All-Oral Therapy With Nucleotide Inhibitors Sofosbuvir and GS-0938 for 14 Days in Treatment-Naive Genotype 1 Hepatitis C (NUCLEAR)

E. J. Lawitz; M. Rodriguez-Torres; J. Denning; A. Mathias; H. Mo; B. Gao; M. T. Cornpropst; M. M. Berrey; W. T. Symonds

Disclosures

J Viral Hepat. 2013;20(10):699-707. 

In This Article

Abstract and Introduction

Abstract

Sofosbuvir and GS-0938 are distinct nucleotide analogues with activity against hepatitis C virus (HCV) in vitro. We evaluated the antiviral activity and safety of sofosbuvir and GS-0938 alone and in combination in HCV genotype 1 patients. In this double-blind study, 40 treatment-naïve patients were randomly assigned to 4 treatment cohorts: (i) GS-0938 for 14 days, (ii) GS-0938 for 7 days followed by GS-0938 plus sofosbuvir for 7 days, (iii) sofosbuvir for 7 days followed by GS-0938 plus sofosbuvir for 7 days and (iv) GS-0938 plus sofosbuvir for 14 days. In each arm, 8 patients received active drug and 2 placebo. After 7 days of dosing, patients in all 4 dose groups experienced substantial reductions in HCV RNA, with median declines (Q1, Q3) of −4.50 (−4.66, −4.24) in Cohort 1, −4.55 (−4.97, −4.13) in Cohort 2, −4.65 (−4.78, −4.17) in Cohort 3 and −4.43 (−4.81, −4.13) in Cohort 4; patients receiving placebo had essentially no change in HCV RNA (+0.07 log10 IU/mL). Seven days after the end of treatment, the proportions of patients with HCV RNA <15 IU/mL were 4 (50%), 8 (100%), 7 (88%) and 5 (63%) for Cohorts 1–4, respectively, vs 0 for placebo. No viral breakthrough or resistance mutations were observed. No serious adverse events or Grade 3 or 4 adverse events were reported. Sofosbuvir and GS-0938—alone and in combination—were well tolerated and led to substantial reductions in viral load. Sofosbuvir is undergoing further investigation as a possible backbone of an all-oral regimen for chronic HCV.

Introduction

Adding the protease inhibitors telaprevir or boceprevir to peginterferon and ribavirin has improved rates of sustained virologic response in patients with genotype 1 chronic hepatitis C virus (HCV) by as much as 30% over those seen with peginterferon and ribavirin alone.[1,2] However, these regimens can be challenging for patients to adhere to and tolerate.[3] Peginterferon in particular is associated with a number of onerous side effects, including flulike symptoms, anaemia and depression.[4] Telaprevir, boceprevir and many other direct-acting antivirals cannot be used as monotherapies because of the potential for viral resistance. To minimize the development of resistance, many experimental all-oral regimens involve combination therapy. Recently, it was reported that an all-oral combination therapy with an NS5A replication complex inhibitor and an NS3 protease inhibitor can lead to sustained virologic response in HCV genotype 1 patients who were prior nonresponders to peginterferon and ribavirin,[5,6] suggesting that interferon-free regimens may be a viable treatment strategy.

Sofosbuvir (GS-7977) is a pyrimidine nucleotide analogue inhibitor of the HCV NS5B polymerase. GS-0938 is a purine nucleotide analogue inhibitor of the NS5B polymerase. They both employ unique prodrug components that deliver the monophosphorylated forms of the respective nucleosides. Like other nucleoside or nucleotide analogues, sofosbuvir and GS-0938 appear to have equal antiviral activity against various HCV subtypes as well as high barriers to genetic resistance.[7–10] Phenotypic evaluation of mutations from an in vitro resistance selection experiment with GS-0938 indicated that single amino acid changes were not sufficient to significantly reduce the activity of GS-0938. Among these, the highest fold-shift in EC50 was 3.7 ± 1.4 attributed to C223H.[8] Combinations of three and four amino acid changes were required to confer 17-fold and 20-fold reduced susceptibility to GS-0938. A resistance selection experiment performed with sofosbuvir identified NS5B S282T and M289L as resistance-associated mutations.[9]In vitro, the combination of sofosbuvir and GS-0938 results in additive to synergistic antiviral activity.[11] In patients with HCV genotype 1 infection, 7 days of monotherapy with GS-0938 resulted in HCV RNA reductions of up to 5.35 log10 IU/mL.[12] Before this trial, sofosbuvir had not been administered as monotherapy, but was studied as one of the two diasteromers of the compound GS-9851 (PSI-7851). In a dose-ranging monotherapy study, patients receiving 400 mg of GS-9851 for 3 days experienced a mean maximal reduction in HCV RNA of 1.95 log10 IU/mL.[13] When sofosbuvir was administered to HCV genotype 1 patients in combination with peginterferon and ribavirin for 28 days, the combination resulted in mean HCV RNA reductions of up to 5.3 log10 IU/mL.[14]

Sofosbuvir and GS-0938 have a number of structural differences; they employ different prodrug cleavage pathways, have largely independent phosphorylation pathways, compete with separate endogenous nucleotide pools (purine/pyrimidine) and have complementary resistance profiles.[15–17] This phase 1, placebo-controlled study of sofosbuvir and GS-0938 alone and in combination for 14 days is the first proof-of-concept study of the feasibility of combining two nucleotides for the treatment of patients with genotype 1 HCV and is the first trial characterizing the activity of sofosbuvir administered as monotherapy for 7 days.

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