Tofacitinib
Encyclopedia
Tofacitinib 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
that transmits information outside the cell 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.
s 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.
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
for the treatment of rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
(RA), psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, inflammatory bowel disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
, and other immunological diseases, as well as for the prevention of organ transplant
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
rejection. It is an inhibitor
Janus kinase inhibitor
Janus kinase inhibitor is a class of medicines that function by inhibiting the effect of one or more of the Janus kinase family of enzymes , interfering with the JAK-STAT signaling pathway....
of the enzyme Janus kinase 3
Janus kinase 3
Tyrosine-protein kinase JAK3 is an enzyme that in humans is encoded by the JAK3 gene.Since JAK3 expression is restricted mostly to hematopoietic cells, its role in cytokine signaling is thought to be more restricted than other JAKs. It is most commonly expressed in T cells and NK cells, but has...
(JAK3), which means that it interferes with the JAK-STAT signaling pathway
JAK-STAT signaling pathway
The JAK-STAT signaling pathway transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell. The JAK-STAT system is a major signaling alternative to the second...
that transmits information outside the cell 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
STAT1
STAT1 is a member of the Signal Transducers and Activators of Transcription family of transcription factors. STAT1 is involved in upregulating genes due to a signal by either type I, type II or type III interferons...
-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 trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s tested the drug in RA patients that had not responded to DMARD therapy. In a tofacitinib monotherapy study, the ACR score
ACR score for rheumatoid arthritis
ACR score is a scale to measure change in rheumatoid arthritis symptoms. It is named after the American College of Rheumatology.Different degrees of improvement are referred to as ACR20, ACR50, ACR70...
improved by at least 20% (ACR-20) in 67% of patients versus 25% who received placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
; and a study that combined the drug with methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. 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
Low density lipoprotein
Low-density lipoprotein is one of the five major groups of lipoproteins, which in order of size, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, that enable transport of cholesterol within the water-based bloodstream...
and 8 to 10 mg/dl HDL
High density lipoprotein
High-density lipoprotein is one of the five major groups of lipoproteins, which, in order of sizes, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...
at medium dosage levels) and neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
. 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.