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AASLD 2015: MiR-122 Inhibitor RG-101 Suppresses Hepatitis C Virus with Single Dose


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 log in people with HCV genotypes 1, 3, and 4, and 21% of treated patients still had undetectable virus levels 28 weeks after dosing, according to research presented at the AASLD Liver Meeting in November.

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. 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.

Meike van der Ree from Academic Medical Center 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.

This multicenter 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 hepatitis C treatment-naive and had absent to mild liver fibrosis (stage F0-F1). People with advanced cirrhosis and HIV or hepatitis B coinfection 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 randomization. At that point, those who experienced more than a 2 log decrease in HCV RNA from baseline with less than 1 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 -4.1 log in the 2 mg/kg cohort and -4.8 log in the 4 mg/kg group.
  • 6 treated patients had viral rebound by 8 weeks, while 22 participants maintained at least a 2 log reduction and were included in the extended follow-up study.
  • Within the latter group, 6 patients -- including all 3 genotypes -- still had undetectable HCV RNA at the end of the 28-week extended follow-up period.
  • Among 11 participants with viral rebound, 5 genotype 1 patients showed a single mutation in the miR-122 binding site, while 2 patients (genotypes 3 and 4) had  double mutations.
  • 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 (5 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 enzymes 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 2 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 resultsin 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, JM de Vree, F Stelma, et al. A Single Dose of RG-101, a GalNAc-Conjugated Oligo- nucleotide Targeting miR-122, Results in Undetectable HCV RNA Levels in Chronic Hepatitis C Patients at Week 28 of Follow-up. AASLD Liver Meeting 2015. San Francisco, November 13-17, 2015. Abstract 208.

MH van der Ree, JM de Vree, F Stelma, 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. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract L07.

 Other Sources

Regulus Therapeutics. Regulus to Present Updated Data Supporting RG-101 as Novel microRNA Therapeutic for the Treatment of HCV at The Liver Meeting 2015 (AASLD). Press release. October 2, 2015.

Regulus Therapeutics. Late-Breaking Oral Presentation at The International Liver Congress (ILC 2015) Highlights RG-101's Potent, Durable and Pan-Genotypic Effects in Diverse HCV Population. Press release. April 25, 2015.