Palomid 529 has been examined in a series of keratinocyte models which have shown the ability to inhibit keratinocyte proliferation as well as stimulate apoptosis of proliferating keratinocytes. These activities along with P529 having anti-angiogenic activity is expected to have an effect on a range of skin diseases including psoriasis, atopic dermatitis and skin aging as described below.
Atopic dermatitis skin lesions are characterized by inflammatory changes and epithelial hyperplasia requiring angiogenesis. Mast cells participate in this process via bidirectional secretion of tissue-damaging enzymes and pro-angiogenic factors by localizing within the papillary dermis and in the epidermal layers of atopic dermatitis lesions. Mast cells located in the papillary dermis migrate through the basal lamina into the epidermis of atopic dermatitis lesions. Once in the superficial epidermal layers, they activate keratinocytes and stimulate endothelial growth. Close to endothelial cells, mast cells stimulate expression of proangiogenic factors, notably bFGF. Via the new vessels, inflammatory cells, together with complement components and antibodies, can be transported to the epidermis to maintain chronic inflammation. P529 has been shown to inhibit both bFGF and VEGF signalling pathways hence would be expected to short circuiting the mast cell derived factors thereby inhibiting chronic inflammation.
Psoriasis is a chronic inflammatory disease of the skin characterized by epidermal hyperplasia, dermal angiogenesis, infiltration of activated T cells, and increased cytokine levels. Endothelial cells have a pivotal role in the initiation and development of inflammation. The dermal microvasculature undergoes distinctive morphological changes. Central to the angiogenic process are endothelial cell division and migration controlled by local expression of angiogenic factors. There is considerable evidence for the development of angiogenesis in psoriatic skin. Quantitative assessment of the endothelium in psoriasis demonstrates a significant increase in surface area of the superficial vascular plexus in lesional skin. The rate of vascular proliferation in active psoriasis is similar to that in other angiogenic pathologies. Anti-angiogenic treatment suppressing VEGF expression and thereby reducing leukocyte infiltration can be correlated with reduced dermal edema and epidermal hyperplasia.
Rosacea is a chronic cutaneous disorder of unclear pathogenesis primarily of the convexities of the central face, often characterized by remissions and exacerbations. Rosacea produces a variety of clinical presentations grouped into four subtypes as erythematotelangiectatic, papulopustular, phymatous and ocular. Rosacea is characterized by inflammation and vascular abnormalities of the facial skin and ocular surface. The principal subtype, erythematotelangiestatic, is characterized by uncontrolled angiogenesis.
Several factors have been implicated in rosacea pathogenesis, such as climatic exposure, vasculature, dermal matrix degeneration, chemical and ingested agents, pilosebaceous unit abnormalities, genetic susceptibility, microbial organisms. Recently, much research has focused on angiogenesis as an essential process in a variety of chronic inflammatory skin diseases such as psoriasis and bullous skin diseases. Macrophages have also been implicated as contributing agents to a number of inflammatory skin disorders by promoting localized vasodilatation, angiogenesis and tissue fibrosis. Both these factors have been speculated to contribute to the pathogenesis of rosacea.
VEGF is a potent angiogenic factor, vasodilator and inflammatory agent strongly expressed by epidermal keratinocytes in many angiogenesis-dependent skin disorders. Expression of VEGF receptors, both by vascular endothelium and infiltrating mononuclear cells, is observed in rosacea. VEGF is present in epidermis and epithelium, and is expressed by infiltrating cells. VEGF receptor ligand binding may contribute to the vascular changes and cellular infiltration that occurs in rosacea. bFGF, another pro-angiogenic factor, has been implicated in rosacea.
As P529 is a potent inhibitor of angiogenesis and has been shown to inhibit both VEGF and bFGF signaling, it is the Company's feeling that P529 may provide benefit to patients with rosacea.
Photodamage and Wrinkle Suppression
Chronic ultraviolet-B irradiation of the skin results in epidermal hyperplasia, degradation of extracellular matrix molecules, and formation of wrinkles. Skin vascularization is greatly increased after chronic ultraviolet-B exposure with a significant increase of both the number and the size of dermal blood vessels, associated with up-regulation of VEGF and bFGF expression in the hyperplastic epidermis. Anti-angiogenic treatment of ultraviolet-B-irradiated mice has been shown to significantly reduce skin vascularization, decreased endothelial cell proliferation, and increased endothelial cell apoptosis rates, compared to wild-type mice. Moreover, dermal photo-damage and wrinkle formation are greatly reduced in mice treated with anti-angiogenic agents. Thus, the role of the cutaneous vascular system in mediating ultraviolet-B-induced skin damage suggests inhibition of angiogenesis as a potential new approach for the prevention of chronic cutaneous photo-damage. .