EFFICACY AND SAFETY OF ORAL TLR8 AGONIST GS-9688
IN VIRALLY-SUPPRESSED ADULT PATIENTS WITH CHRONIC
HEPATITIS B: A PHASE 2, RANDOMIZED, DOUBLE-BLIND
PLACEBO-CONTROLLED, MULTI-CENTER STUDY
Edward J. Gane1, Yang Zhao2, Susanna Tan2, Audrey H Lau2,
Anuj Gaggar2, Mani Subramanian2, Shyam Kottilil3 and Lydia
Tang4, (1)University of Auckland, (2)Gilead Sciences, Inc,
Foster City, California, USA, (3)Division of Clinical Care and
Research, Institute of Human Virology, University of Maryland
School of Medicine, Baltimore, MD, USA, (4)Division of
Clinical Care and Research, Institute of Human Virology,
University of Maryland School of Medicine
Background: GS-9688 is an oral selective small molecule
agonist of Toll-like receptor 8 (TLR8) in clinical development for
the treatment of chronic hepatitis B (CHB) Here we evaluate
the safety and efficacy of GS-9688 in CHB patients who were
virally suppressed on an oral antiviral (OAV). Methods: In this
multicenter, randomized, double-blind, phase 2 study of GS-
9688 in virally suppressed CHB patients on OAV, 48 patients
were enrolled in two cohorts (HBeAg-positive and HBeAgnegative)
evaluating 3.0 mg, 1.5 mg, and placebo (2:2:1) of
GS-9688 once a week (QW) for 24 weeks in combination with
OAV. Safety assessments included monitoring of adverse
events (AE) and laboratory abnormalities. The primary efficacy
endpoint was the proportion of patients with ≥ 1 log10 IU/mL
decline in HBsAg levels from baseline at week 24 Secondary
endpoints include the proportion of patients with HBsAg and
HBeAg loss and changes in pharmacodynamic (PD) markers,
IL-1RA and IL-12p40 Results: Baseline characteristics of
the 48 patients were similar across groups (table) Safety
and pharmacodynamic parameters are also summarized
in the table. Grade ≥ 3 AE were observed in 0%, 10%, and
0% of patients treated with 3 0 mg, 1 5 mg, and placebo,
respectively One patient in the study (HBeAg-negative,
1.5mg group) achieved the primary endpoint of ≥ 1 log10 IU/
mL decline in HBsAg levels at week 24 One patient in the
study (HBeAg-negative, 3 mg group) achieved HBsAg loss
and another patient (HBeAg-positive, 1 5 mg group) achieved
HBeAg loss at week 24 Dose-dependent increases in serum
IL-1RA and IL-12p40 in the GS-9688 treatment groups were
observed Conclusion: Oral GS-9688 is safe, well-tolerated,
and induced dose-dependent PD changes in CHB patients
5% of patients experienced either ≥ 1 log10 IU/mL decline in
HBsAg levels or HBsAg loss at week 24 Further evaluation
of immunologic, antiviral, and pharmacodynamics markers
through week 48 are underway.作者: StephenW 时间: 2019-11-3 18:46