Our lead drug candidate is being developed as a disease modifying, potent and efficacious treatment forparoxysmal nocturnal hemoglobinuria (PNH), an "orphan disease", and is anticipated to be far superior to thecurrent monotherapy Soliris (Eculizumab) treatment. Soliris blocks both the classical (CP) and the alternative(AP) pathways of complement, and is used in treatment of PNH, atypical uremic syndrome (aHUS),neuromyelitis optica (NMO), and myasthenia gravis (MG). The FDA approved Soliris in 2007 despite itspossessing two troubling properties: a) uncontrolled extravascular hemolysis (EVH) that causes incurableanemia and b) vulnerability to secondary infections due to blockade of the classical pathway (CP) which isrequired for host defense, despite vaccination against such ailments as meningitis. Because there is no othertreatment for PNH currently approved by the FDA, use of Soliris continues to increase yearly.Our clinical candidate is a selective inhibitor of the AP and does not block the CP. By mechanistically blockingthe upstream AP specifically, the two issues deficient during Soliris treatment can be addressed. Our leaddrug: a) blocks AP-mediated C3b formation and deposition on erythrocytes and therefore prevents EVH, andb) does not block the CP, which is required for host defense against pathogens and infection. Further to this,potential success of this drug in effectively treating PNH is supported by the following characteristics: a) highaffinity binding, b) high potency of AP inhibition, c) inhibition of AP-mediated lactate dehydrogenase (LDH)release, d) lack of CP inhibition, e) successful toxicology studies, and f) completion of a successful phase Iclinical. A streamlined cGMP manufacturing process has been established, and guarantees robust productionof the quality material for treatment. Given this unique mechanism of action, we believe that this drug willprovide benefits in diseases where specific blockade of proximal AP is required. Preliminary data from therecently completed phase I trial in 48 healthy volunteers suggests that the drug candidate completely blocksthe AP at 1mg/kg, and does not block the CP at any of the doses tested, confirming the beneficial therapeuticpotency of this monoclonal antibody. Furthermore, administration of the lead drug did not require loading dosesand was deemed safe in humans with no reported severe adverse events. This ensures that administration ofthis drug is patient friendly. Results from this phase I trial are supported by multiple in vitro and ex vivo studieson normal human serum and blood, and serum from naïve and Soliris treated PNH patients.This submission outlines a proposed phase II PNH clinical study to examine the effects and benefits ofNovelMed's lead drug in PNH naïve patients, compared to use as an add-on to Soliris treated PNH subjects.Dosing of our clinical candidate is proposed at a single dose of 10 mg/kg administered every 4 weeks for 3months in this pilot study in PNH patients. Plasma samples will be evaluated for pharmacokinetics, APinhibition, CP inhibition, presence of ADA, LDH release, hemoglobin levels, C3b cellular deposition, erythrocytelysis, PNH clone size, as well as other clinical markers of anemia. If successful, this AP-specific inhibitor willreplace Soliris as a far superior and potent therapy for the complications associated with PNH.
Public Health Relevance Statement: PROJECT NARRATIVE The estimated prevalence of PNH is 5-10 cases per million. Patients diagnosed with PNH are often given a dim prognosis, with an approximate median survival outlook of 15 years from the time of their initial diagnosis. Despite the availability of Soliris (Eculizumab) as treatment for PNH, extravascular hemolysis with lingering anemia is still persistent in PNH treated patients (~50%), leading to multiple RBC transfusions to offset the anemia. A new therapeutic option is critical to address these inadequacies, as treatment of PNH is currently an unmet need. Our drug candidate, NM5072, selectively inhibits the AP, without blocking the CP, and is therefore expected to function as a potent and efficacious treatment in modulating the mechanism of this hemolytic disorder. We expect to get a breakthrough designation for NM5072 given its properties, specific mechanism of action, and recent phase I trial results in healthy subjects. This proposal outlines a Phase II, open label, multi-dose trial in PNH patients. NM5072 treatment will be evaluated in PNH patients with and without treatment with Soliris, an intravenous C5 inhibitor that is currently approved as monotherapy for PNH. Patients for the study will include adult patients exhibiting blood transfusion dependent anemia and are actively prescribed Soliris as treatment. In addition to their regimented dose of Soliris, patients will be administered NM5072 once every month at a 10 mg/kg dose as an add-on. Upon treatment with NM5072, we expect the results to demonstrate: a) increased total hemoglobin (reduction in anemia), b) decreased free hemoglobin, c) decreased LDH levels, d) decreased number of red blood cell (packed RBCs) transfusions, e) decrease in reticulocyte count, f) decreased unconjugated bilirubin, g) decreased C3b deposition on RBCs, h) increase in PNH cells (PNH RBCs), i) AP inhibition with lack of CP inhibition and j) improvement in patient reported assessments on the FACIT Fatigue Scale.
Project Terms: Adult ; 21+ years old ; Adult Human ; adulthood ; Affect ; Anemia ; Animals ; inhibitor/antagonist ; inhibitor ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Bilirubin ; Bilirubin IX alpha ; Blood ; Blood Reticuloendothelial System ; Blood Transfusion ; Cell Death ; necrocytosis ; Cells ; Cell Body ; Clinical Markers ; Clinical Research ; Clinical Study ; Complement ; Complement Proteins ; Complement 3a ; C3 a ; C3a ; Complement C3a ; Complement 3b ; C3b ; Complement C3b ; Complement 5a ; C5 a ; C5a ; Complement C5a ; Recombinant C5a ; Complement Membrane Attack Complex ; C 5b-9 ; C5b-9 ; Complement Complex C5b-9 ; Cytolytic Terminal Complement Complex ; Membrane Attack Complex ; Terminal Complement Complex ; Alternative Complement Pathway ; Properdin Pathway ; Control Groups ; Diagnosis ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Erythrocytes ; Blood erythrocyte ; Erythrocytic ; Marrow erythrocyte ; Red Blood Cells ; Red Cell ; blood corpuscles ; Exhibits ; Fatigue ; Lack of Energy ; Female ; Cyclic GMP ; Guanosine Cyclic Monophosphate ; cGMP ; Half-Life ; Hemoglobin C ; Hemoglobin concentration result ; hemoglobin level ; Hemoglobin ; Hemolysis ; erythrolysis ; Human ; Modern Man ; In Vitro ; Infection ; Intravenous infusion procedures ; IV Infusion ; intravenous infusion ; Lactate Dehydrogenase ; EC 1.1.1.27 ; L-Lactate Dehydrogenase ; L-Lactic Acid Dehydrogenase ; NAD-Lactate Dehydrogenase ; lactic acid dehydrogenase ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Macaca mulatta ; M mulatta ; M. mulatta ; Rhesus Macaque ; Rhesus Monkey ; male ; Meningitis ; Monkeys ; Mutation ; Genetic Alteration ; Genetic Change ; Genetic defect ; genome mutation ; Myasthenia Gravis ; Neuromyelitis Optica ; Devic Disease ; Devic's Syndrome ; Nevada ; Patient Outcomes Assessments ; Patient Reported Measures ; Patient Reported Outcomes ; Patients ; Drug Kinetics ; Pharmacokinetics ; Pilot Projects ; pilot study ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Production ; Properdin ; Complement Factor P ; factor P ; Proteins ; Kidney Failure ; Kidney Insufficiency ; Renal Failure ; Renal Insufficiency ; Safety ; Syndrome ; Testing ; Time ; Tissues ; Body Tissues ; Toxicology ; Vaccination ; Measures ; Liver Failure ; Hepatic Failure ; Mediating ; Guidelines ; Secondary to ; Organ ; Blood specimen ; Blood Sample ; Vial device ; Vial ; Transfusion ; Clinical ; Phase ; Reticulocyte count ; Reticulocyte Number ; Ensure ; Serum ; Blood Serum ; Recovery ; Inflammation Mediators ; inflammatory mediator ; Phase II Clinical Trials ; Phase 2 Clinical Trials ; phase II protocol ; Therapeutic ; Contracting Opportunities ; Contracts ; Deposit ; Deposition ; cooking ; Rivers ; Intravenous ; Dependence ; human tissue ; secondary infection ; cell type ; Host Defense ; success ; Orphan Disease ; Rare Disorder ; orphan disorder ; Rare Diseases ; Reporting ; Modeling ; Sampling ; Property ; cross reactivity ; Adverse Experience ; Adverse event ; cell bank ; Molecular Interaction ; Binding ; Lysis ; Cytolysis ; preventing ; prevent ; Address ; Length ; Dose ; Affinity ; Data ; Serious Adverse Event ; Severe Adverse Event ; serious adverse experience ; serious adverse reaction ; Monitor ; Characteristics ; Process ; paroxysmal nocturnal hemoglobinuria ; Pathway interactions ; pathway ; open label ; open label study ; cost ; manufacturing process ; pathogen ; Prevalence ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; healthy volunteer ; trial comparing ; FDA approved ; cGMP production ; drug candidate ; phase 1 study ; Phase I Study ; phase 2 study ; phase II study ; phase III trial ; phase 3 trial ; phase II trial ; phase 2 trial ; phase I trial ; phase 1 trial ; treatment group ; clinical candidate ; in vivo evaluation ; in vivo testing ; overtreatment ; over-treatment ; Rhesus ; efficacious treatment ; efficacious therapy ; Prognosis ;
