Cell Therapeutics, Inc. (CTI), a biopharmaceutical company committed to developing an integrated portfolio of oncology products aimed at making cancer more treatable, has announced that CT-1578's (previously known as SB-1578) unique kinase spectrum that selectively inhibits JAK2 over JAK1 or JAK3, coupled with its inhibition of FLT-3 and c-Fms, produced potency in not only preventing the development of rheumatoid arthritis (RA), but also in its treatment and reversal of bone and joint destruction after the onset of RA in preclinical models. These results were recently published Journal of Immunology.
The authors concluded that CT-1578's selective inhibition of JAK2, FLT-3 and c-Fms, which are the three kinases that are critical to the pathogenesis of RA, is unprecedented in the current stable of kinase inhibitors.
"These results support the hypothesis that inhibition of JAK1 and JAK3 is not mandatory for therapeutic benefit in RA," noted Jack W Singer, MD, EVP Global Medical Affairs and Translational Medicine at CTI. "The results demonstrate that CT-1578's unique kinase spectrum not only blocks the inflammatory response, but prevents the infiltration of macrophages and neutrophils into affected joints, while inhibiting antigen presenting dendritic cells and the autoimmune component of the disease. These attributes resulted in prevention of joint synovial hyperplasia and bone destruction, that was sufficiently impressive that the Journal of Immunology chose to use images of the results on the cover of the October 15 issue."
In the study, when SB1578 was orally administered in a preclinical model of RA, it demonstrated a reduction of the level of proinflammatory cytokines, which was accompanied by a reduction in joint inflammation. In RA patients, the increase in cytokines correlates with disease progression and joint destruction. In the preclinical model, SB1578 was also effective in reversing an elevation in neutrophils, which play an essential role in the initiation of joint inflammation and damage to bone and cartilage resulting in a mitigation of damage to the joints. Additionally, SB1578 showed the ability to modulate the autoimmune component of RA that is involved in the early development of RA by inhibiting a pathway that leads to the initiation of an inflammatory response. The authors state, "The activities against these three kinases [JAK2, FLT-3 and c-Fms], which play crucial roles in the pathogenesis of arthritis, differentiates SB1578 from other less selective JAK family kinase inhibitors that are in clinical development for rheumatoid arthritis and provides a novel and attractive therapeutic alternative."
The JAK family of enzymes are a central component in signal transduction pathways, which are critical to normal blood cell growth and development as well as inflammatory cytokine expression and immune responses. When dysregulated by activating mutations, uncontrolled blood cell growth can occur accompanied by inflammation and immune system activation contributing to disease manifestations in myeloproliferative neoplasms. Autoimmune diseases such as psoriasis and rheumatoid arthritis also have activation of this pathway.
FLT-3 is a tyrosine kinase that is important for RA pathogenesis as FLT-3 mediated signaling is essential in the differentiation of dendritic cells leading to the to the amplification of systemic arthritogenic immune responses. FLT-3 has also been shown to contribute to the bone erosion in arthritic joints.
c-Fms is a tyrosine kinase receptor that is increased in several diseases that involve chronic activation of tissue macrophages, including RA. Elevate levels of its ligand M-CSF are observed in the joints of RA patients, contributing to the development of macrophages and osteoclasts, which are the mediators of bone erosion. Inhibition of c-Fms has been shown to inhibit the progression of arthritis in preclinical models indicating that it may play a pivotal role in the pathogenesis of RA.