The first listed BTK inhibitor – Imbruvica

The sales of 2018 global small molecule drug apixaban replaced lenalidomide with a slight advantage, ranking first, and immediately after the two, it is the Imbruvica, the first listed BTK inhibitor. Since Imbruvica was approved for listing in 2013, global sales have continued to grow. From US$692 million in 2014 to US$6.205 billion in 2018, it ranked 11th in the global drug sales list in 2018, and ranked 3rd in the small group, and became the winner of the Tinib drug. Its clinical expansion indications are still in full swing, the market status of Imbruvica will maintain a certain growth in the next few years.

Introduction of BTK

The target of Imbruvica is Bruton’s tyrosine kinase (BTK), a member of the Tec family of non-receptor protein tyrosine kinases. BTK was identified in 1993 as a defective protein in human X-linked agammaglobulinemia (XLA). This protein is expressed at all stages of development of B cells (except for the final differentiated plasma cells) and is also expressed in small amounts in bone marrow cells and erythroid progenitor cells.

The activation process of BTK is complex. Some receptors on the cell membrane are activated by the corresponding ligands, and the activated receptors recruit and phosphate the intracellular signal transduction kinase PI3K. The phosphorylated PI3K then converts the phosphatidylinositol diphosphate (PIP2) on the membrane into the second messenger molecule inositol triphosphate (PIP3). PIP3 binds to the PH domain of BTK, BTK is then recruited to the cell membrane, and BTK Tyr-551 residues are then phosphorylated by Syk and Lyn kinases. BTK then has physiological activity by autophosphorylation of Tyr-223 residues.

Indications of Imbruvica

Imbruvica, the first listed BTK inhibitor, was approved by the US FDA in 2013 and was approved by the European EMA in 2014. Approved by Japan PMDA in 2016, and approved by China CFDA in 2017. The initial FDA-approved indication for Imbruvica was a mantle cell lymphoma (MCL) that had received at least one previous treatment, and was subsequently approved by the FDA for multiple indications, including chronic lymphocytic leukemia (CLL), and carrying Or do not carry del 17p deleted mutant small lymphocytic lymphoma, Waldenstrom’s Macroglobulinemia (WM), relapsed or refractory marginal zone lymphoma treated with at least one anti-CD20 therapy and requiring systemic therapy, previously accepted Chronic graft versus host disease in which one or more therapies fail. In addition, Imbruvica has clinical studies for other indications, including diffuse large B-cell lymphoma, follicular lymphoma, non-Hodgkin’s lymphoma, pancreatic cancer, acute lymphoblastic leukemia, acute myeloid leukemia, central nervous system tumors, multiple myeloma, gastrointestinal cancer, non-small cell lung cancer, renal cell carcinoma and so on.


Imbruvica, which can be listed as the first drug status of BTK, has achieved such impressive market feedback within 5 years. It can be said that while verifying the target, it also brings various benefits. The drug has a good start. As mentioned in the article, the global target for this target, whether it is a new drug or a generic drug, is under continuous development, and the indications are also expanding. The potential of BTK inhibitors still exists and it is worth digging deep. In general, the BTK inhibitors led by Imbruvica have a huge space for development in the future.


1. Byrd, J. C., Smith, S., Wagner-Johnston, N., Sharman, J., Chen, A. I., Advani, R., … & Liu, L. (2019). Correction: First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. Oncotarget10(38), 3827.

2. Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., … & Jones, J. A. (2013). Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. New England Journal of Medicine369(1), 32-42.