Tofacitinib

Tofacitinib (formerly tasocitinib, CP-690550 ) is a drug being investigated by Pfizer for the treatment of rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection. It is an inhibitor of the enzyme Janus kinase 3 (JAK3), which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.

Recently it has been shown in a murine model of established arthritis, tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3.

Rheumatoid arthritis
Phase II clinical trials tested the drug in RA patients that had not responded to DMARD therapy. In a tofacitinib monotherapy study, the ACR score improved by at least 20% (ACR-20) in 67% of patients versus 25% who received placebo; and a study that combined the drug with methotrexate achieved ACR-20 in 59% of patients versus 35% who received methotrexate alone. In a psoriasis study, the PASI score improved by at at least 75% in between 25 and 67% of patients, depending on the dose, versus 2% in the placebo group.

The most important side effects in Phase II studies were increased blood cholesterol levels (12 to 25 mg/dl LDL and 8 to 10 mg/dl HDL at medium dosage levels) and neutropenia. Phase III trials testing the drug in rheumatoid arthritis have started in 2007 and are scheduled to run until January 2015.

In April 2011, four patients died after beginning clinical trials with Tofacitinib. According to Pfizer, the company that developed the drug, only one of the four deaths was related to Tofacitinib.

By April 2011 three phase III trials for RA had reported positive results.

Psoriasis
a phase III trial for psoriasis is under way.