Treatment of HCV Infection by Targeting MicroRNA

TLDR

The stability and propagation of hepatitis C virus (HCV) depends on a functional interaction between the HCV genome and liver‑expressed microRNA‑122 (miR‑122). This phase 2a study evaluated the safety and efficacy of miravirsen, an antisense oligonucleotide that sequesters miR‑122, in 36 patients with chronic HCV genotype 1 infection. Patients received five weekly subcutaneous injections of miravirsen at 3 mg/kg, 5 mg/kg, or 7 mg/kg, or placebo, over 29 days, and were followed until 18 weeks after randomization. Miravirsen produced a dose‑dependent reduction in HCV RNA, with mean maximum declines of 1.2, 2.9, and 3.0 log10 IU/mL for 3, 5, and 7 mg/kg groups respectively, and undetectable virus in one patient at 5 mg/kg and four patients at 7 mg/kg, with no dose‑limiting adverse events or viral resistance. Funded by Santaris Pharma; ClinicalTrials.gov NCT01200420.

Abstract

The stability and propagation of hepatitis C virus (HCV) is dependent on a functional interaction between the HCV genome and liver-expressed microRNA-122 (miR-122). Miravirsen is a locked nucleic acid-modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function.In this phase 2a study at seven international sites, we evaluated the safety and efficacy of miravirsen in 36 patients with chronic HCV genotype 1 infection. The patients were randomly assigned to receive five weekly subcutaneous injections of miravirsen at doses of 3 mg, 5 mg, or 7 mg per kilogram of body weight or placebo over a 29-day period. They were followed until 18 weeks after randomization.Miravirsen resulted in a dose-dependent reduction in HCV RNA levels that endured beyond the end of active therapy. In the miravirsen groups, the mean maximum reduction in HCV RNA level (log10 IU per milliliter) from baseline was 1.2 (P=0.01) for patients receiving 3 mg per kilogram, 2.9 (P=0.003) for those receiving 5 mg per kilogram, and 3.0 (P=0.002) for those receiving 7 mg per kilogram, as compared with a reduction of 0.4 in the placebo group. During 14 weeks of follow-up after treatment, HCV RNA was not detected in one patient in the 5-mg group and in four patients in the 7-mg group. We observed no dose-limiting adverse events and no escape mutations in the miR-122 binding sites of the HCV genome.The use of miravirsen in patients with chronic HCV genotype 1 infection showed prolonged dose-dependent reductions in HCV RNA levels without evidence of viral resistance. (Funded by Santaris Pharma; ClinicalTrials.gov number, NCT01200420.).