Background/Purpose: Adaptive and innate immune pathways are involved in inflammation and pathogenesis of autoimmune diseases including Rheumatoid Arthritis (RA) and Lupus Erythematosus (LE). Immune complexes found in RA and LE can stimulate production of (pro-) inflammatory cytokines via Toll-like receptor (TLR) activation. Interleukin (IL) receptor-associated kinase 4 (IRAK4) is a key signal transducer downstream of the myddosome-associated TLRs and IL-1 receptors. IRAK4 inhibition blocks (pro-) inflammatory cytokine production and is a potential therapeutic target for RA and LE. This Phase 1 first in human healthy volunteer study evaluated the pharmacodynamics (PD) of GS-5718, a potent and selective IRAK4 inhibitor in clinical development for treatment of RA and LE.

Methods: In this blinded, randomized, placebo-controlled, single and multiple (once daily for 10 days) oral dose Phase 1 study, healthy male and female subjects were enrolled in ascending dose cohorts to receive GS-5718 (15, 50 or 150 mg) or placebo under fasted (single dose cohorts) and fed conditions (multiple dose cohorts). For PD, serial whole blood samples were collected pre-dose and over up to 72 hours after single (Day 1) and multiple dose (Day 1 and 10) administration. A whole blood assay was developed to measure GS-5718 inhibition of ex-vivo (TLR7/8, R848) stimulated secretion of (pro-) inflammatory cytokines. Several (pro-) inflammatory cytokines were evaluated. TNF-α was chosen for the primary PD analysis as it showed the least variability and highest probability to see dose-dependent responses in healthy volunteers in pre-clinical in-vitro studies. The primary PD parameter was percent change of cytokine secretion from baseline (%Δ).

Results: A total of 74 subjects (n = 62 GS-5718; n = 12 placebo) enrolled, completed study drug treatments in this study and were evaluated for PD.

GS-5718 doses > 15 mg significantly decreased ex-vivo stimulated TNF-α compared to placebo in a dose-dependent manner 1 hour until up to 72 hours post single and multiple doses. GS-5718 resulted in sustained >90% inhibition of TNF-α 24 hours after single and multiple doses of 50 mg and 150 mg GS-5718 on day 1 (SAD, MAD) and day 10 after the last dose (MAD), respectively. Administration of 50 mg GS-5718 with food did not result in significantly prolonged time to reach maximal % Δ compared to administration of GS-5718 50 mg under fasting conditions. Percent inhibition of all cytokines measured were highly correlated with each other in all dose cohorts.

Conclusion: GS-5718, administered once daily, resulted in significant and sustained inhibition of ex-vivo stimulated secretion of TNF-α, the main PD biomarker. The PD profile of GS-5718 supports once daily dosing and further development in patients with RA and LE.

« Back to ACR Convergence 2021

ACR Meeting Abstracts - https://acrabstracts.org/abstract/phase-1-study-results-of-gs-5718-an-oral-irak4-inhibitor-pharmacodynamics-of-single-and-multiple-doses-of-gs-5718-in-healthy-subjects/