Disease Modifying Treatment for Hemolytic Disorders

ABSTRACT Our lead drug candidate is being developed as a disease modifying, potent and efficacious treatment for paroxysmal nocturnal hemoglobinuria (PNH), an “orphan disease”, and is anticipated to be far superior to the current 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 its possessing two troubling properties: a) uncontrolled extravascular hemolysis (EVH) that causes incurable anemia and b) vulnerability to secondary infections due to blockade of the classical pathway (CP) which is required for host defense, despite vaccination against such ailments as meningitis. Because there is no other treatment 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 blocking the upstream AP specifically, the two issues deficient during Soliris treatment can be addressed. Our lead drug: a) blocks AP-mediated C3b formation and deposition on erythrocytes and therefore prevents EVH, and b) 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) high affinity 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 I clinical. A streamlined cGMP manufacturing process has been established, and guarantees robust production of the quality material for treatment. Given this unique mechanism of action, we believe that this drug will provide benefits in diseases where specific blockade of proximal AP is required. Preliminary data from the recently completed phase I trial in 48 healthy volunteers suggests that the drug candidate completely blocks the AP at 1mg/kg, and does not block the CP at any of the doses tested, confirming the beneficial therapeutic potency of this monoclonal antibody. Furthermore, administration of the lead drug did not require loading doses and was deemed safe in humans with no reported severe adverse events. This ensures that administration of this drug is patient friendly. Results from this phase I trial are supported by multiple in vitro and ex vivo studies on 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 of NovelMedandapos;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 3 months in this pilot study in PNH patients. Plasma samples will be evaluated for pharmacokinetics, AP inhibition, CP inhibition, presence of ADA, LDH release, hemoglobin levels, C3b cellular deposition, erythrocyte lysis, PNH clone size, as well as other clinical markers of anemia. If successful, this AP-specific inhibitor will replace Soliris as a far superior and potent therapy for the complications associated with PNH.PROJECT NARRATIVEThe 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.