GSK2336805 is an orally bioavailable hepatitis C virus (HCV) inhibitor working through an NS5A-mediated mechanism. This first-time-in-human study was conducted to assess the safety, tolerability, pharmacokinetics, metabolism, and efficacy of GSK2336805 in healthy subjects and subjects infected with HCV genotype 1. We performed a three-part, randomized, doubleblind, placebo-controlled study in 46 healthy subjects and 23 HCV-infected subjects. After an overnight fast, healthy subjects received GSK2336805 as 10 mg, 30 mg, 30 mg plus food, and 60 mg in a single dose and 10 mg (7 days), 30 mg (7 days), and 75 mg (14 days) in a once-daily multiple dose. Subjects with HCV received GSK2336805 as a 1-to 120-mg single dose. In subjects with HCV, reductions in HCV RNA were observed within 4 h and a single dose of GSK2336805 of >10 mg resulted in a statistically significant >2-log reduction in HCV RNA compared with placebo at 24 h postdose. GSK2336805 was readily absorbed in all subjects, and the half-life (t 1/2 ) was suitable for once-daily dosing. Administration of GSK2336805 with food had no effect on plasma GSK2336805 exposure; however, absorption was delayed, with a median t max (time to maximum concentration of drug in serum) of 4.5 versus 2.0 h. Twenty subjects who received GSK2336805 experienced mild to moderate adverse events; none were serious. GSK2336805 was well tolerated and exhibited rapid, significant antiviral activity after a single dose in HCV-infected subjects. These results support the conduct of further studies evaluating GSK2336805 administered once daily for longer durations in combination with peginterferon, ribavirin, and other direct-acting antivirals. (This study has been registered at ClinicalTrials.gov under registration no. NCT01277692.) H epatitis C virus (HCV) is the leading cause of cirrhosis, liver failure, and primary hepatocellular carcinoma and the primary indication for liver transplantation (1). Of the six major HCV genotypes, genotype 1 (GT-1) is the most prevalent and is associated with the highest rate of treatment failure (2-4).Administration of two recently approved HCV nonstructural protein 3 (NS3) serine protease inhibitors, telaprevir and boceprevir, with the standard treatment of peginterferon and ribavirin led to sustained viral response rates of 75% and 68%, respectively (5-8). However, increased side effects, especially skin rash and anemia, are still problematic (9, 10). Therefore, antiviral agents with novel modes of action are necessary for an all-oral combination therapy to further improve sustained viral response rates and reduce side effects (11).NS5A is essential for HCV replication, and NS5A inhibitors have shown potent anti-HCV activity relative to interferon-ribavirin regimens in clinical trials (12)(13)(14)(15). GSK2336805 is an orally bioavailable NS5A inhibitor with selective activity against GT-1a and GT-1b subtypes in HCV replicon systems (50% effective concentration [EC 50 ] for GT-1a, 58.5 pM; for GT-1b, 7.4 pM) in vitro (J. Walker, submitted for publicat...

Background GSK3640254 (GSK’254) is a next-generation HIV-1 maturation inhibitor with pharmacokinetics (PK) supporting once-daily therapy. Methods This phase IIa double-blind (sponsor-unblinded), randomized, placebo-controlled, adaptive study evaluated antiviral effect, safety, tolerability, and PK of once-daily GSK’254 monotherapy administered with food (moderate-fat meal) in HIV-1–positive, treatment-naive adults. In part 1, participants received GSK’254 10 or 200 mg for 10 days. In part 2, participants received GSK’254 40, 80, or 140 mg for 7 days, modified from 10 days by a protocol amendment to decrease potential for resistance-associated mutations (RAMs). The primary endpoint was maximum change from baseline in HIV-1 RNA. Results Maximum changes in HIV-1 RNA of −0.4, −1.2, −1.0, −1.5, and −2.0 log10 occurred with GSK’254 10, 40, 80, 140, and 200 mg, respectively. Regardless of dosing duration, doses ≥40 mg resulted in ≥1-log10 declines in HIV-1 RNA. Plasma PK was generally dose proportional to 140 mg but non-proportional between 140 and 200 mg. Four participants in the 200-mg group developed RAMs on Day 11 in part 1, one with phenotypic resistance. No RAMs occurred in part 2. Adverse events (AEs) were reported by 22 (65%) participants; headache was the most common (n=4). Two non–drug-related serious AEs occurred. All AEs were of mild-to-moderate intensity, except for 2 grade 3 non–drug-related AEs in 1 participant. Conclusions This monotherapy study established a dose–antiviral response relationship for GSK’254. No safety or tolerability concerns were noted. These results supported dose selection for the ongoing phase IIb study (ClinicalTrials.gov: NCT04493216).

SummaryGSK2878175 is a potent, pan-genotypic, non-nucleoside, nonstructural protein 5B palm polymerase inhibitor being developed for the treatment of chronic hepatitis C (CHC). A first-in-human, randomized, placebo-controlled, dose escalation study, evaluated the safety and pharmacokinetics of GSK2878175 administered as single and repeat oral doses (once daily for 14 days) to healthy volunteers. A separate proof-of-concept, placebo-controlled, repeat dose (once daily for 2 days) study evaluated the safety, pharmacokinetics and antiviral activity of GSK2878175 monotherapy in treatment-naïve, noncirrhotic, subjects with hepatitis C virus (HCV) genotype 1 [1a and 1b], 2, or 3. No deaths or SAEs were reported in either study, and treatment was well-tolerated. Across all the HCV genotypes, GSK2878175 monotherapy at doses of 10, 30 or 60 mg once daily for 2 days produced a statistically significant multilog reduction (P<.001) in plasma HCV RNA log 10 IU/mL from Baseline to 24, 48 and 72 hours after the first dose of GSK2878175 compared to placebo. The reduction in HCV RNA was sustained for a prolonged period across all of the active treatment groups, consistent with the long apparent half-life of GSK2878175 that was observed (mean t 1/2 range: 60-63 hours in the CHC subjects). In summary, GSK2878175, when administered to healthy subjects and subjects with CHC, did not reveal any safety concerns that would limit or preclude further clinical development. GSK2878175 monotherapy across a wide dose range produced substantial reduction in HCV RNA, irrespective of HCV genotype. The results from these studies support further evaluation of GSK2878175-based regimens. K E Y W O R D Schronic hepatitis C, clinical trial, direct-acting antiviral, NS5B palm polymerase inhibitor, pan-genotypic