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First in Human Study of GS-9688, an Oral Tolllike
Receptor 8 (TLR8) Agonist, in Healthy
Volunteers: Assessment of Safety, Tolerability,
Pharmacokinetics, Pharmacodynamics and
Food Effect
Maribel Reyes1, Justin D Lutz2, Audrey H. Lau1, Anuj Gaggar1,
Ethan Grant3, Adarsh Joshi4, Richard L Mackman5, John
Ling6, Anita Mathias2, Polina German6 and Edward J. Gane7,
(1)Gilead Sciences, Inc, Foster City, California, USA, (2)
Gilead Sciences, Inc., (3)Biomarker, Gilead Sciences, (4)
Biostatistics, Gilead Sciences, (5)Medicinal Chemistry, Gilead
Sciences, Inc., (6)Clinical Pharmacology, Gilead Sciences,
(7)New Zealand Liver Transplant Unit, Auckland City Hospital,
Auckland, New Zealand
Background: GS-9688 is an oral small molecule agonist
of toll-like receptor 8 (TLR8) in clinical development for
the treatment of chronic hepatitis B (CHB). This study
evaluated the safety, tolerability, pharmacokinetics (PK),
pharmacodynamics (PD) and food effect in healthy volunteers
after a single oral dose of GS-9688. Methods: The study
consisted of Part A (dose escalation) and Part B (food effect
evaluation). Subjects were 18-45 years of age, BMI 19-30
kg/m2, with an approximately even distribution of males and
females. Part A was randomized and placebo-controlled
single ascending dose study of 0.5, 1.5, 3 and 5 mg GS-9688
(N=12 active per dose, N=11 placebo across doses) given in
the fasted state. Part B was fixed sequence food effect study
with a single dose of GS-9688 (1.5 mg, N=12) in fasted and
then fed states (moderate-fat). The primary study endpoints
were safety, tolerability and PK. Plasma PK and serum PD
(IL-1RA and IL-12p40 ) were evaluated on Day 1 and 2 (Parts
A and B) and on Day 8 and 9 (Part B only). GS-9688 PK
parameters were estimated by non-compartmental analysis
and proportionality was examined across doses. PK/PD
relationship was explored. Safety was assessed throughout
the study. Results: All enrolled subjects (N=71) completed the
study. GS-9688 was generally safe at single doses up to and
including 5 mg. No Grade 3 or higher AEs or laboratory AEs
serious AEs, or deaths were reported. The most common AEs
were nausea and vomiting. GS-9688 was rapidly absorbed
with a Cmax between 0.5 - 1.0 hours. GS-9688 exposure was
approximately dose proportional. Oral GS-9688 induced
dose-dependent induction of serum IL-1RA and IL-12p40,
which peaked 4 hours post-dose and returned to near
baseline by 24 hours post-dose. PK/PD (dose/biomarker)
analysis indicated near maximal increases for IL-12p40 at 5
mg and >5 for IL-1RA at >5 mg. Food slightly increased GS-
9688 AUCinf and Cmax by 18% and 8%, respectively compared
with the fasted state. Conversely, dosing with food resulted
in a reduced induction of IL-1RA (40%) and IL-12p40 (30%)
relative to the fasted state (380% and 260%, respectively).
Conclusion: GS-9688 was safe after a single dose of up to
and including 5 mg. The safety, tolerability PK and PD profiles
support further evaluation of this compound in CHB patients.
Disclosures:
Maribel Reyes – Gilead Sciences: Employment
Ethan Grant – Gilead Sciences, Inc: Employment; Gilead Sciences, Inc: Stock
Shareholder
Edward J. Gane – Gilead Sciences: Speaking and Teaching; AbbVie: Speaking
and Teaching; Janssen: Advisory Committee or Review Panel; Roche: Advisory
Committee or Review Panel
Disclosure information not available at the time of publication: Justin D Lutz,
Audrey H. Lau, Anuj Gaggar, Adarsh Joshi, Richard L Mackman, John Ling,
Anita Mathias, Polina German
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发表于 2018-10-10 20:48