Hepatitis C is a result of a hepatocyte specific infection induced by the virus known as HCV. Chronic HCV may lead to significant liver disease, including chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. According to the World Health Organization, up to 170 million people are chronically infected with HCV worldwide, and more than 350,000 people die from HCV annually. The CDC estimates that there are currently approximately 3.2 million persons infected with HCV in the United States. Regulus believes that its’ miR-122 antagonist, RG-101, may be a useful agent in emerging combination regimens to address difficult-to-treat genotypes and to potentially expand upon the current therapies available to clinicians treating HCV patients.
RG-101 is Regulus’ wholly-owned, GalNAc-conjugated anti-miR targeting miR-122 for the treatment of HCV. Regulus has evaluated RG-101 in a completed clinical study conducted in the Netherlands. 58 healthy volunteers and 32 HCV patients with multiple genotypes, liver fibrosis status and treatment history were enrolled in the four part study: (i) a single ascending-dose study in which healthy volunteer subjects received a single subcutaneous dose of RG-101, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 4 mg/kg and 8 mg/kg or placebo; (ii) a multiple-ascending dose study in which healthy volunteer subjects received a monthly single subcutaneous dose for four months of RG-101 or placebo; (iii) a single-dose drug-drug interaction study in which healthy volunteer subjects received a single subcutaneous dose of RG-101 in combination with simeprevir (OLYSIO™), an approved direct acting antiviral; and (iv) a single-dose study in which HCV patients received either a single subcutaneous dose of RG-101 or placebo at two doses, 2 mg/kg of RG-101 (the first dose cohort) or 4 mg/kg of RG-101 (the second dose cohort), to assess the safety and viral load reduction. Dosing in part IV is complete and extended follow up is ongoing. The primary objective is to evaluate safety and tolerability and the secondary objectives are to evaluate pharmacokinetics, viral load reduction and any impact an oral direct-acting antiviral, such as simeprevir (OLYSIO™), may have on the pharmacokinetics of RG-101.
Treatment with a single subcutaneous dose of either 2 mg/kg or 4 mg/kg of RG-101 as monotherapy resulted in significant and sustained viral load reductions in all treated HCV patients, including patients with difficult to treat genotypes, various liver fibrosis status and those who have experienced viral relapse after a prior IFN-containing regimen. At day 29, mean viral load reductions of 4.8 log10 and 4.1 log10 were demonstrated in the 4 mg/kg and 2 mg/kg single dose cohorts, respectively. At day 57, 15 out of 28 patients treated with one single administration of either 2 mg/kg or 4 mg/kg of RG-101 had HCV RNA levels below the limit of quantification and 12 out of these 15 treated patients had HCV RNA levels that cannot be detected. To date, RG-101 has a favorable safety profile with no serious adverse events or discontinuations reported in the treated HCV patients. In early August 2015, Regulus announced that it initiated the planned Phase II study evaluating the efficacy of RG-101, a GalNAc-conjugated anti-miR targeting microRNA-122, when given in combination with marketed anti-HCV agents Harvoni®, Olysio®, and Daklinza™ for 28 days. Patient screening has begun and dosing is expected to commence within the near term. The study will be conducted at multiple sites outside the United States. Regulus expects to report interim data from the Phase II study by the end of 2015 and sustained viral response data 12 weeks following conclusion of treatment (SVR12) in the first quarter of 2016.