.

Standard therapy for chronic hepatitis C, consisting of pegylated interferon (Pegasys or PegIntron) plus ribavirin for 48 weeks, cures only about half of people with hard-to-treat HCV genotype 1. In addition, this regimen can cause difficult side effects that lead many patients to stop treatment prematurely.

Direct-acting agents, including HCV protease and polymerase inhibitors, target the virus directly -- rather than stimulating the immune system like interferon -- and therefore may be better tolerated. Most of these oral agents have so far been studied one at a time in combination with pegylated interferon and/or ribavirin, allowing for a shorter course of treatment. But ideally, people with HCV and their providers are hoping for a regimen that does not require interferon at all.

INFORM-1 is the first clinical trial to evaluate a combination of directing-acting agents without interferon. Edward Gane from Auckland Clinical Studies in New Zealand evaluated the safety, tolerability, and antiviral activity of an all-oral regimen consisting of the HCV NS3/4A protease inhibitor danoprevir plus the cytosine nucleoside polymerase inhibitor RG7128, both being developed by Roche.

A total of 88 genotype 1 chronic hepatitis C patients from 6 centers in New Zealand and Australia were randomly assigned to 7 treatment cohorts, receiving various combinations of danoprevir (100 or 200 mg every 8 hours, or 600 mg or 900 mg twice-daily), RG7128 (500 or 1000 mg twice-daily), and placebo for up to 13 days. Overall, 74 people were assigned to study drugs and 14 to placebo.

Treatment-naive patents received escalating doses, while prior non-responders to standard-of-care therapy were enrolled in higher-dose danoprevir cohorts. (A previous study showed that danoprevir works better when boosted with a low dose of ritonavir [Norvir], but that was not used in this trial.)

After the 14-day randomized study period, all participants started standard therapy with pegylated interferon plus ribavirin.

The primary outcome was changes in HCV RNA viral load from baseline to day 14 in patients who received 13 days of combination therapy. All participants who completed treatment were included in the analysis.


Median decreases in HCV RNA from baseline to day 14 ranged from 3.7 to 5.2 log IU/mL in the cohorts that received danoprevir/RG7128 combination treatment for 13 days.
Among treatment-naive participants who received the highest doses of both drugs (900 mg danoprevir twice-daily plus 1000 mg RG7128), the median decrease in HCV RNA at day 14 was 5.1 log IU/mL.
Among prior null responders receiving the same doses of both drugs, the median decrease was similar, at 4.9 log IU/mL.
Among placebo recipients, HCV RNA decreased by only a median 0.1 log IU/mL.
Viral load decreases were similar in patients with HCV genotypes 1a and 1b (4.8 and 5.1 log IU/mL, respectively).
In the highest dose cohorts, 5 of 8 treatment-naive patients and 2 of 8 prior null responders achieved undetectable HCV RNA (< 15 IU/mL).
The danoprevir plus RG7128 combination was generally well-tolerated.
No participants discontinued treatment or reduced drug doses due to safety concerns.
No treatment-related serious or severe adverse events and no grade 3 or 4 changes in laboratory parameters were observed.
No evidence of treatment-emergent resistance to either danoprevir or RG7128 was identified during the study.

Based on these findings, the researchers stated, "This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV."

"Even though INFORM-1 is a short-term phase 1 study, the findings show that an interferon-free regimen can suppress viral replication," they elaborated in their discussion. "However, we did not show that interferon-free regimens can eradicate HCV (i.e., produce a sustained virological response)."

They noted that INFORM-1 combined drugs that were still in Phase 1 development, in contrast with the traditional development pathway in which studies of combination therapy are delayed until each drug is in late stages of development or has been approved.

"The combination of RG7128 and danoprevir should be further developed and might be a viable interferon-free, all-oral regimen for patients with chronic HCV infection," the authors concluded. "Promising results have been published for use of direct-acting antivirals as monotherapy. However, treatment of patients with an all-oral, interferon-free dual direct-acting antiviral drug combination, as assessed in our study, marks a major shift in the future management of HCV infection and the biggest development in treatment of the disease for the past two decades."

Investigator affiliations: Auckland Clinical Studies, Auckland, New Zealand; The Alfred Hospital, Melbourne, Victoria, Australia; Christchurch Clinical Studies, Christchurch, New Zealand; Austin Hospital, Heidelberg, Victoria, Australia; Royal Adelaide Hospital, Adelaide, South Austraila, Australia; Roche Palo Alto, Palo Alto, CA; Pharmasset, Princeton, NJ; Intermune, Brisbane, CA.


EJ Gane, SK Roberts, CA Stedman, and others (INFORM-1 study team). Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet (Abstract). October 14, 2010 (Epub ahead of print).






















 Google Custom Search
FDA-approved Combination Therapies for Chronic HCV Infection
Pegasys + Copegus
PEG-Intron + Rebetol
Intron A + Rebetol
Roferon A + Ribavirin
Experimental Treatments
Treatment Guidelines

HCV Articles by Topic

Hepatocellular Carcinoma
Liver Transplantation
Liver Biopsy

Children / Infants / Women
Drug Abuse
Experimental Treatments
FAQs About Hepatitis C
Insulin Resistance / Diabetes
Sustained Viral Response (SVR)
Tests for HCV
Vaccines for HCV