ExesaLibero Pharma — Department of Health and Human Services STTR Phase I: NIAMS

Description

We are working on a new approach to treating acute arthritis based on a common pathway in the cellular infiltrates that damage bones and jointsInflammatory arthritis disables thousands of people each yearIt occurs in children and adultsafter trauma and infections but most cases are idiopathicMillions of adults live with chronic RAwhich has similar featuresInflammatory arthritis often requires treatments with serious side effectsLater in arthritisbone erosion is a major problem that causes severe pain and debilitationThere is no small molecule drug available to specifically treat arthritic bone erosionWe show that osteoclast maturation is suppressed by blocking a calcium release activated calcium channelcalled OraiA Orai antagonistN methyldichloropropionanilineN MeDCPAsuppressed osteoclast maturation and strongly suppressed collageninduced arthritisCIAin miceeven after symptoms of arthritis were measureableWe propose that pharmacologically suppressing CRAC channels with N MeDCPA will prevent bone erosion due to arthritic stimuli without major adverse effectsWe hypothesize that Casignals mediated by Orai channels modulate final differentiation of osteoclastsand that related effects on T cells might reinforce bone and joint sparing in acute arthritisWe expect toxicity of N MeDCPA to be low when treatment is for several weeks in animals with mature immune systemsWe propose comprehensive pharmacokinetic and toxicokinetic testing in addition to mechanistic experiments with Casignalingimmunologyand bone biology expertisePhase IAIMDrug formulationroute of administration optimization and Orai specificityNMeDCPA is lipid solubleThis aim will define a suitable nanoparticleNPor liposome formulation of NMeDCPA for parenteral or oral administrationDrug blood levels versus ease convenience and effectiveness will be assessedPhase IAIMComplete the dose response studies of N MeDCPA using the CIA modelHaving demonstrated that N MeDCPA can prevent bone erosion and arrest inflammation in symptomatic micethe emphasis of this aim will be to define its effect against the standard CIA measuresarthritic indexbone erosionvolume byCT and inflammationswellingusing the optimized dosing regimenPhase IIAIMPharmacology and toxicology assessment of N MeDCPA under non GLP and GLP conditions in vitro and in vivoAn extensive suite of tests will be performed by a contract research organizationCROunder contract with ExesaLiberosee letter of support from CovancePhase IIAIMDetermine the therapeutic potential of N MeDCPACritical to demonstrating that NMeDCPA will improve the standard of care quality of lifeis confirmation of equal effectiveness in both sexes using SKG micedetermining its cellular specificitychecking for potential immunotoxicity of N MeDCPA in tests not covered by the CRO and exploring possible additive synergistic effects of N MeDCPA in combination with other current non biological treatmentse gmethotrexateWe will also study the in vitro effects on human cells to avoid the pitfall of rodent human physiological differencesPhase IIAIMAssess the specificity and mechanism of action of N MeDCPAWe will assess the action of the N MeDCPA on monocyte differentiation to osteoclastsand investigate the possible side effects on osteoblasts and its specificity for ion channelsThe development of N MeDCPA as a drug for treatment of bone erosion promises to prevent the lifechanging debilitation associated with RAeffectively with low toxicity We are developing a new approach to treat bone erosion and inflammation associated with arthritis based on inhibiting a signaling pathways activated via Orai calcium channels by a new drug that inhibits Orai activityThis is important because cells that destroy bone in arthritis require calcium via Orai for final differentiation that occurs at the site of bone and joint damageThe work will produce data useful in the treatment of acute arthritis and related conditions such as rheumatoid arthritis