ACHN 2017 Annual Report

months or longer. We had been evaluating several of these compounds, as well as several delivery technologies, to optimize treatment duration. After the announcement that lampalizumab, a product candidate that also targets complement factor D inhibition in GA, was reported to not have met its primary endpoint of reducing GA lesions when compared to a sham treatment, we undertook a reassessment of our factor D preclinical development efforts for GA. This reassessment is ongoing. The Complement System The complement system is part of the body’s immune system. The immune system protects the body by recognizing and eliminating bacteria, viruses and other infectious agents, referred to as pathogens, and abnormal cells such as cancer cells. The activities of the immune system are undertaken by its two components, the innate immune system and the adaptive immune system. The role of the innate immune system is to provide a rapid nonspecific response to pathogens or abnormal cells in the body and to activate the adaptive immune system. The role of the adaptive immune system is to provide a specific response to pathogens or abnormal cells. Once a pathogen or abnormal cell has been recognized, the adaptive immune system generates immune cells and antibodies that specifically attack that pathogen or abnormal cell. Complement is activated via three pathways: the alternative pathway, lectin pathway and the classical pathway. At sites of infection, the complement system activates and triggers a series of potent inflammatory responses. There are also many regulatory mechanisms to prevent uncontrolled complement over-activation. The complement system consists of over 30 small proteins and protein fragments found in the blood, generally synthesized by the liver, and normally circulating in an inactive state. Complement proteins account for about 5% of the globulin portion of blood serum. A number of complement proteins are proteases. When stimulated by one of several triggers, proteases in the system cleave specific proteins and initiate an amplifying cascade of further cleavages. The end-result of this activation cascade is amplification of the response and activation of the pathogen- and cell-killing membrane attack complex, or MAC. The alternative pathway is one of three complement pathways that opsonize, or prepare a pathogen for destruction, and kill pathogens. The alternative pathway is initiated by the spontaneous hydrolysis, or breaking of protein C3 chemical bonds through the introduction of water. This is sometimes referred to as “tickover” and is the initiation of alternative pathway. Many inflammatory, autoimmune, neurodegenerative and age-related diseases are associated with inefficient complement regulation or excessive activity of the complement system and are believed to be specifically related to the alternative pathway. Current therapies, including those in development, to treat PNH target other complement proteins such as C5 or C3 that are active “downstream” of factor D within the protein activation cascade of the complement system. The C3G Market C3G is a life-threatening, ultra-rare disorder characterized by over-activation of the alternative pathway. The condition includes both dense deposit disease, or DDD, and C3 glomerulonephritis, and is typically characterized by abnormalities in complement protein levels which results in deposits of complement protein C3 fragments within the glomeruli of the kidney, thereby inhibiting proper filtration of the blood, tissue scarring, and ultimately impaired kidney function. The overall prognosis for patients with C3G is poor, with approximately 30% to 50% of C3G patients progressing to end-stage renal disease, or ESRD, within 10 years of diagnosis. Dialysis and renal transplantation are options available for patients who reach ESRD; however, disease recurrence is frequent after transplantation, occurring in more than 50% of patients. Only about 50% of patients have a functioning graft 5 years after transplantation. Based on internal research, we estimate that C3G affects at least 8,000 people in the United States and the major European markets, specifically France, Germany, Italy, Spain and the United Kingdom. There are no approved treatments for patients with C3G. 6