Recent evidence suggests that a population of blood-derived macrophages infiltrates tissues to drive numerous inflammatory disease processes, including pain, multiple sclerosis, and various other autoimmune/inflammatory conditions. Pathologica was founded upon these observations, and is developing a novel class of macrophage-targeting drugs to treat inflammation.
Pathologica’s lead development candidate is PA300, an orally-active inhibitor of S-adenosylmethionine decarboxylase (a principal enzyme in the biosynthesis of polyamines) which regulates the function of monocytes/macrophages, a key cell population mediating inflammation and pain. In vitro studies have demonstrated PA300 uptake into monocytes/macrophages with effects on differentiation, but house-keeping processes (e.g. phagocytosis) remain intact. In various rodent models, PA300 has anti-inflammatory/analgesic activity comparable to celecoxib, and suppresses production of inflammatory (pain-driving) prostaglandin E2, while sparing basal levels of this mediator. Given its non-COX1/COX2 mechanism of action, PA300 is also GI-, renal-, and platelet-sparing in animal models. PA300 has a clean in vitro pharmacology profile, and animal toxicology studies suggest a very favorable safety window in humans. An IND has been filed for the initial indication of signs and symptoms of osteoarthritis, with various potential future indications for diseases driven by monocytes/macrophages, including multiple sclerosis.
1. Uptake and regulatory activity in monocytes/macrophages
2. Inhibition of S-adenosylmethionine decarboxylase (SAMDC) and polyamine processes
3. Net effect: Decreased mediators (eg PGE2, 8-isoprostane), analgesia, anti-inflammatory