Fenebrutinib Demonstrates the Highest Potency of Bruton Tyrosine Kinase Inhibitors (BTKis) in Phase 3 Clinical Development for Multiple Sclerosis (MS) (4437)

Objective: To examine the potency of fenebrutinib, tolebrutinib and evobrutinib head to head in healthy subjects using in vitro whole blood myeloid and B cell activation assays. Background: BTK is involved in the pathogenic mechanisms of both acute and chronic inflammation that lead to disease progression in MS. BTK is active in immune cells, including B cells and myeloid cells. Targeted therapies with optimal molecular properties are important to maximize efficacy in MS. Fenebrutinib, tolebrutinib and evobrutinib are BTKis currently in late-stage clinical development as investigational oral therapies for MS. Design/Methods: Fresh whole-blood samples from 11 healthy subjects prescreened for sufficient activation status were preincubated with serial dilution concentrations of fenebrutinib, tolebrutinib and evobrutinib and then stimulated with anti–immunoglobulin (Ig) E or anti-IgM to activate myeloid cells (basophils) or B cells, respectively. Flow cytometry was used to assess myeloid and B cell activation by measuring CD63 and CD69 upregulation, respectively. Expression of high-affinity IgE receptor FcɛRI is dependent on serum IgE levels, but no difference was observed in assay performance between high IgE vs low IgE donors. Results: Mean EC50 ± SEM values of 15 ± 4 nM (fenebrutinib), 80 ± 11 nM (tolebrutinib), and 1271 ± 133 nM (evobrutinib) were observed in the myeloid cell assay. Mean EC90 ± SEM values were 62 ± 12 nM (fenebrutinib), 281 ± 49 nM (tolebrutinib), and 3102 ± 560 nM (evobrutinib). Results of the CD69 assay will be presented at the conference. Conclusions: The high potency of fenebrutinib compared with less potent BTKis tolebrutinib and evobrutinib has the potential to result in better efficacy. Along with its previously established higher selectivity, fenebrutinib is a promising BTKi therapeutic candidate for MS. Disclosure: Martin Weber, MD has nothing to disclose. Christopher Harp has received personal compensation for serving as an employee of Genentech. Christopher Harp has received stock or an ownership interest from Genentech, Inc.. Meire Bremer has received personal compensation for serving as an employee of Genentech. Meire Bremer has received stock or an ownership interest from Genentech Inc.. Dr. Goodyear has received personal compensation for serving as an employee of Genentech. Dr. Goodyear has received personal compensation for serving as an employee of Novartis. Dr. Goodyear has received stock or an ownership interest from Novartis. James Crawford has received personal compensation for serving as an employee of Genentech, Inc. James Crawford has received stock or an ownership interest from Genentech, Inc. ADAM JOHNSON has received personal compensation for serving as an employee of Genentech, A Member of the Roche Group. ADAM JOHNSON has received stock or an ownership interest from Roche. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche Genentech. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen/Actelion. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Atara Biotherapeutics. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merk/EMD Serono. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Atara Biotherapeutics. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck/EMD Serono. Dr. Bar-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi/Genzyme. The institution of Dr. Bar-Or has received research support from Novartis. The institution of Dr. Bar-Or has received research support from Biogen. The institution of Dr. Bar-Or has received research support from Roche/Genentech. The institution of Dr. Bar-Or has received research support from Merck/EMD Serono.