On September 24, 2015, Resverlogix announced the commencement of an orphan disease program specific for complement-mediated diseases. Apabetalone has been shown to modulate the complement pathway, which has known roles in cardiovascular disease and a variety of orphan indications. Based on these findings, Resverlogix plans to pursue proof-of-concept trials in complement mediated diseases, with the first clinical trial targeting Paroxysmal Nocturnal Hemoglobinuria (PNH).
What is the Complement System?
The immune system is made up of special cells, proteins, tissues and organs, which work in concert to defend the human body against germs and microorganisms. It is the body’s defense against foreign pathogens (biological entity that causes disease or illness) as well as abnormal cells that are derived from host tissues. This system is composed of two main parts, the innate immune response and the adaptive immune response. Several molecular components, such as complement proteins, cytokines and acute phase proteins, act in both the innate and adaptive immune responses.
The complement system represents one of the major effector mechanisms of the innate immune response, and comprises more than 30 blood soluble or membrane-associated proteins, the majority of which are synthesized by the liver. Most complement proteins circulate as pro-proteins (inactive until acted upon by specific enzymes) and the complement system remains inactive until triggered. Recognition of an antigen on the surface of a pathogen or a diseased cell activates the cascade that allows for conversion of complement pro-proteins into active components. The end-result of this activation is in the massive amplification of the response and in the generation of the membrane attack complex (MAC) on cell surfaces. The MAC forms a pore that spans the membrane of the target cell, resulting in cell lysis. Specific complement protein cleavage products generated during cascade amplification can also act as inflammatory mediators (C3a and C5a) or recognition molecules that allow for clearance of damaged cells (C3b and C4b) (see figure).
In general, the activation of the complement cascade results in the enhanced clearance of antigens (phagocytosis), the enhanced recruitment of macrophages and neutrophils into the area (inflammation), the cell lysis of foreign and abnormal cells and the enhanced agglutination or the clustering and binding of pathogens. Complement activation occurs through three principal pathways: classical, alternative and lectin (see figure). Though various factors can initiate complement activation (including MBL, C1q, C3), all three main pathways converge at the cleavage of C3, the most abundant complement protein in blood. Several mechanisms regulate complement activity including enzymes such as plasma carboxypeptidases and proteases.
Excessive complement activity is associated with several inflammatory, autoimmune, neurodegenerative and infectious diseases. The involvement of complement in the pathology of such diseases may be a result of either inappropriate initiation of the complement cascade or deficiencies in specific factors or regulators of the various pathways resulting in aberrant activation. Examples of such diseases include PNH and aHUS. Current therapies for complement disorders do not adequately treat the disorder are prohibitively costly. Combined, there is significant unmet need for individuals and families that are coping with the challenges of these disorders.