Pfizer Inc and Incyte Corporation have entered into a global collaborative research and license agreement for the development, manufacture, and marketing of novel, small-molecule, orally bioavailable antagonists of CCR2, a chemokine receptor that plays a central role in the establishment and maintenance of chronic inflammation via recruitment and conversion of peripheral blood monocytes to inflammatory macrophages. Macrophages are among the predominant cell types found at sites of chronic inflammation such as rheumatoid arthritic synovium, multiple sclerosis lesions, and atherosclerotic plaque.
Under the agreement, which is subject to antitrust review and approval and other standard closing conditions, Pfizer gains exclusive worldwide development and commercialization rights to the Incyte portfolio of CCR2 antagonists (excluding certain compounds reserved for Incyte) and to all potential indications, with the exception of multiple sclerosis and one other undisclosed indication for which Incyte retains exclusive worldwide rights. In return, Incyte will receive an upfront payment of $40 million, with the potential for an additional $743 million in milestone payments and royalties on worldwide product sales. Pfizer will also purchase $20 million in subordinated notes (convertible into Incyte common stock), with $10 million to be issued shortly following the closing of the agreement, and the other $10 million to be issued after Incyte files an investigational new drug (IND) application for an indication it retains. Pfizer will also provide Incyte with research funding to expand the CCR2 compound portfolio.
Incyte's lead CCR2 antagonist compound, INCB3284, entered phase I clinical trials in healthy volunteers in May 2004, and is currently under investigation in two 1-month phase IIa clinical trials in rheumatoid arthritis (RA) and insulin-resistant obese patients (Type 2 diabetes). Results from the phase I study revealed no significant adverse effects, safety and tolerability equal to that of placebo, and an investigational agent half-life supportive of once- or twice-daily dosing. Results from the two phase IIa trials are expected to be announced by the end of 2005.
CCR2 and its primary ligand, MCP-1, represent a key signaling pathway for the recruitment of peripheral blood monocytes to sites of immune-mediated inflammation, where they then become inflammatory macrophages. Oral administration of INCB3284 has shown efficacy in multiple animal models of RA.
In addition to RA, multiple sclerosis, and diabetes, inflammatory macrophages have been implicated in preclinical studies in the pathogenesis of a variety of chronic inflammatory diseases including atherosclerosis, neuropathic pain, and inflammatory bowel disease. CCR2 knockout mice show a marked impairment of macrophage influx into sites of inflammation in a range of animal models, and are less susceptible to the development of inflammatory disease in animal models of disease, including experimental autoimmune encephalomyelitis (a model of multiple sclerosis), atherosclerosis, neuropathic pain, and inflammatory bowel disease.
—A. Techman