Pharmacodynamic Modeling of BTK Occupancy Versus Efficacy in Ra and SLE Models Using the Novel Specific BTK Inhibitor Evobrutinib

Philipp Haselmayer¹, Monsterrat Camps², Lesley Liu-Bujalski³, Federica Morandi⁴, Jared Head⁴, Simone C. Zimmerli⁵, Lisa Bruns⁶, Andrew Bender⁷, Patricia Schroeder⁸ and Roland Grenningloh⁹, ¹CBD, Merck KGaA, Darmstadt, Germany, ²Immunology, Merck Serono S.A., Geneva, Switzerland, ³Medicinal Chemistry, EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, ⁴Biomolecular Pharmacology, EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, ⁵Immunology, EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, ⁶Immunology, Merck KGaA, Darmstadt, Germany, ⁷TIP Immunology, EMD Serono Research and Development Institute, Billerica, MA, ⁸Translational Pharmacology, EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA, ⁹EMD Serono Research & Development Institute, Inc. (a business of Merck KGaA, Darmstadt, Germany), Billerica, MA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: BTK, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)

Session Information

Date: Tuesday, November 7, 2017

Title: Systemic Lupus Erythematosus – Animal Models Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Bruton’s tyrosine kinase (BTK) is a clinically-proven target in several hematological indications. Due to its role in mediating the signaling of both B cell receptors (BCR) and Fc receptors (FcR), BTK is also a potential target for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), where B cell and innate immune cell activation are key drivers of pathology. We are developing evobrutinib, a novel, highly selective irreversible BTK inhibitor that may be suitable for the treatment of chronic diseases. This work aimed to characterize the activity of evobrutinib in various in vitro cellular assays and in disease models of RA and SLE. In vivo efficacy and target occupancy data were used to build a pharmacokinetic and pharmacodynamic (PKPD) model describing the correlation between BTK inhibition and disease severity reduction.

Methods: The potency and specificity of evobrutinib was characterized using biochemical and cellular assays. The SLE disease-modifying potential of evobrutinib was assessed in a NZB/W F1 mouse model induced using replication-deficient interferon (IFN)-alpha-expressing adenovirus. Efficacy was determined by measuring proteinuria and histological kidney damage. The RA disease-modifying potential of evobrutinib was tested in a mouse collagen-induced arthritis (CIA) model, with efficacy evaluated by paw scores. A biochemical assay was developed to determine BTK occupancy rates in blood cells and splenocytes. These assays were used to build a translational PKPD model relating target occupancy to efficacy.

Results: Evobrutinib potently inhibited BCR- and FcR-mediated signaling and subsequent activation and function of B cells and certain myeloid cells. In mouse models of RA and SLE, evobrutinib displayed robust efficacy as demonstrated by a marked reduction of disease severity. In the NZB/W F1 IFN-accelerated SLE model, efficacy correlated with B cell inhibition, reduction of autoantibodies, and decreased circulating memory B and T cells. In addition to SLE, RA-like symptoms were inhibited in a collagen-induced arthritis model. In order to translate preclinical efficacious doses to humans, we determined the degree of target occupancy necessary to achieve disease reduction. Pharmacodynamic modeling showed that BTK occupancy of 60 and 80% was linked to 80% and near complete disease inhibition, in both the RA and SLE models, respectively.

Conclusion: These results demonstrate the potential of evobrutinib to treat autoimmune disease and may inform rational dose decisions as evobrutinib is advanced for development in rheumatologic diseases.

Disclosure: P. Haselmayer, Merck KGaA, 3; M. Camps, Merck Serono S.A., 3; L. Liu-Bujalski, EMD Serono, Inc, 3; F. Morandi, EMD Serono, Inc, 3; J. Head, EMD Serono, Inc, 3; S. C. Zimmerli, EMD Serono, Inc, 3; L. Bruns, Merck KGaA, 3; A. Bender, EMD Serono, Inc, 3; P. Schroeder, EMD Serono, Inc, 3; R. Grenningloh, EMD Serono, Inc, 3.

To cite this abstract in AMA style:

Haselmayer P, Camps M, Liu-Bujalski L, Morandi F, Head J, Zimmerli SC, Bruns L, Bender A, Schroeder P, Grenningloh R. Pharmacodynamic Modeling of BTK Occupancy Versus Efficacy in Ra and SLE Models Using the Novel Specific BTK Inhibitor Evobrutinib [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/pharmacodynamic-modeling-of-btk-occupancy-versus-efficacy-in-ra-and-sle-models-using-the-novel-specific-btk-inhibitor-evobrutinib/. Accessed .

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