ANCA-Associated Vasculitis

ANCA-Associated Vasculitis (AAV) is a type of autoimmune disease caused by autoantibodies, which are abnormal antibodies that attack one's own cells and tissues. AAV encompasses various conditions including:

• Renal limited vasculitis or ANCA glomerulonephritis: the blood vessel damage occurs in the kidneys. No other organs are affected.

• Microscopic polyangiitis: caused by injury to blood vessels in multiple tissues at the same time. It can be seen in the kidneys, skin, nerves, and lungs.

• Granulomatosis with polyangiitis (Wegener's granulomatosis): the blood vessel damage occurs in connection with a process called granulomatous inflammation. This often affects the lung, sinuses, nose, eyes or ears.

These autoantibodies lead to the activation and increased adhesiveness of neutrophils to the walls of small blood vessels in different tissues and organs of the body. These accumulating adhering neutrophils initiate an inflammatory cascade in the small blood vessels by secreting proinflammatory cytokines and chemoattractants. Activation of the complement pathway occurs with production of complement 5a (C5a), one of the most potent pro-inflammatory mediators of the complement system. C5a, through binding to its receptor C5aR, induces expression of adhesion molecules and chemotactic migration of neutrophils, eosinophils, basophils and monocytes. It also mediates inflammatory reactions by causing smooth muscle contraction, increasing vascular permeability, inducing basophil and mast cell degranulation and inducing release of lysosomal proteases and oxidative free radicals.

If left untreated, ANCA-associated vasculitis (AAV) may lead to renal and pulmonary failure and is often fatal. AAV is currently treated with high-dose corticosteroids and cyclophosphamide, azathioprine, mycophenolate mofetil, rituximab, and plasma exchange in severe cases. Little advance in the treatment of these diseases has been made since the 1970's when these treatments were first introduced. Corticosteroids and cyclophosphamide are associated with substantial morbidity and mortality, particularly as a result of serious infections. Cyclophosphamide is also associated with an increased risk of cancer, bladder conditions and infertility in patients. Azathioprine and mycophenolate mofetil are also general immunosuppressive therapies, associated with increased infection risk. Rituximab is a mouse-human chimeric anti-CD20 antibody, which depletes B cells and is associated with increased risk of serious infections, as well as progressive multifocal encephalopathy. Because of the serious adverse effects of these current therapies, we believe that there is an important unmet medical need for AAV therapies that are safe, effective, and corticosteroid-sparing.

ChemoCentryx has completed a Phase I clinical trial with CCX168 in 40 healthy subjects and we have initiated a Phase II clinical trial in AAV.

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