PROJECT SUMMARY Psoriasis is a chronic inflammatory skin disease affecting approximately 7.5 million Americans that can become debilitating and severely impact quality of life. While an estimated 20% of patients suffer moderate to severe disease forms that require systemic therapy with immune suppressants and ultraviolet phototherapy, the majority (80%) of patients exhibit milder symptoms. For these patients, topical agents such as steroids, vitamin D analogues, and calcineurin inhibitors are prescribed but remain associated with poor efficacy and tolerability. Despite advances in the development of targeted biologics, including cytokine inhibitors, many psoriasis patients remain inadequately treated due to the risk of serious adverse side effects, loss of efficacy and high cost. There is a pressing need for the clinical development of effective, safe, easy to use, affordable topical psoriasis therapeutics that target the upstream proteomic mediators of the disease. Human psoriatic lesions have a profound upregulation of HSP90 versus normal skin, where data support a role in the interplay between the innate and the adaptive immune system. Regranion has recently acquired a potent novel small molecule HSP90 inhibitor with a good safety profile and proven preclinical and anecdotal clinical efficacy data for the treatment of psoriasis. In a xenograft transplantation model of psoriasis, oral delivery of CTXT-102 (previously called Debio 0932) resulted in significant clinical alleviation of psoriasis, reduced epidermal thickness, and dramatic reduction in levels of TNF? and IL-17, pro-inflammatory cytokines linked to the persistence of psoriasis. Similarly, topical delivery of CTXT-102 significantly decreased psoriatic symptoms in psoriasis mouse models. Clinical safety of CTXT-102 has been validated in a CTXT-102 Phase 1 oncology trial; where after 43 days of daily treatment with 800mg CTXT-102, a patient with severe psoriasis covering more than 40% of the skin surface showed complete remission. Based on this supporting preclinical data and serendipitous clinical finding, we plan to develop CTXT-102 in a topical formulation targeting patients with mild to moderate forms of plaque psoriasis. Our strategy is to address the wider and pressing unmet need for patients with mild to moderate from of psoriasis with topical delivery of CTXT-102; to be followed by an oral form in the future for severe psoriasis. The major objectives of this SBIR Phase II proposal are threefold. 1.) A rigorous evaluation of the efficacy and mechanism of action of topical CTXT-102 will be performed in a clinically validated psoriasis model that incorporates a comparative efficacy study versus topical corticosteroid treatment; 2.) completion of necessary IND-enabling GLP dermal sensitivity, dermatopharmacokinetic, and toxicokinetic studies, and 3.) preparation and submission of an IND-package for a future Phase 1b/2 human clinical study. Furthermore, the proposal will enable the formulation of a clinical and regulatory strategy for accelerated development. The completion of the Phase II SBIR aims will provide full characterization of CTXT- 102 in a topical formulation in order to advance into clinical trials following IND approval.