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

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.

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.