GSK2878175 Shows Early Promise Against Hepatitis C in Phase 1 Dose-Escalation Trial
GlaxoSmithKline tests a novel NS5B inhibitor across four dose groups in chronic HCV patients, evaluating safety and short-term antiviral activity.
Summary
This Phase 1 clinical trial investigated GSK2878175, a new type of antiviral drug called a site IV NS5B non-nucleoside inhibitor, in approximately 44 adults with chronic hepatitis C virus infection. Participants were divided into four groups and received either the drug or a placebo once daily for two days at escalating doses ranging from 10 mg to 60 mg. The trial aimed to determine how the drug behaves in the body — how much enters the bloodstream and how quickly it is eliminated — while also checking for side effects and measuring its ability to reduce hepatitis C viral levels over the short treatment window. This type of early-phase safety and pharmacokinetics study is a critical first step before larger, longer-term efficacy trials can proceed.
Detailed Summary
Chronic hepatitis C infection remains a significant global health burden, capable of progressing to cirrhosis, liver failure, and hepatocellular carcinoma if untreated. While direct-acting antivirals have transformed HCV treatment in recent years, the pipeline of novel mechanism agents remains important for addressing resistance, tolerability, and access challenges.
This Phase 1 randomized, placebo-controlled, dose-escalation study evaluated GSK2878175, a site IV NS5B non-nucleoside inhibitor (NNI), in approximately 44 adults with chronic HCV infection. The NS5B RNA-dependent RNA polymerase is an essential viral replication enzyme with no human equivalent, making it an attractive drug target. Site IV NNIs represent a distinct binding pocket compared to earlier NS5B inhibitors, potentially offering differentiated resistance profiles.
Participants were enrolled into four sequential dose groups (A through D), receiving either GSK2878175 or placebo once daily for two consecutive days. Planned doses were 10 mg, 30 mg, 60 mg, and 60 mg respectively, though adaptive design allowed dose modification between cohorts based on accumulating safety and pharmacokinetics data. Groups A, B, and C enrolled 8 participants each (6 active, 2 placebo), while Group D enrolled 20 (15 active, 5 placebo), enriching the 60 mg dataset.
Primary endpoints included pharmacokinetic parameters — peak plasma concentration, area under the curve, and half-life — alongside safety and tolerability. Secondary endpoints captured antiviral activity, measured as change in HCV RNA from baseline after just two days of dosing, providing early proof-of-concept data.
The trial's adaptive, sequential design reflects best practices for Phase 1 antiviral development, minimizing participant risk while gathering dose-response information efficiently. Limitations include the very short two-day treatment duration and the small sample size, both of which preclude conclusions about sustained virologic response or long-term safety. Full results were not available from the abstract alone.
Key Findings
- GSK2878175 targets the NS5B site IV pocket, a distinct mechanism from earlier HCV polymerase inhibitors.
- Four sequential dose cohorts (10–60 mg) were evaluated using an adaptive design to optimize safety.
- Two-day dosing provided early antiviral activity signal, serving as proof-of-concept for HCV viral suppression.
- Approximately 44 participants enrolled across genotype-stratified groups, with placebo controls in each cohort.
- Pharmacokinetic profiling assessed drug absorption and clearance to guide future dosing regimens.
Methodology
Phase 1 randomized, placebo-controlled, sequential dose-escalation trial in approximately 44 adults with chronic HCV infection across four cohorts. Doses ranged from 10 mg to 60 mg once daily for two days, with adaptive dose adjustments permitted between cohorts based on emerging safety and PK data. Sponsored by GlaxoSmithKline; completed status confirmed on ClinicalTrials.gov.
Study Limitations
This summary is based on the abstract and ClinicalTrials.gov registration only, as the full study data are not publicly available. The two-day treatment window is extremely short and cannot establish sustained antiviral efficacy or long-term safety. Small sample sizes per cohort (as few as 6 active participants) limit statistical power for detecting uncommon adverse events.
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