Preclinical and Clinical Evaluation of Humanized NM

DESCRIPTION provided by applicant NovelMed has developed an anti properdin antibody hNM for the treatment of intra and extravascular lysis in paroxysmal nocturnal hemoglobinuria PNH The selection of this antibody was based on positive results obtained from in vitro ex vivo in vivo and PK PD studies in rabbits and primates These strong positive results have provided a firm foundation for initiation of our Phase I clinical trial Our lead drug candidate is indicated for PNH an andquot orphan disease andquot and aims to fill an urgent need for this devastating condition With this application NovelMed is proposing to conduct Investigational New Drug IND enabling studies for its lead drug candidate In PNH red blood cells RBCs are attacked by the bodyandapos s own complement activation products causing significant cell lysis RBC lysis increases the levels of hemolglobin and lactate dehydrogenase LDH in the circulating blood Elevated levels of these compounds cause further damage to multiple organs ultimately risking total organ failure s of one or multiple organs The chronic nature of the disease necessitates a safe highly effective and low cost therapeutic which can prevent erythrocyte lysis in vivo NovelMedandapos s lead therapeutic hNM is a specific inhibitor of the alternative complement pathway This upstream inhibitor of the complement system prevents the formation of both C b a key molecule for extravascular hemolysis EVH and C b a key molecule for intravascular hemolysis IVH Moreover hNM selectively blocks the alternative pathway without compromising the full functionality of the classical pathway Full functionality of the classical pathway is required in order to maintain optimal immune host defense Preliminary in vitro ex vivo and in vivo studies have demonstrated that hNM prevents the formation of C a C b C a C b and C b prevents the lysis of erythrocytes from PNH and rabbit sera inhibits the production of LDH and displays long PK and AP inhibition in non human primates This proposal will evaluate efficacy of our lead drug candidate in human Phase I trial In planning for the development of the Phase clinical protocol NovelMed has engaged key leaders in the PNH field The Phase trial is being proposed in approximately healthy human subjects in an Open Label Single Ascending Dose SAD escalation study to evaluate the safety and pharmacokinetics of hNM These studies will form the basis of regulatory filings for the FDA The two specific aims of this proposal are a perform GLP safety studies in non human primates with single and repeat dose toxicological studies and b perform Phase I clinical safety studies in human healthy volunteers to evaluate the safety and pharmacokinetics of hNM as a therapeutic It is anticipated that successful completion of the Phase I study will lead to further trials with the eventual goal of registration FDA approval and launch of hNM as a new treatment for PNH via prevention of hemolysis in PNH patients without the chronic knockout of host defense PUBLIC HEALTH RELEVANCE The estimated prevalence of PNH is cases per million Patients diagnosed with PNH are given a dim prognosis which includes an approximate median survival of years from the time of their initial diagnosis Extravascular and intravascular hemolyses are two major contributing factors to the anemia seen in PNH patients which contributes to significant kidney damage and ultimately death This proposal is for the development of hNM a significantly improved therapeutic over currently approved Eculizumab to prevent excessive hemolysis in PNH patients The hNM blocks the alternative pathway arm of the complement pathway without blocking the classical pathway required for host defense and thereby is expected to be a much more powerful treatment Because PNH is an orphan disease clinical development timelines are shorter and FDA approval is expected to be faster as compared to other non orphan indications