Brutonís tyrosine kinase (Btk) plays a critical role in B cell maturation and survival in addition to regulating myeloid cell inflammatory cytokine production, making it an attractive target for the treatment of immunological disorders such as rheumatoid arthritis (RA) and lupus, as well as B-cell malignancies. Mice deficient in BTK enzyme activity (X-linked immune defect, xid) have marked depletion of B cell populations and are resistant to developing collagen-induced arthritis and lupus. Male patients with BTK mutations have a condition known as X-linked agammaglobulinemia, characterized by a severe block in B cell development and diminished serum immunoglobulin levels; however, when treated with intravenous immunoglobulins, they are generally able to lead fairly normal lives which speaks to the potential safety of the target when modulating Btk activity as a therapeutic intervention. To date, Imbruvica® is the only BTK inhibitor to launch in oncology indications, while none have yet been approved in immunology indications. Thus there have been significant efforts from the pharmaceutical community with the goal of identifying Btk inhibitors for clinical development in immunology.

Dr. Young will describe the work at Genentech to develop a series of highly potent, selective, non-covalent Btk inhibitors that have proven to be efficacious in several rodent models of RA and lupus. Additionally, compounds in this chemical series were found to remain highly active against the C481S Btk mutant that has been identified in patients that have relapsed on Imbruvica®. In this presentation, the SAR, preclinical DMPK and toxicology investigations leading up to the discovery and selection of the lead clinical candidate, GDC-0853 will be described. Additionally, the initial results from Phase 1 clinical trials will be shared.