Development of PAR2 Pepducins for the Treatment of Atopic Dermatitis

DESCRIPTION provided by applicant Atopic dermatitis AD or severe eczema is a very common life long skin disease with of adults in the US requiring systemic therapy Clinical manifestations of AD include multiple inflamed lesions erosions accompanied by lichenification thick leathery skin fibrotic papules and severely dry skin with increased susceptibility to infection A major uncontrolled symptom is intense itching and excessive scratching that can cause further excoriation erosions and infections The two mainstays of current treatment of AD are immunosuppressant corticosteroids and calcineurin inhibitors However these immune suppressing agents can cause untoward side effects during chronic treatment Anti histamine creams are not effective in suppressing AD associated itching which creates the vicious circle of excoriation skin thickening and infection Protease activated receptor PAR
has been identified as an emerging therapeutic target in AD that may significantly impact itch inflammation and skin thickening in humans PAR is highly expressed on keratinocytes and inflammatory cells in the AD lesions and is cleaved and activated by inflammatory and environmental proteases such as mast cell tryptase mite allergen proteases and a number of endogenous dermal proteases kallikrein cathepsin S involved in filaggrin and epidermal homeostasis in the skin Notably knock out of the PAR gene results in major suppression of AD lesions in animal models and nearly complete suppression of thymic stromal lymphopoietin TSLP which is a major regulator of the Th driven inflammatory response PAR deficient mice also exhibit significant suppression of itching in response to dermal irritants The goal of this proposal is based on our new discovery of the cell penetrating pepducin PZ as a potent inhibitor of PAR in AD Pepducin technology offers a unique opportunity to target the intracellular surface of G protein coupled receptors GPCRs such as PAR with exquisite specificity potency and long half lives with prolonged drug exposure to the target tissue namely skin The PZ pepducin effectively suppresses skin inflammation itch and skin thickening in multiple dermatitis and pruritus models Rapid completion of the proposed preclinical and IND enabling studies would generate a novel drug candidate with a triple anti inflammatory anti itch anti skin thickening mode of action for the treatment of AD Phase I will formulate PZ for topical skin penetration and to extensively test the pharmacologic properties of PZ with the milestones of showing significant delivery into the dermal layer and efficacy data to demonstrate suppression of AD lesions itching in animal models Phase II goals are to produce pharmaceutical grade GMP active drug substance for topical administration demonstrate efficacy and GLP safety in appropriate animal models obtain a pre IND meeting with the FDA and produce clinical protocols for Phase I and II studies in humans with our dermatology clinical collaborators

PUBLIC HEALTH RELEVANCE Atopic Dermatitis AD or severe eczema is the most common chronic inflammatory skin disease present in about million people in the US Current treatment consists of topical or oral immune suppressing agents for the most severely afflicted patients which can exhibit severe side effects and are not suitable for long term use In this proposal we identify Protease Activated Receptor PAR as an emerging new target in AD and provide a blueprint for a drug development plan using cell penetrating pepducins to effectively suppress the inflammation itching and skin thickening that afflicts AD patients