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EASL 2016: 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 chronic hepatitis C patients, according to study results presented at the European Association for the Study of the Liver's International Liver Congress (EASL 2016) 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 by cellular enzymes. 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, is a oligonucleotide that targets miR-122, linked to a carbohydrate known as GalNac.

At the AASLD Liver Meeting last November, researchers reported that a single injection of RG-101 reduced hepatitis C virus (HCV) levels by more than 4 log 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 Center in Budapest presented findings from a multicenter Phase 2 study evaluating a 4-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 log IU/mL, and 86% had absent or mild liver fibrosis (stage F0-F1) according to FibroScan. People with HIV or hepatitis B coinfection were excluded.

All participants received a 2 mg/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. Follow-up will continue through week 48.

Results

• 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 8 weeks of post-treatment follow-up, the corresponding SVR8 rates were 100%, 100%, and 91%.
• 1 person in the simeprevir group relapsed between weeks 8 and 12 of post-treatment follow-up, and 1 in the daclatasvir group did so by week 8.
• 1 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 2 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.

"We believe the data reported at the ILC meeting further demonstrate the clinical utility of RG-101 to shorten oral HCV treatment regimens to just 4 weeks," Regulus president and CEO Paul Grint said in a company press release.  "With interim data now through 24 weeks of follow-up, the consistent trend in efficacy and safety is encouraging, which supports the potential of RG-101 to become a backbone agent in combination with all classes of oral therapies."

4/18/16

Reference

G Horvath, G Papatheodoridis, M Fabri, M Makara, et al. 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. EASL International Liver Congress 2016. Barcelona, April 13-17, 2016. Abstract GS08.

Other Sources

EASL. Investigational treatment, RG-101 combined with direct-acting antivirals shows potential to be effective in Hepatitis C with a ‘shorter than standard’ four week course. Press release. April 15, 2016.

Regulus Therapeutics. Regulus Presents Additional Interim Data on RG-101 at International Liver Congress (ILC 2016). Press release. April 15, 2016.