Selective inhibition of CYP26A1 in the skin for the treatment of ichthyosis

Project SummaryAbstract DermaXon s project goal is to develop efficacious substrate based and highly selective inhibitors of CYPsthe enzymes responsible or retinoic acidRAmetabolism in the epidermisfor the topical treatment of ichthyosisThis approach will provide a therapeutic advantage in ichthyosis without the potential adverse effects mediated by non targeted Pinhibitionassociated with previously described non specific azole containing CYPinhibitorssuch as liarozoleCongenital ichthyosis is a family of hereditary disorders of keratinization characterized by dryscaling skin that may be thickened or very thinimpacting the quality of life of patients and their family membersCurrentlythere is no cure for ichthyosis and available medicines are aimed only at moisturizing and exfoliating to reduce drynessscaling and cracking of skinRA derivatives are known to normalize abnormal differentiation of keratinocytes and have keratolytic effects that mitigate hyperkeratosis in patients with ichthyosisHoweverRA has poor pharmacokinetics in humans because it induces its own clearance by upregulating metabolic enzymes and its topical use is limited due to mucocutaneous side effects and irritationThe clearance of RA in the skin is predominantly mediated by cytochrome Pfamilyisoforms CYPAand CYPBCurrently approved topical RARselective retinoidswhose effects are mediated by direct receptors activationare also potent inhibitors of both CYPAand Bwhich likely explains their adverse side effects including retinoid dermatitisand induced by retinoid overloadIn a preliminary Phase I studywe have identified a potent and selective dual inhibitor of CYPAand Bwith a promising safety profileand a good efficacy at potentiating the effect of a physiological dose of RA in lamellar ichthyosisrecessive X linked ichthyosis and Darier s disease derived reconstruct human epidermisThe major milestones in this Phase II project areto identify a backup compound originating from a different chemical scaffoldwith efficacy in patient derived reconstruct human epidermiswhich will be ready for preclinical development if our identified preclinical candidate fails in early toxicological studiesto advance our dual CYPinhibitor from optimized lead molecule to preclinical candidate suitablefor preclinical toxicity studies andfinally to initiate preclinical development studies to demonstrate the safety of our pharmaceutical grade preclinical candidateBy the end of this projectDermaXon will have identified a potentselectivetopically activesafe and efficacious CYPinhibitor that can treat keratinization disorders in preclinical skin models of ichthyosiswith efficacy at potentiating the effect of endogenous RA in vivoand ready for IND enabling formal pivotal in vivo studies to address the therapeutic needs in disorders of epidermal differentiation PROJECT NARRATIVEPublic Health RelevanceIchthyosis is a family of rare and neglected genetic disorders characterized by persistently dryrough and scaly skinCurrent treatment options do not adequately address patient needspresenting significant efficacy or tolerability concernsDermaXon has successfully identified a potential preclinical candidate acting through retinoic acid metabolism inhibition in the skinas novel class of therapeutic agents for the topical treatment of hyperkeratosis associated with ichthyosisIn this applicationwe propose to initiate IND enabling studies for our novel topically delivered CYPinhibitor