Alternative Pathway Inhibitors for Orphan Indication

描述（由申请人提供）：阵发性睡眠性血红蛋白尿症（PNH）是一种罕见疾病，其特征是严重贫血、肾和肝衰竭，如果不治疗，最终死亡。2007年，FDA批准了第一个补体抑制剂Eculizumab（Soliris（R））用于治疗PNH。依库珠单抗与C5结合并防止C5裂解和C5 b-9的形成，C5 b-9是一种负责红细胞溶血的补体产物。这种机制可以防止血管内溶血（IVH），减少LDH释放，并减少患者对输血的需求;然而，接受依库珠单抗治疗的患者仍然显示贫血症状，并且接受治疗的患者中有一半继续依赖输血生存。最近的研究表明，在依库珠单抗治疗的患者中，红细胞上的C3 b积累水平增加，导致一种突出的现象-血管外溶血（EVH）。尽管每位患者的药物治疗费用惊人，但由于持续和不受控制的血管外溶血，结果仅部分令人满意。此外，依库珠单抗抑制经典途径，进一步使致病性感染的风险复杂化。对旁路途径特异性的上游抑制似乎在预防患有溶血性疾病（如PNH）的患者中的IVH和EVH中是至关重要的。NovelMed已经开发了替代途径特异性抗备解素单克隆抗体hNM 9405。这种上游抑制剂阻止EVH的关键分子C3 b和IVH的关键分子C5 b-9的形成。此外，hNM 9405对旁路途径具有选择性，使经典途径完全发挥功能。初步的体外、离体和体内研究表明，hNM 9405可以防止a）C3 a、C3 B、C5 a、C5 B和C5 B-9的形成，B）PNH和兔红细胞的溶解，以及c）细胞因子和LDH的产生。初步结果证明了其作为PNH的新型和更有益的治疗方法的有效性，超过了目前现有的治疗方法Eculizumab。该提案将在I期部分中比较依库珠单抗与hNM 9405。在第二阶段，我们将生产和表征适用于临床前研究的材料。我们还将在II期开展家兔PK-PD研究。这些研究对于开发具有潜在更好益处的新疗法至关重要。

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.