FRI0129 THE BTK INHIBITOR, FENEBRUTINIB, EFFECTIVELY MODULATES B AND MYELOID CELL BIOLOGY IN RHEUMATOID ARTHRITIS PATIENTS
Authors: Alyssa Morimoto, Julie Rae, Leslie Chinn, Nandhini Ramamoorthi, Olivia Hwang, Alexandra Ward, D. James Haddon, Caroline Looney, Rupal Desai, Balazs Toth, Katie Tuckwell, Michael J. Townsend
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Bruton's tyrosine kinase (BTK) plays an essential role in B cell development. BTK acts downstream of the B cell receptor in B cells, and Fc receptor signaling in myeloid cells, pathways thought to be involved in the pathogenesis of RA. Fenebrutinib (FEN) is a non-covalent small molecule inhibitor of BTK with greater than 100-fold selectivity relative to other kinases<sup>1</sup>. <h3>Objectives:</h3> To characterize the mechanistic effects of FEN on B and myeloid cell biology and determine the potential of biomarkers to predict response to FEN treatment in patients with RA. <h3>Methods:</h3> The ANDES study included RA patients (pts) on background methotrexate (MTX) with inadequate response to prior MTX (n=480, Cohort 1, MTX-IR) or anti-TNFs (n=98, Cohort 2, TNF-IR). Cohort 1 pts were randomized to receive PBO, adalimumab (ADA) 40 mg Q2W, or FEN 50 mg QD, 150 mg QD or 200 mg BID. Cohort 2 pts were randomized to receive PBO or FEN 200 mg BID. Clinical efficacy was assessed based on the proportion of pts achieving ACR50 at week 12. Pts for whom samples were available were assessed for levels of rheumatoid factor (RF), total IgM and IgG, CCL4, CXCL13, CRP and IL6. <h3>Results:</h3> Primary study results are reported separately. Overall, treatment with FEN caused significant reductions in RF (by week 12) and total IgM and IgG (at weeks 4-12) relative to PBO (<b>Table 1</b>). Early and sustained reductions of the B cell chemokine CXCL13 and the myeloid-enriched biomarker CCL4 were observed with FEN or ADA relative to PBO by week 1. CRP levels were significantly reduced with 200 mg BID FEN by week 8, and with ADA by week 2 relative to PBO. By week 12, there was a trend toward lower IL6 levels with FEN treatment relative to PBO, whereas ADA significantly reduced IL6 levels by week 1 relative to PBO in MTX-IR pts. In TNF-IR patients, IL6 was significantly reduced by FEN treatment by week 12 relative to PBO. PK-PD relationships were observed for multiple B and myeloid cell biomarkers. No single biomarker at baseline was associated with clinical response (at 12 weeks) in MTX-IR and TNF-IR pts. However, greater baseline RF titers were associated with increased FEN clinical response in TNF-IR pts. <h3>Conclusion:</h3> FEN treatment resulted in strong pharmacodynamic effects on multiple biomarkers of B and myeloid cell biology in RA. This included reductions in total IgM and IgG that were not observed with ADA. Conversely, ADA reduced IL6 and CRP faster than FEN, highlighting key mechanistic differences between FEN and ADA. Baseline RF titer was associated with FEN clinical response in the more refractory TNF-IR pts. These data provide mechanistic insights into the efficacy of FEN in RA patients. <h3>Reference:</h3> [1] Crawford, et al., J Med Chem 2018 61(6) 2227-2245. <h3>Disclosure of Interests:</h3> Alyssa Morimoto Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Julie Rae Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Leslie Chinn Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Nandhini Ramamoorthi Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Olivia Hwang Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Alexandra Ward Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, D. James Haddon Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Caroline Looney Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Rupal Desai Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Balazs Toth Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Katie Tuckwell Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Michael J. Townsend Shareholder of: Stockholder of Genentech/Roche, Employee of: Genentech/Roche