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Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models.

ABSTRACT: Because of its role in mediating both B cell and Fc receptor signaling, Bruton's tyrosine kinase (BTK) is a promising target for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Evobrutinib is a novel, highly selective, irreversible BTK inhibitor that potently inhibits BCR- and Fc receptor-mediated signaling and, thus, subsequent activation and function of human B cells and innate immune cells such as monocytes and basophils. We evaluated evobrutinib in preclinical models of RA and SLE and characterized the relationship between BTK occupancy and inhibition of disease activity. In mouse models of RA and SLE, orally administered evobrutinib displayed robust efficacy, as demonstrated by reduction of disease severity and histological damage. In the SLE model, evobrutinib inhibited B cell activation, reduced autoantibody production and plasma cell numbers, and normalized B and T cell subsets. In the RA model, efficacy was achieved despite failure to reduce autoantibodies. Pharmacokinetic/pharmacodynamic modeling showed that mean BTK occupancy in blood cells of 80% was linked to near-complete disease inhibition in both RA and SLE mouse models. In addition, evobrutinib inhibited mast cell activation in a passive cutaneous anaphylaxis model. Thus, evobrutinib achieves efficacy by acting both on B cells and innate immune cells. Taken together, our data show that evobrutinib is a promising molecule for the chronic treatment of B cell-driven autoimmune disorders.

SUBMITTER: Haselmayer P

PROVIDER: S-EPMC6500888 | biostudies-other | 2019 May

REPOSITORIES: biostudies-other

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Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models.

Haselmayer Philipp P Camps Montserrat M Liu-Bujalski Lesley L Nguyen Ngan N Morandi Federica F Head Jared J O'Mahony Alison A Zimmerli Simone C SC Bruns Lisa L Bender Andrew T AT Schroeder Patricia P Grenningloh Roland R

Journal of immunology (Baltimore, Md. : 1950) 20190415 10

Because of its role in mediating both B cell and Fc receptor signaling, Bruton's tyrosine kinase (BTK) is a promising target for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Evobrutinib is a novel, highly selective, irreversible BTK inhibitor that potently inhibits BCR- and Fc receptor<b>-</b>mediated signaling and, thus, subsequent activation and function of human B cells and innate immune cells such as monocytes and basophils. W ...[more]

PMID: 30988116

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Project description:Bruton's tyrosine kinase (Btk) is a signaling molecule involved in development and activation of B cells through B-cell receptor (BCR) and Toll-like receptor (TLR) signaling. We have previously shown that transgenic mice that overexpress human Btk under the control of the CD19 promoter (CD19-hBtk) display spontaneous germinal center formation, increased cytokine production, anti-nuclear autoantibodies (ANAs), and systemic autoimsmune disease upon aging. As TLR and BCR signaling are both implicated in autoimmunity, we studied their impact on splenic B cells. Using phosphoflow cytometry, we observed that phosphorylation of ribosomal protein S6, a downstream Akt target, was increased in CD19-hBtk B cells following BCR stimulation or combined BCR/TLR stimulation, when compared with wild-type (WT) B cells. The CD19-hBtk transgene enhanced BCR-induced B cell survival and proliferation, but had an opposite effect following TLR9 or combined BCR/TLR9 stimulation. Although the expression of TLR9 was reduced in CD19-hBtk B cells compared to WT B cells, a synergistic effect of TLR9 and BCR stimulation on the induction of CD25 and CD80 was observed in CD19-hBtk B cells. In splenic follicular (Fol) and marginal zone (MZ) B cells from aging CD19-hBtk mice BCR signaling stimulated in vitro IL-10 production in synergy with TLR4 and particularly TLR9 stimulation, but not with TLR3 and TLR7. The enhanced capacity of CD19-hBtk Fol B cells to produce the pro-inflammatory cytokines IFNγ and IL-6 compared with WT B cells was however not further increased following in vitro BCR or TLR9 stimulation. Finally, we used crosses with mice deficient for the TLR-associated molecule myeloid differentiation primary response 88 (MyD88) to show that TLR signaling was crucial for spontaneous formation of germinal centers, increased IFNγ, and IL-6 production by B cells and anti-nuclear autoantibody induction in CD19-hBtk mice. Taken together, we conclude that high Btk expression does not only increase B cell survival following BCR stimulation, but also renders B cells more sensitive to TLR stimulation, resulting in increased expression of CD80, and IL-10 in activated B cells. Although BCR-TLR interplay is complex, our findings show that both signaling pathways are crucial for the development of pathology in a Btk-dependent model for systemic autoimmune disease.

Project description:Clinical development of BTK kinase inhibitors for treating autoimmune diseases has lagged behind development of these drugs for treating cancers, due in part from concerns over the lack of selectivity and associated toxicity profiles of first generation drug candidates when used in the long term treatment of immune mediated diseases. Second generation BTK inhibitors have made great strides in limiting off-target activities for distantly related kinases, though they have had variable success at limiting cross-reactivity within the more closely related TEC family of kinases. We investigated the BTK specificity and toxicity profiles, drug properties, disease associated signaling pathways, clinical indications, and trial successes and failures for the 13 BTK inhibitor drug candidates tested in phase 2 or higher clinical trials representing 7 autoimmune and 2 inflammatory immune-mediated diseases. We focused on rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE) where the majority of BTK nonclinical and clinical studies have been reported, with additional information for pemphigus vulgaris (PV), Sjogren's disease (SJ), chronic spontaneous urticaria (CSU), graft versus host disease (GVHD), and asthma included where available. While improved BTK selectivity versus kinases outside the TEC family improved clinical toxicity profiles, less profile distinction was evident within the TEC family. Analysis of genetic associations of RA, MS, and SLE biomarkers with TEC family members revealed that BTK and TEC family members may not be drivers of disease. They are, however, mediators of signaling pathways associated with the pathophysiology of autoimmune diseases. BTK in particular may be associated with B cell and myeloid differentiation as well as autoantibody development implicated in immune mediated diseases. Successes in the clinic for treating RA, MS, PV, ITP, and GVHD, but not for SLE and SJ support the concept that BTK plays an important role in mediating pathogenic processes amenable to therapeutic intervention, depending on the disease. Based on the data collected in this study, we propose that current compound characteristics of BTK inhibitor drug candidates for the treatment of autoimmune diseases have achieved the selectivity, safety, and coverage requirements necessary to deliver therapeutic benefit.

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Dataset Information

Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models.

Publications

Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models.

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