Novel therapy RG-101 plus antivirals could cure hepatitis C in 4 weeks

Liz Highleyman
Published:
20 April 2016

Two 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.

At 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.

Glossary

FibroScan

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 91%.

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 reactions (11%).

"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.

Reference

Horvath G et al. (Makara M presenting) RG-101 in combination with 4 weeks of oral direct acting antiviral therapy achieves high virologic response rates in treatment naive genotype 1 and 4 chronic hepatitis C patients: interim results from a randomised, multi-center, phase 2 study. International Liver Congress, Barcelona, abstract GS08, 2016.