Akari Therapeutics Announces Publication in American Journal of Pathology Highlighting Potential of Nomacopan in Treatment of Uveitis and Retinal Disease
- New data highlight role of leukotriene B4 (LTB4) in the pathophysiology of retinal inflammation and degeneration
- In the experimental allergic uveitis (EAU) disease model nomacopan reduced Th17 effector T cell and macrophage activity in addition to known downregulation of neutrophils
- Long-acting forms of nomacopan were at least as effective in downregulating disease in EAU model as standard of care dexamethasone, which is associated with steroid related side effects
- Akari is investigating the potential of two long-acting forms of nomacopan which inhibit, (1) LTB4 and C5 combined or (2) LTB4 alone for treatment of back of the eye diseases
These data point to the potential importance of LTB4 in the development of inflammatory retinal diseases which potentially include proliferative age-related macular degeneration (wet AMD), diabetic retinopathy, diabetic macular oedema and autoimmune uveitis.
While complement C5 activation has previously been shown to have a causative role in late stage EAU1,2, the authors of the paper focused on the less well understood contribution of LTB4 to uveitis disease pathology.
Key findings were that IVT administration of the long-acting engineered form of nomacopan that only binds to LTB4 was at least as effective as the steroid dexamethasone in reducing retinal inflammation. Nomacopan significantly decreased proliferation, differentiation and infiltration of Th17 and Th1/17 effector CD43 T cells and reduced activated macrophage cell populations, each of which is reported as having a causative role in uveitis disease pathology.
Intravitreal LTB4 and C5a was elevated in response to EAU and the level rose from initiation until the disease peaked at Day 21. Few LTB4 or C5a receptors were detected in healthy human donor eyes, but significant numbers of infiltrating cells displaying these receptors were detected in uveitic eyes of EAU mice and in post-mortem retinal sections from patients with uveitis, supporting the likely role of LTB4 and C5 in the disease pathology.
Corticosteroids such as dexamethasone are the current standard of care for uveitis but may be associated with significant steroid related side effects such as increased risk of raised intraocular pressure, cataract formation, keratopathy and macular oedema, hence an equally effective and safer alternative treatment would be well received.
In conclusion, the new data highlight the likely importance of LTB4 in the aetiology of retinal inflammation and effectiveness of nomacopan’s LTB4 inhibitory activity in the model of uveitis. The data also show that inhibition of LTB4 decreases Th17 effector cell differentiation and proliferation and activation of macrophages, which, along with complement inhibition, may not only be relevant in uveitis but also for other autoimmune diseases for which nomacopan is being developed, including bullous pemphigoid.
2 S. Reinehr,
3 Eskandarpour M, Chen YH, Nunn MA, Coupland SE,
About Akari Therapeutics
Akari is a biopharmaceutical company focused on developing inhibitors of acute and chronic inflammation, specifically for the treatment of rare and orphan diseases, in particular those where the complement (C5) or leukotriene (LTB4) systems, or both complement and leukotrienes together, play a primary role in disease progression. Akari’s lead drug candidate, nomacopan (formerly known as Coversin), is a C5 complement inhibitor that also independently and specifically inhibits leukotriene B4 (LTB4) activity.
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Source: Akari Therapeutics Plc