Novartis’/Schering’s VEGF receptor tyrosine kinase inhibitor, PTK787/ZK222584 as a candidate treatment of rheumatoid arthritis.
SummaryRheumatoid arthritis is one of the more common autoimmune diseases. LeadDiscovery’s recent state of the art evaluation of rheumatoid arthritis therapeutics evaluates advances in our understanding of the etiology of the disease. One field of research extensively analyzed in this report is angiogenesis. Inhibitors of receptor tyrosine kinase with specific activity against the VEGFRs have been developed in an attempt to prevent angiogenesis. One such molecule is PTK787/ZK222584, synthesized and dev
Rheumatoid arthritis (RA) is one of the more common autoimmune diseases affecting approximately 5 million individuals in the Western world. As described in LeadDiscovery’s state of the art evaluation of rheumatoid arthritis therapeutics (click here), this field is attracting massive interest in the wake of resurgent R&D activity which has advanced our understanding of the etiology of RA.
One field of research extensively analyzed in “Rheumatoid arthritis: Emerging drug discovery targets and therapeutic candidates” is angiogenesis. The joint in RA contains a proliferating synovium, which forms an invading tissue termed the pannus. Persistent angiogenesis is critical to maintaining the chronic architectural changes in the RA synovium via delivery of nutrients and inflammatory cells. Although the importance of angiogenesis in arthritis progression has been well recognized, the molecular mechanisms promoting angiogenesis in RA have not been clearly identified although VEGFR-1 plays a key role and thus represents a therapeutic target.
Discovered in the 1980's, VEGF is one of the archetypal angiogenic growth factors. VEGF specifically acts on endothelial cells binding to endothelial tyrosine kinase receptors including Flt-1 (VEGFR-1) and KDR/flk-1 (VEGFR-2). In addition to VEGF, placental growth factor also binds to VEGFR-1 and the activation of this receptor leads to vasculogenesis. VEGFR-2 is exclusively expressed in endothelial cells and appears to play a pivotal role in endothelial cell differentiation. A third receptor, VEGFR-3 has been implicated in lymphogenesis.
VEGF receptors have been localized in the synovial vascular endothelium, while VEGF is elevated in RA patients, distributed in the perivascular space, subsynovial macrophages and synovial lining cells. VEGF and has been implicated in RA-associated endothelial cell migration, proliferation and chemotaxis. In addition, endothelial fenestration, a characteristic of synovial vessels, is induced by VEGF. In an animal model of RA, treatment with anti-VEGFR-1 or soluble VEGFR-1 strongly attenuated the disease; treatment with anti-VEGFR-2 had no effect on disease progress although the effect that VEGFR-2 blockade has on arthritic angiogenesis in humans remains to be established.
Efforts towards the discovery of receptor tyrosine kinase inhibitors with specific activity against the VEGFRs have led to the synthesis and characterization of a number of novel compounds. One of these is PTK787/ZK222584, synthesized and developed by Novartis Pharma AG and Schering AG. PTK787/ZK222584 exhibits strong inhibition of VEGF-R2 and slightly weaker inhibition of VEGFR1. It is also active against other tyrosine kinases belonging to the same family as the VEGF receptors. It appears however, to be specific for this class of receptors.
PTK787/ZK222584 has been shown to inhibit VEGF-mediated cell proliferation, survival and migration, and also inhibits capillary like sprout formation in vitro. PTK787/ZK222584 treatment was associated with decreased density of newly formed tumor capillaries, the number of tumor microvessels, and the hemodynamic dilation of the remaining vessels, leading to a reduction in tumor size in animal models. Hence this molecule is currently in phase III trials for the treatment of cancer. Now Novartis researchers have investigated the anti-arthritic effects of PTK787/ZK222584 in animal models of RA.
In an initial study, PTK787/ZK222584 was able to prevent inflammation and neovascularization of the murine granulomatous air pouch, a structure resembling the synovium, in response to croton oil challenge. PTK787/ZK222584 also had a preventative effect in an antigen model of RA, reducing the swelling of knee joints at 10mg/kg po although this was not mirrored by a reduction in histological damage. The effect was similar to that of COX inhibitors. In a second collagen model of RA, PTK787/ZK222584 was also able to reduce joint swelling as well as overall disease severity, and in contrast to the antigen model histological damage was also reduced. The reasons for this difference are unclear however the reproducible reduction in joint swelling in response to this angiogenesis inhibitor prompts further evaluation of this RA candidate. The promise of PTK787/ZK222584 is perhaps elevated still further by observations that it has analgesic activity in a model of hyperalgesia that is independent of neovascularization. Thus PTK787/ZK222584 has the potential to both modify the course of RA by preventing angiogenesis and to reduce pain associated with this condition.
Original article: Inflamm Res. 2004 Mar;53(4):133-42.
Editorial Source: TherapeuticAdvances, June 2004
See also a second editorial in this edition of TherapeuticAdvances, "Drug delivery technology predicted to allow safer and more effective use of steroids in the treatment of rheumatoid arthritis" - click here