Alexion's most advanced drug development program is based on the Company's expertise regarding selective interruption of the complement cascade. Complement can be activated in a variety of ways. Notably, certain stimuli include antibodies binding to foreign tissue, proteases associated with inflammation and infectious agents. Furthermore, complement can be activated in settings where tissues are damaged, suffer restricted blood flow (ischemia), or undergo restoration of blood flow (reperfusion). In the case of cardiopulmonary bypass procedures, contact of blood with the artificial surfaces of the bypass equipment can also activate complement proteins.

Diagram of the central features of the Complement Cascade.

The Complement Cascade
Complement activation results in a unidirectional sequence of enzymatic and biochemical reactions known as the complement cascade. In this cascade, a specific complement protein, C5, forms two highly active, inflammatory byproducts, C5a and C5b-9, which jointly activate white blood cells. This in turn evokes a number of other inflammatory byproducts, including injurious cytokines, inflammatory enzymes, and cell adhesion molecules. Together, these byproducts can lead to the destruction of tissue seen in many inflammatory diseases. The body’s cells normally are protected by a shield of naturally-occurring complement inhibitors on the surface of the cells. A deficiency of such inhibitors, as found in blood cells in PNH patients, leaves these cells exquisitely sensitive to complement attack and destruction.

Selective Inhibition of C5
The early steps of the complement cascade are important in the normal removal of infectious agents and several normal functions of the immune system. Alexion believes that the optimal point to block Complement is at C5, so that the normal upstream disease-preventing functions of complement remain intact while production of the abnormal downstream disease-causing actions of complement are blocked. Therefore, Alexion's researchers have developed anti-inflammatory products that selectively and potently bind to C5 and block the production of the downstream inflammatory byproducts.

C5 Inhibitors in Models of Cardiac Diseases
In preclinical models of cardiopulmonary bypass, our C5 Inhibitor therapy reduced complement activation and inflammation. In preclinical models of coronary artery disease, C5 Inhibitor therapy substantially reduced complement activation, white blood cell activation (a key indicator of inflammation), and myocardial infarction (heart attack).

C5 Inhibitors in Models of Blood Diseases
In laboratory models of a severe hemolytic blood disease, paroxysmal nocturnal hemoglobinuria, our C5 Inhibitor therapy reduced complement activation and prevented red blood cell destruction. In laboratory models of PNH, C5 Inhibitor therapy substantially reduced production of free hemoglobin which would be expected to bind to and reduce nitric oxide.

C5 Inhibitors in Models of Autoimmune Diseases
In preclinical models of arthritis, nephritis, and systemic lupus, our C5 Inhibitor therapy reduced joint damage, kidney injury, and mortality, respectively.

Alexion's C5 inhibitors (pexelizumab and eculizumab) will initially target cardiovascular and hematologic disorders. Eculizumab will target paroxysmal nocturnal hemoglobinuria within the area of hematological disorders. With chronic autoimmune indications, eculizumab has been studied in early clinical trials of patients with rheumatoid arthritis, membranous nephritis, dermatomyositis, and systemic lupus. Pexelizumab will target acute myocardial infarction.