Alternative Pathway Inhibitors for Orphan Indication

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DESCRIPTION (provided by applicant): Paroxysmal Nocturnal Hemoglobinuria (PNH) is an orphan disease characterized by severe anemia, kidney and liver failure, and ultimately death, if left untreated. In 2007, FDA approved the first complement inhibitor, Eculizumab (Soliris(R)), for the treatment of PNH. Eculizumab binds to C5 and prevents C5 cleavage and the formation of C5b-9, a complement product responsible for erythrocyte hemolysis. This mechanism prevents intravascular hemolysis (IVH), reduces LDH release, and reduces the need for transfusion in patients; however, patients treated with Eculizumab still show signs of anemia and half of those who are treated continue to rely on blood transfusions for survival. Recent studies have shown an increased level of C3b accumulation on erythrocytes in Eculizumab-treated patients, causing a prominent phenomenon - extravascular hemolysis (EVH). Despite the staggering cost of the drug treatment per patient, results are only partially satisfactory due to the continuous and uncontrolled extravascular hemolysis. In addition, Eculizumab inhibits the classical pathway further complicating the risk of pathogenic infections. Upstream inhibition specific to the alternative pathway appears to be critical in preventing both IVH and EVH in patients suffering from hemolytic diseases such as PNH. NovelMed has developed an alternative pathway specific anti-properdin monoclonal antibody hNM9405. This upstream-inhibitor prevents the formation of both C3b, a key molecule for EVH, and C5b-9, a key molecule for IVH. Furthermore, hNM9405 is selective to the alternative pathway, leaving the classical pathway fully functional. Preliminary in vitro, ex vivo, and in vivo studies have demonstrated that hNM9405 prevents the a) formation of C3a, C3b, C5a, C5b and C5b-9, b) lysis of erythrocytes from PNH and rabbits, and c) cytokine and LDH production. The preliminary results provide proof of validity for its development as a novel and more beneficial therapeutic for PNH over the currently existing treatment, Eculizumab. This proposal will compare Eculizumab with hNM9405 in the phase I segment. In phase II, we will produce and characterize the material suitable for the preclinical studies. We will also conduct Rabbit PK-PD studies in phase II. These studies are essential for the development of a new therapeutic with potentially better benefits.