Aviari's research organizes around modulating the activity of integrins - a large family of adhesion molecules found on most cell surfaces mediating a wide variety of physiological processes, including cell adhesion, migration, survival and differentiation. Integrins play a key role in the inflammatory and immune response to disease addressing a diverse range: cancer, infection, thrombosis and autoimmune disorders. Aviara is exploring new ways of modulating the effects of stem cells and the stem cell niche. A single stem cell is unique and can proliferate and differentiate into other cell types with specialized functions such as those of muscle, brain, blood or skin. In adults, cells contribute to repair damaged tissue by regenerating those cell types necessary for proper organ function. Supporting the maintenance of stem cell identity and regulating their function, the stem cell niche is the micro-environment located within the bone marrow where the stem cells reside. Hematopoietic Stem Cell Mobilization: Aviaras lead clinical candidate - AVA4746 - is being developed for use as a mobilization agent in cancer patients undergoing autologous hematopoietic stem cell (HSC) transplantation. HSC being stem cells that mature to form blood and immune cells such as erythrocytes, leukocytes, etc. Produced in the bone marrow, they egress into the circulation and are ultimately responsible for the constant renewal of blood: production of billions of new blood cells each day. However, because only a small amount of HSC circulate in the peripheral blood at any time, it is necessary to use mobilization agents to drive them to the peripheral circulation where they can be collected for transplantation. Recent research has shown a strong role for integrin antagonists to be used in the role of HSC mobilization. Aviara has conducted multiple studies of AVA4746 in preclinical models of HSC mobilization, results of which demonstrate a clear opportunity for the use of AVA4746 in HSC mobilization. The development goal of the program is to increase the yield of HSC in the peripheral blood so that fewer collection procedures are needed to collect the required number of HSC needed for transplantation. An addiitonal arena of particular interest for integrin antagonists is that of cell mediated drug resistance (CAM-DR). CAM-DR is developed when some cancerous cells remain sequestered and viable in the bone marrow and not affected by chemotherapy. These cells have been shown to act as source for a relapse of the cancer (referred to as Minimal Residual Disease (MRD)). AViara believe the use of integrin antagonists may play a key role in overcoming chemotherapy resistance and disease relapse by inhibiting the bond between the cancerous cells and the bone marrow niche, making the cancerous cells more susceptible to chemotherapeutic agents. Inflammatory Bowel Disease (IBD): broad term that describes conditions with chronic or recurring immune response and inflammation of the gastrointestinal tract. The ?4?7 integrin is considered to be the adhesion molecule principally involved in inflammation of the intestinal lining. Recently, a human monoclonal antibody to the ?4?7 integrin was approved by the FDA, providing further validation of targeting the ?4?7 integrin clinically. Estimates suggest c.1.4 million US persons suffer from IBD, - one of the five most prevalent gastrointestinal disease burdens in US. Aviara is developing an oral, small molecule inhibitor of the ?4?7 integrin as an alternative to injectable biologic products currently used in IBD - potentially $7.70 billion market. Dry Eye Syndrome (DES) aka keratoconjunctivitis sicca, is a common ocular surface disease affecting tens of millions of people worldwide.One of leading reasons for patients seeking treatment of symptoms of ocular discomfort and visual disturbance, and commonly leads to problems with activities that require sustained visual attention such as reading and driving. One mechanisms underlying DES symptoms is chronic inflammation of the ocular surface caused by an integrin-mediated response. Recent studies using a topically applied integrin antagonist demonstrated a significant reversal in corneal epithelial damage, a key driver of the chronic symptoms associated with dry eye. With the worldwide market opportunity for dry eye treatments being in excess of $1 billion, we believe a topically applied integrin antagonist would represent a significant improvement in currently used therapies. Aviara will be developing the topical form of AVA3486 for use in the treatment of DES with the help of a corporate partner specializing in diseases of the eye.
