injections of RG-101, an experimental drug that targets the micro-RNA miR-122
in liver cells, combined with direct-acting antiviral agents (DAAs) taken for
just 4 weeks, led to 12-week post-treatment sustained response in 97% of people with chronic
hepatitis C, according to study results presented at the International Liver Congress last week in Barcelona.
MiR-122 is a liver-specific micro-RNA that regulates cholesterol and
fatty acid production. It also plays an important role in the hepatitis C virus
(HCV) lifecycle by binding to the viral genome and protecting it from
degradation. Agents 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. RG-101, produced by
Regulus Therapeutics in San Diego,
California, is an oligonucleotide that targets miR-122, linked to a carbohydrate
known as GalNac.
the American Association for the Study of Liver Diseases (AASLD) Liver Meeting last November, researchers reported that a single injection of RG-101 reduced HCV levels by more than 4 log10
in people with HCV genotypes 1, 3 and 4. Further, 21% of treated patients still
had undetectable HCV RNA at 28 weeks after administration. An
earlier miR-122 inhibitor known as miravirsen previously
showed less impressive results, but attaching GalNAC promotes uptake of the
inhibitor in the liver and increases its potency.
A non-invasive test, used instead of a biopsy, to measure the stiffness
or elasticity of the liver using an ultrasound probe.
At last week's meeting, Mihaly
Makara from Buda Hepatology Centre in
Budapest presented findings from a multicentre phase 2 study evaluating a four-week
regimen of RG-101 in combination with DAAs in previously untreated people with
HCV genotypes 1 or 4. The typical duration of current combination DAA therapy
is 8 or 12 weeks, extending to 24 weeks for some difficult-to-treat patients.
This study recruited 79 treatment-naive participants
without cirrhosis. Just over half were women, almost all were white and the
mean age was 45 years. Most (77%) had HCV genotype 1, the mean baseline viral
load was 5.8 log10 IU/ml and 86% had absent or mild liver fibrosis
(stage F0-F1) according to FibroScan.
People with HIV or hepatitis B co-infection were excluded.
All participants received a 2mg/kg subcutaneous
injection of RG-101, followed by treatment with sofosbuvir/ledipasvir (Harvoni), simeprevir (Olysio) or daclatasvir (Daklinza) taken for 4 weeks, and ending
with a second RG-101 injection on day 29.
Results were presented for 64 people who had reached 8
weeks of post-treatment follow-up, 41 who had reached 12 weeks post-treatment
and a few who had been followed longer. Continued undetectable HCV RNA at 12
weeks post-treatment (SVR12) is considered a cure.
Virological response was rapid, with all patients
reaching undetectable viral levels by the end of treatment. Overall, 40 of the
41 patients – 97% – followed through 12 weeks post-treatment achieved SVR12.
By regimen, SVR12 rates were 100% (14/14) for those
treated with sofosbuvir/ledipasvir, 93% (14/15) with simeprevir and 100%
(12/12) with daclatasvir. Among the larger number of patients with eight weeks of
post-treatment follow-up, the corresponding SVR8 rates were 100%, 100%, and
One person in the simeprevir group relapsed between
weeks 8 and 12 of post-treatment follow-up, and one in the daclatasvir group
did so by week 8. Another patient in the daclatasvir group was a slow responder
who still had detectable HCV at week 8 but achieved SVR by week 12.
Treatment was generally safe and well-tolerated, with
most adverse events being mild or moderate. There were two serious adverse
events, but no one discontinued therapy due to side-effects. The most commonly
reported adverse events were fatigue (17%), headache (13%) and injection site
"RG-101, a potent antagonist vs miR-122, in
combination with 4 weeks of oral DAA therapy resulted in high virologic
response rates," with similar efficacy regardless of which DAAs were used,
the researchers concluded.