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Complement & PNH

The complement system is a central component of the innate immune system. Dysregulation of the complement system is considered central to a seemingly diverse set of diseases ranging from ocular indications such as dry age-related macular degeneration (dry AMD) to transplant rejection, ischemia/reperfusion injury, sepsis and other systemic inflammatory response syndromes (SIRS), lupus nephritis, and several rare hemolytic diseases.

Numerous diseases and pathologic states are associated with dysregulation of the complement system. There are multiple pathways leading to activation of the complement system, all of which lead to the cleavage of C5 to C5a and C5b by one of several C5 convertases. C5a acts as a potent anaphylatoxin to recruit inflammatory cells to a site of injury or damage, while C5b initiates the formation of the membrane attack complex (MAC or C5b-9) . Under normal conditions, MAC is responsible for the lysis of pathogens. However, under certain pathological states, it can cause uncontrolled red blood cell lysis. C5a and C5b are jointly responsible for much of the damage caused by unregulated complement activity in a variety of disease states, the consequences of which can be catastrophic.

Ra believes that its family of peptide C5 inhibitors can be used in a number of life-threatening or debilitating conditions for which there are no effective therapies. In particular, there is a critical need for the development of therapeutic agents able to inhibit the damage caused by the recruitment of inflammatory cells and the formation of the MAC without disturbing beneficial contributions from upstream elements of the complement system such as C3-mediated bacterial opsonization.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder that results from uncontrolled activation of the Alternative Pathway (AP) of complement, with intravascular hemolysis leading to potentially fatal thromboembolism. Patients suffer from severe anemia, which often requires transfusions, hemoglobinuria, abdominal pain, smooth muscle dystonias, and fatigue. It is currently treated with the monoclonal antibody eculizumab, a highly expensive product administered by intravenous infusion.