Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes

CP-690,550 is an orally active and selective inhibitor of the janus kinase (JAK) molecules. The molecular pathways through which the JAK moieties function are described along with the clinical mechanisms associated with their inhibition. Animal models of JAK inhibition are reviewed as a background for the possible inhibition of JAK in humans. The pharmacokinetics of CP-690,550 in humans is described, and the Phase IIA and IIB trials are reviewed in some detail. These trials were dose-ranging and showed a general dose response with relatively robust American College of Rheumatology 20 (ACR20) responses. A proof-of-concept 6-week trial in which CP-690,550 was given as monotherapy was associated with highly efficacious responses at the mid and higher twice-daily dose ranges employed. A subsequent 24 week dose-ranging trial in which CP-690,550 was administered in combination with methotrexate showed ACR20 responses, which were also statistically significant versus placebo interventions.

CP-690,550 treatment was associated with side effects, which included headache and nausea. Infections were more common versus placebo as were elevations in transaminase enzymes when administered in combination with methotrexate, and increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. Decreases in haemoglobin and white blood cell (WBC) counts were also observed along with small increases in serum creatinine. Occasional significant decreases of haemoglobin (>2 g dl ⁻¹) were observed, although decreases of WBC to less than 1000 per mm ³were not seen. Plans for long-term follow-up of the described trials are described along with the features of five presently ongoing Phase III trials of the CP-690,550 janus kinase (JAK) inhibitor. Future directions include completion and publication of these trials along with study of JAK inhibition for other indications.

Background

The Janus kinase (JAK) family of tyrosine kinases (JAK1, JAK2, JAK3 and TYK2) plays a critical role in mediating the intracellular signal transduction of cytokines involved in immune regulation . Following binding of the cytokine to its cognate receptor, JAK proteins are recruited to and bound to the cytoplasmic tail of the receptor complexes, and undergo transphosphorylation ( Fig. 1 ). The phosphorylated JAK complexes facilitate binding of monomeric STAT proteins, which, in turn, are phosphorylated at a tyrosine residue at their C-terminus. The phosphorylated STAT proteins dissociate from the JAK complexes, form dimers within the cytoplasm and then are translocated to the nucleus where they associate with gene promoter regions to mediate gene transcription in regulating the host immune response. Upon completion of transcription, the STAT proteins are dephosphorylated and transported back to the cytoplasm.