Discovery of BIIB068: A Selective, Potent, Reversible Bruton’s Tyrosine Kinase Inhibitor as an Orally Efficacious Agent for Autoimmune Diseases

Abstract

Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these antibodies bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes and NETosis by neutrophils. Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase that signals downstream of Fc receptors and plays a transduction role in antibody expression following B cell activation. Given the roles of BTK in both the production and sensing of autoreactive antibodies, inhibitors of BTK kinase activity may provide therapeutic value to patients suffering from autoantibody-driven immune disorders. Starting from an in-house proprietary screening hit followed by structure-based rational design, we have identified a potent, reversible BTK inhibitor, BIIB068 (1), which demonstrated good kinome selectivity with good overall drug-like properties for oral dosing, was well tolerated across preclinical species at pharmacologically relevant doses with good ADME properties, and achieved >90% inhibition of BTK phosphorylation (pBTK) in humans.

Next‐generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells

“…PCT Int Appl 2018, WO 2018191577 A1 20181018) (Figure 1a) was discovered during medicinal chemistry efforts targeting BTK, 10 a member of the TEC family of kinases. We reported previously an earlier generation BTK inhibitor (BIIB068) 11 ; however, BIIB091 showed a differentiated profile characterised by an improved potency while maintaining a favorable selectivity profile 10 . Like BIIB068, BIIB091 was designed as a reversible small‐molecule inhibitor of BTK and showed potent inhibitory activity against purified BTK protein in an enzymatic assay with an average IC 50 of 450 p m .…”

“…(a) Dot plot showing IC 50 values for constitutive BTK phosphorylation in unstimulated cells (pBTK, x ‐axis) and CD69 expression in anti‐IgD‐stimulated B cells (CD69, y ‐axis) in whole blood (WB) assays. Data from n = 420 Biogen‐reversible BTK inhibitors are shown with BIIB091 and BIIB068 (early generation BTK inhibitor 11 ) highlighted in red and blue, respectively. Dashed lines indicate the equal potency line and the 10‐fold deviation from the equipotency line.…”

“…(g) Dot plot showing IC 50 values (mean and SD) for CD69 expression in anti‐IgD‐stimulated B cells (CD69, x ‐axis) and basophil degranulation (CD63, y ‐axis) in whole blood assays. Data from n = 11 BTK inhibitors including Biogen BIIB091 and BIIB068 (early generation BTK inhibitor 11 ), 2 reversible competitor inhibitors (R) and 7 covalent competitor inhibitors (C). The dashed line indicates the equipotency line.…”

Btk Inhibitors: A Medicinal Chemistry and Drug Delivery Perspective

“…BIIB068 demonstrated good kinome selectivity (IC 50 = 1 nM for Btk) and good overall drug-like properties for oral dosing; it was well tolerated across preclinical species at pharmacologically relevant doses with good ADME properties and achieved >90% inhibition of Btk phosphorylation in humans [ 85 , 86 ]. BIIB068 seems to be effective in SLE disease (clinical study NCT02829541).…”

Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases

“…BIIB068 also inhibited B-cell activation, though the inhibition was not as robust as inhibition of BTK phosphorylation. However, no further clinical trials have been ongoing since 2017 [ 93 ].…”