In his abstract, Dr. Mousa describes how OT-551 operates within the cell to downregulate Nuclear Factor kappa B (NF-kB), a transcription factor whose overexpression is associated with a host of inflammation-related ocular and non-ocular diseases. In combination with OT-551's previously known antioxidant and antiangiogenic activities, elucidation of this new mechanism provides strong support for the ophthalmic indications that Othera is currently pursuing with OT-551, as well as new non-ophthalmic indications for analogous oral compounds. Specific diseases of interest to Othera that have been linked to NF-kB overactivity in the scientific literature include age-related macular degeneration (AMD), cataracts, dry eye, resistance to cancer chemotherapy, cancer-related thrombosis and rheumatoid arthritis.
A New Understanding of How OT-551 Works in Ocular Disease
In conjunction with Othera scientists, Dr. Mousa performed large-scale gene expression studies using microchip arrays that provided evidence of OT-551 's effect on several human inflammatory genes regulated by NF-kB. Subsequent animal studies confirmed that OT-551 treatment reduces levels of TNF-(alpha), a key inflammatory cytokine that is regulated in large part by NF-kB. Specific to the area of blood clotting (thrombosis), Dr. Mousa has shown that OT-551 downregulates the expression of tissue factor (TF), an important downstream component of the clotting pathway that is also controlled by NF-kB. Dr. Mousa further demonstrated that OT-551 inhibits thrombosis in whole blood, reversing the clotting that occurs after addition of certain biomolecules, such as anti-VEGF agents for which thrombosis has been identified as a clinical side effect.
"We were impressed by the broad spectrum effect of Othera's compounds in terms of their ability to inhibit not only genes involved in oxidative stress responses, but also inflammatory response genes that control angiogenesis," said Dr. Mousa. "These clues pointed us towards a more complex mechanism of action than the antioxidant activity we had previously observed. We have now proven this hypothesis in multiple animal studies where we induced an inflammatory response and demonstrated an inhibitory effect. This new picture of OT-551's mechanism and its unique ability for topical delivery and high bioavailability supports Othera's choice of ocular clinical targets and strategy."
The OT-300 Program: Building on Lead Compound Mechanism to Identify New Treatments for Oncology and Inflammatory Disease
Based on this new mechanism understanding, Othera has initiated the OT-300 series program, which is aimed at developing orally available analogs of OT-551 for the treatment of non-ophthalmic therapeutic areas. Othera's OT-300 series will target NF-kB mediated diseases including oncology and inflammatory disease. Through a focused drug discovery program that follows the OT-551 mechanism, Othera is identifying and screening novel small molecules for oral delivery to tr eat serious diseases where there is a need for safer and/or more efficacious therapies. Othera has already identified potential lead molecules for its initial disease targets: cancer-associated thrombosis, tumor resistance to chemotherapy (chemoresistance) and rheumatoid arthritis.
Thrombosis associated with cancer remains one of the leading complications leading to death among cancer patients, and select OT-300 compounds could represent a treatment. Dr. Mousa will present data on one or more compounds from the OT-300 Program at the ISTH meeting. Othera intends to complete pre-clinical work in the coming months to support corporate partnering activity for further development of these compounds.
About Othera Pharmaceuticals
Othera Pharmaceuticals, Inc. is a privately-held, specialty pharmaceutical company located in Exton, PA. Othera is designing and developing small molecule products with novel mechanisms of action for ophthalmic and other indications. In ophthalmics, we are developing topical eye drop products for age-related diseases, including some of the leading causes of blindness. Othera is also engaged in the discovery of a novel set of orally-administered compounds to address severe medical conditions including cancer and chronic inflammatory diseases.
Othera's lead compound, OT-551, is an eye drop currently in Phase 2 clinical development. OT-551 has application to several major eye diseases and conditions, including the dry and wet forms of age-related macular degeneration (AMD), cataracts, and dry eye syndrome. Othera's second lead compound, OT-730, is a novel improved beta-blocker in preclinical development for the treatment of glaucoma. More information on Othera Pharmaceuticals is available on the company's website at www.othera.com.
Othera Pharmaceuticals, Inc., Exton
FD Life Sciences
Matt Dallas, 212-850-5627