ABSTRACT The treatment of dry eye disease (DED) has been hampered by weak agents, significant side effects and high cost. The pathophysiological hallmark of DED that unifies its diverse etiologies is inflammation of the ocular surface that accounts for its clinical manifestations. The optimal treatment of DED must provide strong efficacy; topical analgesia; safety; convenient dosing; and low cost. None of the available treatments for DED meets these criteria. Phosphosulindac (PS) is a proprietary compound. We developed novel robust rabbit models of DED encompassing its main pathophysiological subgroups (evaporative, aqueous deficient and mixed). PS showed remarkable efficacy against DED; excellent safety; practically instantaneous topical analgesia; superiority in terms of efficacy over cyclosporine and lifitegrast, the two currently available drugs for the treatment of DED; and has projected low cost Additional preliminary data include the IND-enabling development of a scaled-up synthesis of PS; and development and validation of all the required analytical methods. We have also identified molecular targets of PS; and developed several formulations for PS encompassing the main physicochemical categories. Our goal is to develop PS as an efficacious drug for DED. In this Fast Track application, we propose the following studies: Phase I studies: Aim#1: Study the effect of PS in an evaporative model of DED, complementing our results with the aqueous deficient and mixed models. Aim #2: Develop the lead formulation of PS. Phase II studies: Aim #3: Optimize the lead formulation from aim #2. Aim #4: Study the in vitro metabolic stability and plasma protein binding of PS. Aim #5: Perform toxicity studies of PS. And Aim # 6: Prepare the IND protocol and package for the FDA. The proposed work, if successful, will contribute greatly towards a successful treatment of DED, a prevalent human disease, which represents an unmet medical need.