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

https://doi.org/10.1016/j.berh.2010.02.003Get rights and content

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 mm3 were 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.

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)

  • D.C. Thomis et al.

    Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3

    Science

    (1995)
  • P. Macchi et al.

    Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID)

    Nature

    (1995)
  • S.M. Russell et al.

    Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development

    Science

    (1995)
  • P.S. Changelian et al.

    Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor

    Science

    (2003)
  • K. West

    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

    (2009)
  • Li X, Jesson M, Lee J et al. Characterization of a potent inhibitor of JAK kinases, CP-690,550, and inhibition of...
  • A.J. Milici et al.

    Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis

    Arthritis Research & Therapy

    (2008)
  • R. Paniagua et al.

    Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts

    Transplantation

    (2005)
  • D.C. Borie et al.

    Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates

    Transplantation

    (2005)
  • Cited by (0)

    Disclosures: Richard Riese and Sriram Krishnaswami are employees of Pfizer. The CP-690,550 studies reviewed in this article were sponsored by Pfizer Inc.

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