The Emerging Potential for New Oral Agents in the Treatment of Rheumatoid Arthritis
Abstract
Abstract
The introduction of tumor necrosis factor (TNF) inhibitors has contributed to considerable advances in the treatment of patients with rheumatoid arthritis (RA). However, it has become increasingly clear that a significant proportion of patients treated with these agents will have at least some evidence of persistent disease, suggesting that there is still a need for new therapies. Recently, a new generation of small molecules, such as those targeting both Janus kinases (JAK) and spleen tyrosine kinase (Syk), has gained much attention as potential therapeutic targets in RA. These generally modulate the function of cellular structures such as surface receptors, signaling proteins, and enzymes and thereby alter their downstream effects. The primary advantages of these compounds lie in their selectivity for targets that are intimately involved in the pathogenesis of disease and their oral bioavailability. Theoretically, immunopathogenic cellular activities may be specifically inhibited while the disruption of necessary cellular functions is minimized.
Targeting of Janus Kinases
Cytokine stimulation of cells begins with binding of interleukins (IL), interferons (IFN), colony-stimulating factors, and hormones to receptors on cell surfaces. These receptors lack enzymatic activity capable of mediating signal transduction intrinsically, but are able to signal through activation of a class of four protein tyrosine kinases known as JAK (JAK1, JAK2, and TYK2, which are widely expressed, and JAK3, which may be more limited to hematopoietic cell lines).1–2 Upon cytokine receptor engagement, the associated JAKs are activated and phosphorylatespecific tyrosine residues accumulate in the cytoplasmic domain of the receptor.2 This provides a recruitment site for the signal transduction and activators of transcription (STAT) family of transcription factors, which are then phosphorylated. Dissociation and cytoplasmic dimerization of STATs follow, with subsequent translocation to the nucleus for the regulation of gene expression.3
The cytokine receptor system appears to be selective in that different classes of receptor characteristically activate a specific JAK or combination of JAKs: JAK1 is activated by receptors for gp130 cytokines, type I IFNs, IFN-γ, and common γ-chain (γc) cytokines; JAK2 is activated by receptors for erythropoietin, thrombopoietin, prolactin, growth hormone, common β-chain cytokines, IFN-γ, and IL-12; JAK3 is activated by γc cytokines; and TYK2 is activated by type I IFNs, IL-12, and IL-23.3–4 Additionally, in a description of a single patient with hyperimmunoglobulin E (Job’s syndrome) who was found to have a mutation of TYK2, signaling by IL-6 and IL-10 was also noted to be impaired.5
JAK3 is thought to have perhaps the most discriminatory function because it is activated by just one receptor subunit, γc, which is involved in signaling by IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.6 In humans, mutations of γc and JAK3 account for the majority of cases of T-B + natural killer (NK) severe combined immunodeficiency disorder (SCID).6 The observation of a lack of involvement of other organ systems and a curative response with hematopoietic stem cell transplant in this disorder suggested that JAK3 may be an appealing target for immunosuppressive therapies.4 Interestingly, it was recently demonstrated that expression of JAK3, signal transducers, and STAT-1, STAT4, and STAT6 in RA synovium decreases in response to successful treatment of RA with standard disease- modifying antirheumatic drugs (DMARDs). 7
Clinical Trials with a Relatively Selective Janus Kinase Inhibitor CP-690,550 is an orally available compound with nanomolar potency against JAK3 (median inhibition concentration [IC]-50 1nM), which is approximately 20 and 100 times less potent for JAK2 (IC50 20nM) and JAK1 (IC50 112nM), respectively. 8 A phase IIa trial studied three dose levels of CP-690,550 versus placebo in 264 patients with active RA who had an inadequate response to, or discontinued therapy due to toxicity from, methotrexate (MTX) or a TNF inhibitor.9 All DMARD and/or biologic therapies were discontinued prior to receiving the study drug, which was administered twice a day (BID) for six weeks with a six-week follow-up. Background non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, and low-dose glucocorticoids were allowed. The primary efficacy endpoint, American College of Rheumatology (ACR) 20, at week six was achieved by 70, 81, and 77% in the 5, 15, and 30mg BID groups, respectively, compared with 29% for placebo. ACR 50 and 70 responses occurred in 33–54% and 13–28% of patients, respectively. Additionally, Disease Activity Score 28 (DAS28) decreased from 5.7–6.2 at baseline to 3.1–4.2 at week six, with 76–84% of patients achieving a European League Against Rheumatism (EULAR) moderate response. The authors noted that improvements could be evident in all groups as early as week one.
