single injection of RG-101, an experimental drug that targets the micro-RNA
miR-122 in liver cells, reduced hepatitis C virus (HCV) levels by more than 4
log10 in people with HCV genotypes 1, 3 and 4, according to research
presented at the 2015 AASLD Liver Meeting in November. In addition, 21%
of treated patients still had undetectable virus levels 28 weeks after dosing.
MiR-122 is a liver-specific micro-RNA that regulates
cholesterol and fatty acid synthesis. It also plays a crucial role in the HCV
lifecycle by binding to the viral genome and protecting it from degradation by
cellular enzymes. Drugs that interfere with the action of miR-122 could
therefore inhibit HCV replication, acting earlier in the viral lifecycle than
currently approved HCV protease, polymerase or NS5A inhibitors.
Meike van der Ree of
Academic Medical Centre in Amsterdam and colleagues conducted a phase 1 study to evaluate the
safety and efficacy of a single dose of RG-101 in chronic hepatitis C patients
with various viral genotypes. RG-101 is an oligonucleotide that targets miR-122
linked to a carbohydrate known as GalNAc.
Chemical "messengers" exchanged between immune cells that affect the function of
the immune system. Interleukins such as IL-2 are a particular type of
This multicentre study conducted in the Netherlands
included 32 patients with HCV genotypes 1, 3 or 4. Most were white men and the
mean age was approximately 50 years. A majority were previously untreated for hepatitis
C and had absent to mild liver fibrosis (stage F0-F1). People with advanced
cirrhosis and HIV or hepatitis B co-infection were excluded.
Participants in the first cohort received a single
subcutaneous injection of 2 mg/kg RG-101 (n = 14) or placebo (n = 2), while the
second cohort received a single injection of 4 mg/kg (n = 14) or placebo (n = 2).
Both cohorts were followed for 8 weeks after randomisation.
At that point, those who experienced more than a 210 log decrease in
HCV RNA from baseline with less than 110 log viral rebound from
their nadir, or lowest, level were included in an extended follow-up group, which
was followed through 28 weeks after dosing.
Van der Ree presented data from the extended follow-up
period at the Liver Meeting. She previously presented interim 20-week data at
the 2015 International Liver Congress last April.
All participants treated with RG-101 experienced
substantial initial reductions in HCV RNA after the injection. At week 4 the
mean viral load reductions were -4.110 log in the 2 mg/kg cohort and
-4.8 log10 in the 4 mg/kg group.
Six treated patients experienced viral rebound by 8 weeks,
while 22 participants maintained at least a 210 log reduction and
were included in the extended follow-up study.
Among 11 participants who had viral rebound, either
during the first 8 weeks or during extended follow-up, five genotype 1 patients
showed a single mutation in the miR-122 binding site, while two people
(genotypes 3 and 4) had double mutations.
Six people with extended follow-up still had
undetectable HCV RNA at the end of the 28-week follow-up period. All three viral
genotypes were represented in this long-term response group.
A single dose of miR-122 was generally safe and
well-tolerated, with no serious adverse events of study discontinuations. The
most common side effects were fatigue (14 patients) and injection site
reactions (five patients). Fatigue, injection site reactions, gastrointestinal
symptoms, headache and insomnia were more common among RG-101 recipients
compared to placebo recipients. Adverse events were mostly mild and transient
and there were no clinically significant changes in blood or kidney laboratory
Treated participants experienced increased alkaline
phosphatase and decreased cholesterol levels, which are known effects of
miR-122 inhibition. Mean ALT and AST liver enzyme levels decreased to within
the normal range. Treated patients experienced a
decline in circulating IP-10 levels, but other cytokines and chemokines did not
differ between RG-101 and placebo recipients.
Van der Ree said that further studies of
RG-101 are ongoing, including a phase 2 study combining two doses with
An earlier miR-122 inhibitor known as
miravirsen – the first miRNA antagonist to be tested
in human clinical trials – previously showed less impressive results in a phase 2
study. Van der Ree explained at the International Liver Congress that attaching
the GalNAc carbohydrate promotes uptake of the inhibitor in the liver and
increases its potency.