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, the only complement-targeted drugs approved in the clinic are the C1 inhibitor and the C5-targeting mAb eculizumab, which are effective in a number of complement-mediated conditions. However, there are still significant unmet medical needs 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 CLINICAL PROGRAMS
COVID-19: In the middle of the unprecedented human and health global crisis driven by the SARS-CoV-2 pandemic, research efforts are intensifying toward developing effective countermeasures to contain the spread of the novel coronavirus and relieve the huge socioeconomic burden imposed on healthcare systems globally. Emerging evidence from preclinical studies and ongoing trials in COVID19 patients indicates that the immunopathology of this disease has unique features that all converge at a deregulated and overwhelming host inflammatory response to the infectious agent, which is mainly driven by innate immune pathways. COVID19 patients with severe disease succumb to acute lung injury and ARDS but mounting evidence suggests that COVID-19 is also characterized by a systemic hyper-inflammatory syndrome that affects multiple organs and is underpinned by complement-mediated microvascular injury, excessive cytokine release, endothelial damage and a hypercoagulable state likely perpetuated by systemic complement activation. The upstream positioning of C3 activation in the inflammatory circuit that drives neutrophil and macrophage activation, excessive cytokine release and thrombogenic responses in COVID19 indicates that C3 inhibitors such as AMY-101 may offer broader and more comprehensive therapeutic coverage in COVID-19 patients. C3 inhibition by AMY-101 is expected to attenuate multiple pathogenic processes that are exacerbated by excessive thromboinflammation in COVID19. Amyndas is now conducting a clinical study in COVID19 patients to evaluate the safety and clinical efficacy of the C3 inhibitor AMY-101. See: Complement as a target in COVID-19, the immunothrombosis mechanism in COVID-19, and the C3 vs C5 inhibition in severe COVID-19.
Periodontitis: Periodontitis is a gum disease that occurs in approximately 50% of adults at some point in their life and is characterized by inflammation of the gums, bleeding and bone loss. Patients experiencing severe periodontitis, the disease is associated with inflammatory conditions such as atherosclerosis and rheumatoid arthritis. Besides dental cleaning done in the effort of reducing plaque and inflammation of the gums, there are currently no effective treatment options. Recent studies in monkeys that had developed chronic periodontitis showed that AMY-101 effectively reversed the periodontitis over 6 weeks after topical administration of the drug once a week. These impressive results make AMY-101 a promising treatment option that can provide hope to millions of people who are likely to develop periodontal disease at some point in their lives. The clinical development of AMY-101 in periodontitis is guided by a team of distinguished clinical periodontologists and periodontal disease scientists.
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 are highly promising treatment options, 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, is a which 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 being developed with the advantages of local administration, reduced frequency of injections and no PEG burden.
Kidney Transplantation: ABO-incompatible (ABOi) kidney transplantation is a method of allocation in kidney transplantation that permits more efficient use of available organs regardless of ABO blood type, which would otherwise be unavailable due to hyperacute rejection. Recent studies reveal that complement is instrumental in preventing ABOi organ rejection during transplantation. Amyndas is developing the novel C3 complement inhibitor AMY-101, for prevention of organ rejection during ABOi kidney transplantation and the treatment of patients with end-stage renal disease (ESRD). For the development of AMY-101, Amyndas has been awarded a European Union 7th Framework Program grant. AMANDEN shows a very attractive safety profile and excellent PK/PD in pre-clinical studies.
Paroxysmal Nocturnal Hemoglobinuria (PNH): PNH is a rare but life-threatening hemolytic anemia. Currently the only available therapy for PNH is eculizumab, an antibody, which acts by inhibiting the C5 component of the complement system. Anti-C5 treatment generally leads to significant improvement in the patient’s quality of life; however about a third of all patients do not respond to the drug, thus continuing to require blood transfusions to manage ongoing anemia. Amyndas is developing a new strategy to treat PNH by targeting the C3 component, a more central part of the complement system; using the small inhibitor AMY-101 to inhibit C3, Amyndas intends to prevent both intravascular and extravascular hemolysis, thus aiming to also benefit the currently untreated PNH patients. Moreover, as a small peptide AMY-101 is also more cost-effective when compared to the existing antibody-based treatment. A number of high impact scientific publications endorse the development of AMY-101 for the treatment of PNH. The US FDA and the European Medicines Agency (EMA) have designated AMY-101 an orphan drug for the treatment of PNH. Moreover, a series of compstatin derivatives with improved pharmacokinetic properties and appreciable levels of oral bioavailability in NHP, are now in preclinical development. Enhancing the bioavailability of these peptidic C3 inhibitors is expected to revolutionize complement therapeutic intervention especially in indications that rely on chronic treatment, such as PNH and C3G.
C3 glomerulopathy (C3G): C3G refers to a group of rare renal disorders characterized by the local imbalance in complement activation leading to proteinuria, hematuria, and renal failure. Half of the patients suffering from this condition progress to kidney failure within 10 years of diagnosis. Kidney transplantation is not recommended, because allograft loss and disease recurrence are observed in more than 50% of all cases. Currently there is no treatment for C3G and the management of the disease includes drugs for blood pressure control and immunosuppressive therapy. Because the pathology in C3G is indicative of a dysfunctional alternative complement pathway (AP) C3 inhibition could constitute a useful treatment strategy. Recent (ex vivo) data demonstrate that AMY-101 corrects the complement dysregulation that characterizes C3G and constitutes a potentially beneficial treatment strategy. As AMY-101 represents a novel and promising therapeutic option that may offer C3G patients a disease-specific, cost-effective, targeted therapeutic approach, the US FDA and and the EMA have each designated AMY-101 an orphan drug for the treatment of C3G.
Cancer Immunotherapy: According to the World Health Organization, cancer is among the leading causes of death worldwide. In 2012, there were 14 million new cases and 8.2 million cancer-related deaths worldwide. In the US alone, health care expenses totaled nearly $125 billion in 2010 and are estimated to reach $156 billion in 2020. The National Cancer Institute projects breast, lung, prostate, colon, bladder, melanoma, thyroid, kidney, renal, leukemia, endometrial, pancreatic and non-Hodgkin lymphoma as the most common cancers for the next years. Given the extensive list of causes and molecular mechanisms that lead to disease and the individuality of each tumor, successful therapy continues to be challenging. Complement has been implicated in various settings of cancer by interfering with cell proliferation, survival and invasiveness. Recent research indicates that the targeting of the protein programmed cell death ligand 1 (PD-L1) in T cells acts as an immune check point inhibitor by stimulating the T cells to attack tumors. Additionally, pre-clinical studies suggest that combined immunotherapy targeting PD-L1 and complement is more efficient in the combat of tumors than PD-L1 therapy alone. Based on these studies, AMY-101 is an attractive complement inhibitor which can be tested in combination with PD-L1 immunotherapy in cancer patients.