Targeting TRP channels for novel topical treatment of atopic dermatitis

SUMMARY We have developed TB16-8, a small molecule that is an effective inhibitor of both TRPV4 and TRPA1 ion channels. These two ion channels are associated with atopic dermatitis (Atopic Derm) and its dominating clinical hallmark, chronic and debilitating pruritus (itch). We have demonstrated that the topical application at low microgram amounts of this compound effectively inhibits itch and inflammation in mice and swine—used as animal models—for various symptoms of Atopic Derm. Currently there are treatments approved for Atopic Derm and its symptoms; however, none is a universal drug, and not all Atopic Derm drugs are appropriate for all the patients. TB16-8 is intended as a single therapy, applied topically, potentially replacing immunomodulatory drugs, or as a complement for current treatments with a perspective of lowering applied doses. TB16-8 is intended for topical application; therefore, in addition to providing short term relief, an objective is chronic use for extended periods of time with minimal or no adverse effects. In the present Phase I proposal we will perform studies intended to position TB16-8 in pre-IND status. First, an optimized chemical synthesis will be achieved. Every step of the synthesis process will be carefully analyzed and optimized to generate a final drug product that satisfies FDA and ICH GMP requirements. The effect of TB16-8 will be studied in mouse preclinical models for contact dermatitis by sensitizing them with DNFB (2,4- dinitrofluorobenzene) and by chronic pruritogenic dermatitis using a dry skin model based on acetone-diethyl ether. Scratching behavior and skin inflammation will be measured. Skin inflammation and biodistribution of TB16-8 in the blood and integument of swine will also be evaluated. Our preliminary data are strong and could be perceived as if our product ought to be considered for a Direct to Phase II; however, dermal concentrations and detection of TB16-8 in the systemic circulation following topical administration in swine, a relevant model for topical administration in humans, have not been collected, making this Phase I a necessary stage prior to reaching pre-IND status. We will complement the safety and up to 48h biodistribution data of TB16-8 currently available in two animal models, and we will optimize the chemical synthesis of TB16-8. These studies will be followed by a Phase II application in which IND-required studies such as eye-irritation analysis, toxicology, and other relevant studies will be performed. These future studies will provide data required to meet with the FDA and discuss the necessary experiments to position TB16-8 for a topical treatment of Atopic Derm.NARRATIVE Atopic dermatitis (Atopic Derm) is one of the most common chronic skin conditions globally, with many patients suffering from clinically debilitating itch. The current therapeutic options continue to leave patients with inadequate disease management and/or the burden of significant risks. We developed a small molecule, TB16- 8, that inhibits two ion channels known to contribute to the molecular mechanisms driving Atopic Derm, and that we intend to develop as a new treatment for Atopic Derm as a topical application to skin. We are proposing a series of experiments to further confirm this compound in terms of safety and biodistribution that should help position TB16-8 as a promising new therapeutic for Atopic Derm.