MiR-122 inhibitor RG-101 suppresses hepatitis C virus with a single dose

Liz Highleyman
15 February 2016
Meike van der Ree, presenting at AASLD 2015. Photo by Liz Highleyman, hivandhepatitis.com

A 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 cytokine.

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 values.

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 direct-acting antivirals.

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.


MH van der Ree et al. A single dose of RG-101, a GalNAc-conjugated oligonucleotide targeting miR-122, results in undetectable HCV RNA levels in chronic hepatitis C patients at week 28 of follow-up. AASLD Liver Meeting, abstract 208, 2015.

MH van der Ree et al. A single subcutaneous dose of 2 mg/kg
or 4 mg/kg of RG-101, a GalNAc-conjugated oligonucleotide with antagonist activity against miR-122, results in significant viral load reductions in chronic hepatitis C patients. EASL International Liver Congress, abstract L07, 2015.