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

Abstract

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.

A Brief Review on the Regulatory Roles of MicroRNAs in Cystic Diseases and Their Use as Potential Biomarkers

“…For example, RGLS4326 (the only miRNA-based drug currently available in clinical settings to treat cystic disease) is a first-in-class anti-miR-17 oligonucleotide with promising potential for treating PKD evidencing favorable potency, stability, safety, pharmacokinetics, and pharmacodynamic characteristics [ 57 ]. Furthermore, Miravirsen and RG-101 (miRNA inhibition therapy for hepatitis C) [ 79 , 80 ], MRX34 (miRNA mimic for cancer therapy) [ 81 ] are some of the most promising therapies based on miRNA technologies. As a result, investors are becoming more interested in this field of research, and numerous pharmaceutical companies have started to develop miRNA-based therapeutics (e.g., miRagen Therapeutics Inc., Mirna Therapeutics Inc., and Santaris Pharma) [ 82 , 83 ].…”

γ Peptide Nucleic Acid-Based miR-122 Inhibition Rescues Vascular Endothelial Dysfunction in Mice Fed a High-Fat Diet

“… 73 − 78 However, the miR-122 inhibitor (RG-101) developed by Regulus Technologies was put on clinical hold due to the development of jaundice. 76 , 79 Further, studies in hepatocellular carcinoma patients and mice lacking miR-122 raised concern over the long-term effects of inhibiting miR-122 on hepatic function. 80 − 82 In general, the moderate efficacy of previous miR-targeted inhibitors and the associated adverse effects are the critical roadblocks in developing miR therapeutics.…”

“…In prior studies, inhibiting miR-122 in the context of the hepatitis C virus showed promise. − However, the miR-122 inhibitor (RG-101) developed by Regulus Technologies was put on clinical hold due to the development of jaundice. , Further, studies in hepatocellular carcinoma patients and mice lacking miR-122 raised concern over the long-term effects of inhibiting miR-122 on hepatic function. − In general, the moderate efficacy of previous miR-targeted inhibitors and the associated adverse effects are the critical roadblocks in developing miR therapeutics. Other concerns associated with using miR inhibitors for clinical applications are their moderate efficacy and adverse effects.…”

Noncoding RNA therapeutics — challenges and potential solutions

“…A recent phase II clinical trial reported the use of a single injection of the anti-miR-122 therapeutic RG-101 in combination with viral protein inhibitor GSK2878175, administered orally for 12 weeks as a single-visit curative regimen for chronic hepatitis C (EudraCT 2015-004702-42). This study reported high cure rates with an oral GSK2878175 administration scheme of longer than 9 weeks 79 ; however, the development of RG-101 was halted owing to adverse effects observed in a different clinical trial (discussed below) 80 .…”