Mutations in the BTK gene are implicated in the
primary immunodeficiency disease
X-linked agammaglobulinemia (Bruton's agammaglobulinemia); sometimes abbreviated to XLA and selective IgM deficiency. Patients with XLA have normal pre-B cell populations in their
bone marrow but these cells fail to mature and enter the circulation. The BTK gene is located on the
X chromosome (Xq21.3-q22). At least 400
mutations of the BTK gene have been identified. Of these, at least 212 are considered to be disease-causing mutations. BTK is important for the survival and proliferation of leukemic B cells, which motivated efforts to develop BTK inhibitors as treatments for B cell malignancies such as
mantle cell lymphoma (MCL) and
chronic lymphocytic leukemia (CLL). As BTK is also linked to autoimmune disorders, recent efforts have sought to evaluate BTK inhibition as a therapeutic strategy for treatment of diseases such as
multiple sclerosis (MS) and
rheumatoid arthritis (RA).
BTK inhibitors Approved drugs that inhibit BTK: •
Acalabrutinib (Calquence), approved in October 2017 for relapsed
mantle cell lymphoma and in October 2019 for
Chronic lymphocytic leukemia (CLL) and Small lymphocytic lymphoma (SLL) •
Ibrutinib (Imbruvica), a selective Bruton's tyrosine kinase inhibitor. •
Orelabrutinib, approved in China for patients with
mantle cell lymphoma (MCL) and
chronic lymphocytic leukemia/
small lymphocytic lymphoma (CLL/SLL), who have received at least one treatment in the past. •
Pirtobrutinib (Jaypirca), a reversible (non-covalent) inhibitor of BTK, for mantle cell lymphoma. •
Remibrutinib (Rhapsido), for
chronic spontaneous urticaria •
Rilzabrutinib (Wayrilza) approved for
immune thrombocytopenia •
Tirabrutinib (Velexbru), approved in March 2020, in Japan, for the treatment of recurrent or refractory primary central nervous system lymphoma. •
Zanubrutinib (Brukinsa) for mantle cell lymphoma, chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL). It can be taken
by mouth. Various drugs that inhibit BTK are in clinical trials: • Phase 3: •
Evobrutinib for
multiple sclerosis. •
Fenebrutinib (RG7845) for multiple sclerosis. •
Tolebrutinib, for multiple sclerosis. • Phase 2: •
ABBV-105 for systemic lupus erythematosus (SLE) •
Fenebrutinib (GDC-0853) for rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and
chronic spontaneous urticaria. • Phase 1: •
Elsubrutinib •
Poseltinib, for
autoimmune diseases, under development by
Hanmi Pharmaceutical and
Lilly as of 2015 •
Luxeptinib (CG-806), for CLL, SLL, non-Hodgkin lymphoma,
acute myeloid leukaemia, and
myelodysplastic syndromes (Phase I Trial; Phase I Trial). The inhibitor targets multiple kinase pathways, including BTK and
FLT3. •
Nemtabrutinib •
Spebrutinib (AVL-292, CC-292) •
Tirabrutinib, for
non-Hodgkin lymphoma and/or CLL. Renamed GS-4059 and now in trial NCT02457598. •
Vecabrutinib •
Branebrutinib •
Catadegbrutinib •
Bexobrutideg /
Bexodegbrutinib •
Sunvozertinib •
Avitinib == Discovery ==