TREATMENT OF LUNG FIBROSIS : IND PHARMACOLOGY AND TOXICOLOGY

Activation of lung myofibroblastsLMFof different origins is responsible for the development of lung fibrosis in in IPF and remarkablyLMF clearance by apoptosis may prevent development of lung fibrosis and lung injuryand possibly allow recovery from reversal of lung fibrosisInhibiting or reversing myofibroblast activation and macrophage activationthe therapeutic cellular targetsmay be critical for the treatment of lung fibrosis in IPFBoth preventing progression of lung fibrosis and inflammationas well as possiblyregression of lung fibrosis despite continued lung injuryas we documented in our pre clinical studiesare considered important clinical targets for patients with IPFFinallyblocking the progression of lung fibrosis may decrease the demand for lung transplantsThe basis for our Research is the development of a novelhumanizedtherapeutic peptideWe created a library using analog synthesis to prevent potential pitfalls for human therapyWe have performed in a step wise manner assays to select the safest and most efficienthumanizedpeptideincluding apoptosis assays in activated primary human lung myofibroblastscell free caspaseactivation assayslung injury fibrogenesis modelpharmacokineticsbioassayCYPinhibition studiescardiotoxicity assaysand preliminary toxicology assaysWe have developed novel and highly effective anti fibrotic peptides in animal modelswith no evidences of immunogenicity in state of the art human CDT cell and Bcell assaysand with exceptional stability in human lung microsomal systems and human plasmaThe therapeutic peptide has excellent solubility in waterThese features should facilitate administration by subcutaneous injection once per weekLwith excellent bioavailability during preclinical PK studies judging by the steady state release in plasma of the peptide from the PEGkDa Peptideachieving therapeutic lung concentrationsXfibra will maintain the inhalation route as an alternative formulation for developmentThe proposed compound markedly inhibits the activation of human lung myofibroblast in culture and in vivo in miceThis compound was not toxic to mice in the preliminary toxicology studiesat least atfold the therapeutic doseWe found no evidence of liverlung or cardiac toxicity or inhibition of CYPisoenzymesThe Aims of this SBIR are to complete FDA mandatedIND enabling studiesThe available IPF medications are very expensiveand not highly effective in most patientsThe FDA agreed with Xfibra to proceed with IND enabling studies for XFBPre INDPROJECT NARRATIVE Idiopathic Pulmonary FibrosisIPFthrough inflammation and injury induces the development of scar tissue in the lungthis is called lung fibrosisThe personalmedical and financial burden of IPF is substantialand IPF is associated with a very poor prognosis and high mortalityAdditional knowledge gained by Xfibra with the proposed research may facilitate the development of a medication for the treatment of IPFgiven under the skin or by inhalation