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本帖最后由 StephenW 于 2018-10-15 09:01 编辑
401
Safety, Pharmacokinetics and
Pharmacodynamics of Oral TLR8 Agonist GS-
9688 in Patients with Chronic Hepatitis B: A
Randomized, Placebo-Controlled, Double-Blind
Phase 1b Study
Edward J. Gane1, Hyung Joon Kim2, Kumar Visvanathan3,
Yoon Jun Kim4, Anh-Hoa Nguyen5, Adarsh Joshi5, Maribel
Reyes6, Audrey H. Lau7, Anuj Gaggar7, Mani Subramanian6,
Stuart Keith Roberts8 and Young-Suk Lim9, (1)New Zealand
Liver Transplant Unit, Auckland City Hospital, Auckland,
New Zealand, (2)Chung-Ang University College of Medicine,
(3)Gastroenterology, St Vincent’s Hospital Melbourne,
(4)Department of Internal Medicine and Liver Research
Institute, Seoul National University Hospital, (5)Biostatistics,
Gilead Sciences, Inc., (6)Gilead Sciences, Inc., (7)Gilead
Sciences, Inc, Foster City, California, USA, (8)Department
of Gastroenterology, The Alfred, (9)Gastroenterology, Asan
Medical Center, University of Ulsan College of Medicine,
Seoul, Korea (the Republic of)
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). GS-9688 was
previously shown to induce immunomodulatory (e.g. IL-12p70)
and antiviral (e.g. IFN-γ) cytokine production and to activate
human immune effector cells (e.g. CD8+ T cells and NK cells)
in vitro. Oral GS-9688 also demonstrated sustained efficacy
and seroconversion in the woodchuck model of CHB. Here
we evaluate the safety, tolerability, pharmacokinetics (PK)
and pharmacodynamics (PD) of GS-9688 in CHB patients.
Methods: This is a randomized, blinded, placebo-controlled
study of GS-9688 in up to 6 cohorts of approximately 10 CHB
patients (virally suppressed or untreated viremic). Patients
received once weekly doses of 1.5 mg (Cohort 1) or 3 mg
(Cohort 2) on Days 1 and 8. Remaining adaptive cohorts will
receive 2 or 4 weekly doses of up to 3 mg. Periodic evaluation
of PK, viral parameters, and PD (e.g. IL-12p40 and IL-1RA)
response was performed in addition to safety assessments
(e.g. adverse events [AEs] and laboratory abnormalities).
Results: Blinded patient demographics for the first 2 cohorts
in virally suppressed CHB patients are summarized in the
table. GS-9688 was well tolerated in patients with no serious
AEs, Grade ≥3 AEs or laboratory AEs, and no study drug
discontinuations. The most common AEs were headache
and nausea. The PK was comparable between Day 1 and
Day 8 with no accumulation observed after two doses. Dosedependent,
induction of serum PD biomarkers IL-12p40 and
IL-1RA was observed, with similar levels of induction after
the first and second doses. Peak induction occurred 4 hours
postdose with levels returning to approximate baseline within
24 hours. Complete data from all cohorts will be presented.
Conclusion: Oral administration of GS-9688 and is safe and
well-tolerated in CHB patients and induces PD response.
Based on the encouraging safety and tolerability profiles,
together with the immunological response in this study, GS-
9688 is now being evaluated in two Phase 2 clinical trials.
These longer duration studies are designed to evaluate
the antiviral efficacy of GS-9688 in virally suppressed and
untreated viremic CHB patients. |
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发表于 2018-10-15 08:59
