Background/Purpose: Clinical development of BTK/Tec family kinase inhibitors for treating autoimmune diseases has lagged that of their successful application in oncology. The lack of selective BTK inhibitors to date has partly limited progress in developing drugs that target BTK for autoimmune diseases, where the tenant is held that long term therapy in nonlife threatening diseases necessitates minimizing off-target effects. Autoimmune diseases, however, often demonstrate alterations in multiple immune cell types and signaling pathways, making it difficult to decipher which of these factors are causal and to what degree. The objective of this study was to perform a meta-analysis on available BTK inhibitor pre-clinical and clinical data to develop guidelines and predictors of successful therapeutic applications in autoimmune diseases.

Methods: Biochemical and functional data were collected and analyzed for BTK inhibitors in clinical development from public data sources and Clarivate Analytics database content using a repertoire of programs and services including PubMed, Web of Science, Cortellis Intelligence, Cortellis Integrity, Metacore, Metabase, OFF-X, and CBDD. Development candidates were assessed and categorized for their target specificity profiles, signaling pathways, immunocyte functions, biomarkers, and their reported biological activities in clinical trials.

Results: BTK inhibitor profiles showed remarkably similar specificity profiles within the Tec family kinase group of enzymes. Some differences, however, were observed in T-, B-, and macrophage cell associated enzymes across development candidates that were inconsistent with functional effects, suggesting additional mechanism of action participation. Clinical trial failures in rheumatoid arthritis despite BTK inhibition and effects on B cell biomarkers suggest insufficiency of BTK inhibition as well as off-target pathways associated with those drugs.  In contrast, enzymes involved in pathways targeting antibody and T cell activities showed correlation with clinical trial success in diseases where these processes are implicated, including multiple sclerosis and pemphigus vulgarus. Overlap of these disease mechanisms and additional biological pathways associated with lupus strongly suggest a future therapeutic application in this yet to be validate clinical indication.

Conclusion: Current BTK inhibitors in development for autoimmune diseases demonstrate significant lack of specificity with similar patterns of off-target enzyme activities. Some specificity differences, however, were evident. Overall, similarities and differences in specificity showed strong correlation with most reported immunocyte functions, but inconsistencies were evident in some activities that challenge current ascribed functional assumptions for BTK inhibitors. Meta-analysis of BTK inhibitor specificity profiles validated by current clinical trials demonstrate the potential for the collective use of data to understand autoimmune disease pathology and to enhance efficiency in disease indication selection for drugs in clinical development.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/brutons-tyrosine-kinase-btk-inhibitors-and-autoimmune-disease-making-sense-of-btk-inhibitor-specificity-profiles-and-recent-clinical-trial-successes-and-failures/