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.
Results
 |
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.
10/22/10
Reference
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).
