Efficacy and resistance mechanisms of LD-aminopterin in psoriasis

DESCRIPTIONprovided by applicantPsoriasis is a chronicgenetically influencedremitting and relapsing scaly and inflammatory skin disorder that affectsof the worldandapos s populationresulting in total annual costs of $billion in the United States inApproximatelyof patients with moderate to severe chronic plaque psoriasis require phototherapy and or a variety of systemic treatmentswhere methotrexateMTXis the mostly widely used oral systemic agentDespite the relative effectiveness of MTXas a monotherapyit does not achieve greater than areduction in the baseline psoriasis area and severity indexPASIinof patientsand fails to achieve remissioni eandgtPASIinof patientsFurthermoreup toof patients with moderate to severe plaque psoriasis discontinue oral MTX primarily because of intolerance to the drugWhile much effort has been directed to identifying the mechanism behind poor and or toxic responses to MTX based on genetic factor and quantitation of its active metabolitesthe majority of MTX failures remain unexplainedGiven the efficacy and safety limitations of MTX and the cost of biologics compared to MTX$vs$per yearthere is a clear market opportunity for an improved antifolate with better efficacy and or safety than MTXbut that is priced between MTX and biologicsLD AminopterinLD AMTis a patented composition developed by Syntrix Biosystems that studies indicate has greater cellular uptakei epolyglutamylation to the active metabolitesthan MTXand less liver and CNS toxicityproperties that may translate into better efficacy and or safetyIn addition to identifying LD AMT as a potential improvement on MTXgaining a mechanistic understanding of antifolate resistance in general has important clinical implications for treating inflammation with LD AMT or MTXby possibly identifying clinical biomarkers to predict optimal response or risk of toxicity in advance of initiating treatmentThis UFast Track proposal aims to advance LD AMT to the clinic by testing LD AMT for efficacy in a placebo controlled phasetrial and advancing a novel hypothesis driven mechanistic explanation for antifolate resistance PUBLIC HEALTH RELEVANCEPsoriasis is a chronic scaly and inflammatory skin disorder that affectsof the worldandapos s populationCurrent treatments often involve the use of methotrexateMTXwhich is not effective in many patients or causes side effectsor exceedingly expensive biologic therapies that can cost $to $per yearThis proposal aim to develop a drugLD aminopterin that is better than MTX and less expensive than biologicsAlsowe aim to carry out studies that we hope will tell us how drugs like MTX and LD aminopterin fail in patients