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

Yanli Deng; Fiona Campbell; Kelong Han; Dickens Theodore; Mark Deeg; Michael Huang; Robert Hamatake; Soumi Lahiri; Shuguang Chen; Gabor Horvath; Spilios Manolakopoulos; George N. Dalekos; George Papatheodoridis; Ioannis Goulis; Tivadar Banyai; Bernd Jilma; Martin Leivers

Disclosures

J Viral Hepat. 2020;27(7):699-708. 

In This Article

Abstract and Introduction

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.

Introduction

The standard of care for chronic hepatitis C has greatly improved over the last decade. The approval of a new generation of direct-acting antivirals (DAA) has notably shortened chronic hepatitis C treatment with improved tolerability and efficacy.[1] The majority of patients are accessing care and achieving SVR, but there remain subpopulations where even highly effective shortened-duration therapies may fall short.[2] A single-visit treatment regimen can provide a valuable addition to the armamentarium to address the unmet medical need for patients such as the homeless, the incarcerated and intravenous drug users.

GSK2878175 is a second-generation non-nucleoside nonstructural 5B protein (NS5B)-palm polymerase inhibitor. The oral formulation of this molecule has been administered to both healthy volunteers and to chronic hepatitis C patients and has demonstrated acceptable safety, tolerability and pan-genotypic antiviral activity, especially for genotype 3 that is often considered as 'difficult to treat' by sofosbuvir-based regimens.[3,4] Moreover, GSK2878175 has the physico-chemical properties that allow formulation as a long-acting injectable.[5]

RG-101 is a hepatocyte-targeted, carbohydrate-acetylgalactosamine-conjugated oligonucleotide with potent antagonist activity against miR-122. MiR-122 is a critical host factor for HCV replication and accumulation.[6] Results of a Phase 2 study (RG101-02) have demonstrated the safety and efficacy of subcutaneous injections of RG-101 in combination with DAAs in treatment-naïve chronic hepatitis C patients.[7]

We conducted two early phase clinical studies to test the feasibility of combining GSK2878175 and RG-101 for single-visit cure. In the first study (RG101-04), we tested the combination of these two agents by assessing the safety and efficacy of daily oral tablets of GSK2878175 with single subcutaneous injection of RG-101 in chronic hepatitis C patients. The aim of this first study was to understand what duration of GSK2878175 exposure was required in the context of a single injection of RG-101 to achieve high cure rates of chronic hepatitis C (SVR ≥ 90%). In the second study (RG101-06), we evaluated the safety, tolerability and pharmacokinetics (PK) of a long-acting injectable formulation of GSK2878175 (GSK2878175 LAI) in healthy participants. In this report, we describe the results of these two studies and discuss the potential of combining these two novel agents for single-visit cure.

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