Our Focus

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 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. AMY-101 has been evaluated in a phase 2, randomized, single blind, placebo-controlled clinical trial to evaluate the safety and efficacy of the complement C3 inhibitor, AMY-101, in approximately 30 COVID-19 patients with acute respiratory distress syndrome (ARDS). The study completed interim analysis and relevant top-line data are published in Science Advances: \Complement C3 inhibition in severe COVID-19 using compstatin AMY-101

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. Amyndas has completed a phase 2a clinical trial of AMY-101 in adults with Gingivitis and Periodontal disease at the Forsyth Institute in Boston. The study met its primary endpoint and key secondary endpoints with statistically significant and clinically meaningful resolution of periodontal inflammation, as reflected by reductions in the mean gingival index and bleeding on probing. AMY-101 was shown to be safe and well-tolerated and exerted a prolonged therapeutic effect that persisted for 3 months after treatment discontinuation. The gingival crevicular fluid levels of matrix metalloproteinases (MMP-8 and MMP-9), which are indicators of inflammatory tissue destruction, were also significantly reduced by AMY-101. The ability of AMY-101 to mediate resolution of gingival inflammation indicates its potential to provide an innovative, disease-modifying treatment option for human periodontal diseases. 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. Extending on these most promising clinical results, Amyndas is now planning a pivotal phase 3 study in patients with periodontal disease. The clinical development of AMY-101 in periodontitis is guided by a team of distinguished clinical periodontologists and periodontal disease scientists and is strongly supported by 31 international Key Opinion Leaders in the dental medicine space.

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.

Kidney Transplantation: According to The US National Kidney Foundation (NKF), In 2014, 17,107 kidney transplants took place in the US. Based on the literature and physician interviews, it is estimated that ~5% of transplant recipients or 700 and 900 patients in the U.S. and E.U., respectively, are at high risk of antibody mediated rejection (AMR). Additionally, the NKF estimated (as of 1/11/16) that 100,791 patients in the US awaited kidney transplants, while 3,381 patients died waiting for a kidney transplant in 2013. 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 AMY-101 for prevention of organ rejection during ABOi kidney transplantation and the treatment of patients with end-stage renal disease (ESRD). If AMY-101 can make non-matched donor transplantations safer, the number of procedures per year may increase substantially, since kidney transplantation is considered the most desired and cost-effective treatment solution for patients in ESRD. Amyndas is supported by a team of transplantation experts and was awarded European Union research funds for the development of AMY-101 in this indication.

Paroxysmal Nocturnal Hemoglobinuria (PNH): PNH is a rare but life-threatening hemolytic anemia. Until recently 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.

The therapeutic potential of AMY-101 in PNH has recently been validated by an earlier generation predecessor molecule APL-2/ pegcetacoplan, which was also originally discovered by Dr. Lambris at U Penn and exclusively licensed to Potentia Pharmaceuticals – now Apellis Pharmaceuticals. In a successful phase III trial in PNH patients, APL-2/ pegcetacoplan showed superior efficacy to Soliris (eculizumab) in terms of improving hemoglobin levels, reducing blood transfusion requirements and improving clinical/ hematologic outcomes by affording broader therapeutic control of intravascular and extravascular hemolysis. Pegcetacoplan/ EMPAVELI® is now approved by the FDA for the treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH). EMPAVELI® is the first C3 complement inhibitor to get approval for the treatment of PNH.

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.