7Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes☆
Section snippets
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 *[1], [2], *[3]. 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,
Animal models
The ability of CP-690,550 to modulate the immune response was investigated in two rodent models of arthritis: mouse collagen-induced arthritis (CIA) and rat adjuvant-induced arthritis (AA) [13]. CIA and AA were induced using standard protocols and animals received CP-690,550 via osmotic mini-pump infusion at doses of 0 (vehicle control), 1.5, 5 and 15 mg kg−1 day−1 following disease induction (therapeutic). Arthritis was assessed by clinical scores in the CIA model and paw swelling using a
Pharmacokinetics
The pharmacokinetics (PK) of CP-690,550 has been characterised in healthy volunteers (with or without psoriasis), patients with RA, psoriasis, Crohn’s disease and renal transplant recipients at single oral doses ranging from 0.1 to 100 mg, and multiple oral doses ranging from 1 to 50 mg twice daily and from 20 to 60 mg once daily over durations ranging between 2 weeks and 3 years, respectively. CP-690,550 PK is characterised by rapid absorption and elimination, with a time to peak concentration
Clinical development
In the CP-690,550 Phase 2 RA programme, over 1000 patients with RA were treated with CP-690,550 in four placebo-controlled randomised studies (Table 1). These studies ranged from 6 to 24 weeks in duration with doses ranging from 1 mg to 30 mg twice daily. Study B included an arm dosed with CP-690,550 at 20 mg once daily, and Study C included an active comparative arm dosed with adalimumab at 40 mg SC every other week for 10 weeks (six injections) followed by CP-690,550 for 12 weeks. The primary
Future directions
Dose selection for the CP-690,550 Phase 3 studies was primarily based on dose–response modelling of safety and efficacy data (ACR20, ACR50 and ACR70 response rates and the incidence of severe anaemia) observed in Study B and confirmed with the safety and efficacy data in Study C. Based on this evaluation, doses of 5 and 10 mg twice daily were selected for further evaluation in the Phase 3 programme.
Phase 3 trials investigating the safety and efficacy of CP-690,550 in patients with
References (39)
STAT3 in CD4+ T helper cell differentiation and inflammatory diseases
Cytokine
(2009)- et al.
Cytokine receptor signaling through the Jak–Stat–Socs pathway in disease
Molecular Immunology
(2007) - et al.
Developmental defects of lymphoid cells in Jak3 kinase-deficient mice
Immunity
(1995) - et al.
The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models
American Journal of Transplantation
(2004) - et al.
The JAK-3 inhibitor CP-690550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia
European Journal of Pharmacology
(2008) - et al.
Double-blind, placebo-controlled, dose-escalation study to evaluate the pharmacologic effect of cp-690,550 in patients with psoriasis
The Journal of Investigative Dermatology
(2009) - et al.
Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP690,550: a pilot study in de novo kidney allograft recipients
American Journal of Transplantation
(2009) - et al.
Jaks and STATs: biological implications
Annual Review of Immunology
(1998) - et al.
Molecular cloning of L-JAK, a Janus family protein–tyrosine kinase expressed in natural killer cells and activated leukocytes
Proceedings of The National Academy of Sciences of the United States of America
(1994) - et al.
Defective lymphoid development in mice lacking Jak3
Science
(1995)
Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3
Science
Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID)
Nature
Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development
Science
Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor
Science
CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders
Current Opinion in Investigational Drugs
Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis
Arthritis Research & Therapy
Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts
Transplantation
Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates
Transplantation
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Disclosures: Richard Riese and Sriram Krishnaswami are employees of Pfizer. The CP-690,550 studies reviewed in this article were sponsored by Pfizer Inc.