Randomized clinical trials towards a single-visit cure for chronic hepatitis C: Oral GSK2878175 and injectable RG-101 in chronic hepatitis C patients and long-acting injectable GSK2878175 in healthy participants.

Single-visit cures for chronic hepatitis C are lacking. We conducted two clinical studies towards the goal of developing a regimen for single-visit cure. In a randomized, open-label, Phase 2 study (RG101-04), investigators enrolled 26 adult chronic hepatitis C patients to evaluate safety and efficacy of single subcutaneous injection of RG-101 (4 mg/kg) and daily oral tablets of GSK2878175 (20 mg) for 6, 9 or 12 weeks. In another randomized, double-blind, single dose Phase 1 study (RG101-06), investigators enrolled 18 healthy men to assess safety and PK of GSK2878175 long-acting injectable at 100, 200 or 400 mg. In RG101-04, SVR48 rates were 50%, 56% and 89%, for the 6, 9 and 12 weeks treatment arms, respectively. All AEs were mild or moderate in severity (≤Grade 2). In RG101-06 at 400 mg, the mean duration of GSK2878175 plasma levels above in vitro therapeutic concentrations for GT1b was 41 days. All AEs were Grade 2 or less. In conclusion, single injection of RG-101 combined with 12 weeks of GSK2878175 oral tablets was generally well tolerated and resulted in high SVR rates in chronic hepatitis C patients. Single injections of GSK2878175 long-acting injectable were also well tolerated; however, higher doses would be required if used in combination with RG-101 to achieve the SVR rates observed in the oral combination study to enable a single-visit curative regimen.

The therapeutic potential of new investigational hepatitis C virus translation inhibitors.

INTRODUCTION: Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis, hepatocellular carcinoma and liver-related death worldwide. Currently, the anti-HCV armamentarium encompasses several direct-acting antivirals (DAA) that achieve very high response rates and have an excellent tolerability profile. However, they do not represent a final solution for HCV global eradication for at least these two reasons: i) some patients harbour resistant strains to DAAs and cannot benefit from currently available treatments; ii) the cost of these drugs remains very high. AREAS COVERED: This review summarizes pre-clinical and clinical data regarding HCV translation inhibitors, a new class of drugs currently in the pipeline with novel mechanisms of action. EXPERT OPINION: The availability of DAAs resolved most issues related to HCV treatment compared with the previous interferon-based therapies. However, there are some patients that cannot achieve a viral clearance with currently available treatments. Therefore, there is still room for new drugs in this setting, providing that they demonstrate an advantage in terms of efficacy, safety, cost or or simplicity of use. Based on preliminary results, at least for some promising molecules (e.g. miravirsen and RG-101), studies on safety and efficacy on this intriguing class of drugs are needed.