No financial relationships with ineligible companies to disclose
Grace Teng1, Thomas Fung2, Annamaria Mocciaro2, Ceyda Llapashtica1, Angie Hammond3, Jesse Gurgel4, zhiyu Huang1, Maria Mouchess1, Vanessa Gorney5, Wesley Minto1, Sunish Mohanan1, Adam Schrier1, Wylie Palmer2, Alexandra Borodovsky2 and Gundula Min-oo1, 1Gilead Sciences, Foster City, CA, 2Nurix Therapeutics, San Francisco, CA, 3Gilead Sciences, Inc., Seattle, WA, 4Gilead Sciences, Seattle, CA, 5Alterome Therapeutics, San Diego, CA Background/Purpose: Despite advances in treatment, chronic inflammatory diseases such as rheumatoid arthritis (RA) represent areas of high unmet medical need. IRAK4 is a proximal mediator of TLR and IL-1R family signaling and has emerged as a therapeutic target in multiple chronic inflammatory diseases. Due to the dual functions of IRAK4 as (A) a serine/threonine kinase and (B) as the key scaffolding component of the Myddosome, kinase inhibition alone is insufficient for full blockade of TLR/IL-1R signaling in certain cellular contexts1.In contrast, targeted protein degradation of IRAK4 nullifies both kinase and scaffolding functions, thus fully inhibiting the pro-inflammatory outputs of TLR and IL-1R engagement in immune and non-immune cell types.Here, we report that IRAK4 degradation by GS-6791 inhibits TLR- and IL-1R-driven responses in vitro and in vivo across a range of cell types and achieves robust efficacy in a preclinical arthritis model. Methods: IRAK4 protein levels and TLR- or IL-1R-induced cytokine production were measured in cells treated with GS-6791 or control inhibitors, by flow cytometry or ELISA. In vivo IRAK4 degradation was assessed in rodents (using Western blot or mass spectrometry) and non-human primates (NHP, using flow cytometry) after oral dosing with GS-6791.Pharmacodynamic effects of IRAK4 degradation on pro-inflammatory cytokine production in plasma were assessed in mice challenged with TLR ligand or IL-1b. The effect of IRAK4 degradation on joint swelling and pathology was assessed in an 18-day rat collagen-induced arthritis (CIA) model. Results: GS-6791 demonstrated potent IRAK4 degradation and inhibited R848, CpG, and LPS-induced cytokine secretion in human PBMCs, as well as human and NHP whole blood, and mouse splenocytes.Importantly, IRAK4 degradation resulted in deeper inhibition of TLR9 and IL-1b-driven responses in human B cells and rheumatoid-arthritis synovial fibroblasts, respectively, compared to IRAK4 kinase inhibition.Oral administration of the degrader achieved >90% IRAK4 degradation in rodents, resulting in dose-dependent reduction of induced plasma cytokines following acute challenge with CpG or IL-1β.Robust IRAK4 degradation was similarly achieved in NHP (PBMC, >85%) at a daily oral dose of 6 mg/kg. Importantly, IRAK4 degradation ameliorated disease in a rat CIA efficacy model, effectuating dose-dependent reduction of ankle swelling and comparable reduction of joint pathology to a dexamethasone-treated control group. Conclusion: IRAK4 protein degradation by GS-6791 inhibited in vitro TLR and IL-1R-mediated cellular responses, with a differentiated profile from IRAK4 kinase inhibition in human B cells and RA synovial fibroblasts.Similarly, GS-6791 robustly inhibited pro-inflammatory signaling in vivo, triggered by both TLR ligands and IL-1-family cytokines.The striking efficacy of GS-6791 in a preclinical arthritis model supports the use of this treatment modality in RA and supports further evaluation in other TLR- or IL-1R-driven inflammatory indications. 1. DeNardo et al. JBC 2018 (DOI 10.1074/jbc.RA118.003314)
G. Teng: Gilead, 3; T. Fung: Nurix Therapeutics, 3, 11; A. Mocciaro: None; C. Llapashtica: None; A. Hammond: Gilead Sciences, 3; J. Gurgel: Gilead, 3; z. Huang: Gilead Sciences, 3; M. Mouchess: Gilead, 3; V. Gorney: None; W. Minto: Gilead Sciences, 3; S. Mohanan: Gilead Sciences, 3; A. Schrier: Gilead, 3; W. Palmer: Nurix Therapeutics, 3, 11; A. Borodovsky: Nurix Therapeutics, 3, 11; G. Min-oo: Gilead, 3.