Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that typically affects the hands and feet, although any joint lined by a synovial membrane may be affected. Now Pfizer has announced progress for their drug tofacitinib. Tofacitinib is a unique, oral Janus kinase (JAK) inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for RA.
More than 4,000 RA patients have been treated with tofacitinib in clinical trials to date. RA affects approximately 1.3 million people in the U.S. and one percent of the adult population worldwide.
The Janus kinase family is one of ten recognized families of non-receptor tyrosine kinases. Mammals have four members of this family, Jak1, Jak2, Jak3 and Tyrosine kinase 2 (Tyk2).
Each protein has a kinase domain and a catalytically inactive pseudo-kinase domain, and they each bind cytokine receptors through amino-terminal FERM (Band-4.1, ezrin, radixin, moesin) domains. Upon binding of cytokines to their receptors, Jaks are activated and phosphorylate the receptors, creating docking sites for signaling molecules, especially members of the signal transducer and activator of transcription family. Mutations of the Drosophila Jak (Hopscotch) have revealed developmental defects, and constitutive activation of Jaks in flies and humans is associated with leukemia-like syndromes.
The new study (ORAL Standard) is a completed twelve-month study in patients with moderate-to-severe active rheumatoid arthritis who had an inadequate response to methotrexate (MTX) and were randomized to receive either tofacitinib, adalimumab every other week or placebo, each of which was added to stable background MTX.
The ORAL Step study met all primary endpoints at the 5 and 10 mg BID doses and no new safety signals emerged in the ORAL Standard and ORAL Step studies. The efficacy and safety profile of tofacitinib in these studies remains consistent with that seen previously in the clinical program.
The joints most commonly affected by rheumatoid arthritis are those of the hands, feet, wrists, knees, elbows, knees and ankles. Joint involvement is usually symmetrical, meaning if one joint is affected the same joint on the opposite side of the body is affected as well. The disease can also affect many organs, including the skin, heart, blood vessels and lungs.
Although rheumatoid arthritis is chronic, its symptoms can come and go. Periods of mild disease activity can be punctuated by flares, or periods or more intense disease activity and symptoms. In some cases, with appropriate treatment, the disease may become inactive and symptoms may go away completely.
Unlike more recent therapies for RA, which are directed at extracellular targets such as pro-inflammatory cytokines, tofacitinib takes a novel approach, targeting the intracellular signaling pathways that operate as hubs in the inflammatory cytokine network.
Pfizer is studying tofacitinib for RA in the Phase 3 ORAL program, which consists of five pivotal trials and a sixth long-term treatment study at more than 350 locations in 35 countries worldwide. ORAL Standard and ORAL Step are the final two pivotal trials in the program.
Pfizer is also studying orally administered tofacitinib in psoriasis, inflammatory bowel disease (Crohn’s disease and ulcerative colitis) and renal transplant, and topical tofacitinib in both psoriasis and dry eye disease.
Sources: Genome Biology, Arthritis Today and Pfizer
Written by Sy Kraft