THE COMPLEMENT SYSTEM
Complement is a network of more than 50 proteins in the blood and on cell surfaces, part of the innate immune system, that quietly cruise the body, keeping a low profile until triggered into action. But this defense system can also be inappropriately activated and attack cells, contributing to a broad spectrum of immune, inflammatory, and age-related diseases. Indeed, the Complement System is a very attractive target for development of anti-inflammatory drugs because of its central role in inflammatory processes in both health and disease. Deregulated or excessive complement activation is now recognized as a key pathogenic driver in a wide spectrum of immune-mediated and inflammatory diseases, ranging from haematological and ocular pathologies to cancer, autoimmunity, oral dysbiotic diseases and ageing-related neuroinflammatory and neurodegenerative disorders. Inhibition or modulation of complement activity is therefore recognized as a promising therapeutic strategy. The Complement System is a very attractive target for development of anti-inflammatory drugs because of its central role in inflammatory processes. So far, there are only a few complement-targeted drugs approved in the clinic. However, there is still significant unmet medical need in complement-mediated complications, not targeted by the available drugs. Amyndas is developing novel therapeutics with enhanced properties to fight complement-mediated diseases that remain untreated and improve existing treatment modalities.
AMYNDAS’ PRIORITY PROGRAMS
Age-Related Macular Degeneration (AMD): AMD is a multi-factorial disease involving both genetic and environmental risk factors; its pathology and progression are strongly associated with complement-mediated ‘housekeeping’ and inflammatory processes. The disease is a leading cause of blindness in industrialized countries; it is closely correlated with age and is significantly more prevalent in caucasians; in the US, AMD has a prevalence of 2.5% in caucasians aged ≥50 years and a prevalence of over 14% in the population aged ≥80 years (NEI-NIH 2010 data). In 2010 there were approximately 2.07 million US individuals with AMD and as a result of the increasing average age of the population this number is estimated to increase to 5.44 million by 2050. Despite improved knowledge of the disease and its severe impact on patient health and quality of life, and its economic cost, effective options for therapeutic intervention in AMD remain limited. There is therefore an urgent need for earlier therapeutic intervention in AMD, where preservation of functionality can be achieved and reversal of disease remains a possibility. While therapies like Avastin, Lucentis and Eylea are approved for the treatment of patients with wet AMD, there are no therapies approved to treat Geographical Atrophy (GA) or intermediate AMD. The existing therapies act by inhibiting vascular endothelial growth factor, or VEGF, a naturally occurring protein in the body that causes the growth of abnormal blood vessels in the eye. No FDA approved therapies are currently available to prevent conversion of dry to wet AMD, or the progression of intermediate- to advanced-stage AMD. Given the role of complement in disease etiology, complement inhibitors are very attractive candidates for the treatment of earlier-stage AMD. Amongst these, Amyndas’ novel C3 inhibitors and mini-H are especially promising. Amyndas’ novel C3 inhibitors have already been validated in part, by the predecessor molecule, Compstatin POT-4, which was developed by Dr. Lambris and exclusively licensed by UPenn to Potentia Pharmaceuticals (now Apellis Pharmaceuticals) in 2006. Compstatin POT-4 has been shown to be safe and well tolerated after intravitreal injection in a Phase I clinical trial for treatment of wet AMD and demonstrated encouraging effects on drusen formation and neovascularization in AMD patients. The drug, later designed with improved solubility characteristics by Apellis and named APL-2/pegcetacoplan, has now successfully completed phase III studies for GA and was approved by the FDA as the first and only treatment for GA (Syfovre®).
Amyndas’ AMY-106, is a novel C3 inhibitor and a promising treatment option, which is expected to be beneficial for patients with GA or intermediate AMD by preventing or reducing the rate of retinal cell death and the progression of intermediate AMD to GA and wet AMD. AMY-106 has shown prolonged residence in ocular tissues at C3-saturating levels, extending over 3 months after a single intravitreal injection in cynomologous monkeys. The increased bioavailability of AMY-106 highlights its clinical potential for ocular indications associated with C3 dysregulation (e.g., AMD). AMY-106 is being developed with the advantage of local administration, reduced frequency of injections and no PEG burden.