Alternative Pathway Inhibitors for Orphan Indication

用于孤儿适应症的替代途径抑制剂

基本信息

批准号：
8524040
负责人：
Rekha Bansal
金额：
$ 54.26万
依托单位：
NOVELMED THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8524040
关键词：
Affect Affinity Anemia Antibodies Autologous Binding Biological Assay Bioreactors Blood Blood Transfusion Brain Cell Culture Techniques Cell Line Cells Cessation of life Chinese Hamster Ovary Cell Chronic Clinical Data Clinical Paths Coagulation Process Complement Complement 3a Complement 3b Complement 5a Complement Activation Complement Inactivators Complement Membrane Attack Complex Conditioned Culture Media Cytolysis Deposition Development Disease Dose Drug Costs Drug Kinetics Ensure Erythrocytes Excision FDA approved Fatigue Future Health Hemolysis Host Defense Human In Vitro Infection Inflammatory Kidney Failure Knock-out Lactate Dehydrogenase Left Legal patent Letters Life Liver Liver Failure Measures Mediating Modeling Monoclonal Antibodies Organ failure Orphan Oryctolagus cuniculus Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase Platelet Activation Population Primates Production Properdin Rare Diseases Reference Standards Risk Role Running Safety Sampling Serum Staging Technology Testing Therapeutic Transfusion Variant base complement C5b cooking cytokine driving force drug candidate effective therapy flasks in vitro Assay in vivo inhibitor/antagonist novel novel therapeutics pre-clinical preclinical study prevent programs public health relevance rat Piga protein screening success

项目摘要

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.

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、肾和肝功能衰竭，如果不及时治疗，最终会导致死亡。 2007年，FDA批准了第一种补体抑制剂Eculizumab (Soliris(R))用于治疗PNH。 Eculizumab 与 C5 结合，防止 C5 裂解和 C5b-9（一种导致红细胞溶血的补体产物）的形成。这种机制可以防止血管内溶血（IVH），减少LDH释放，并减少患者输血的需要；然而，接受依库珠单抗治疗的患者仍然表现出贫血迹象，并且一半的接受治疗的患者继续依靠输血生存。最近的研究表明，接受依库珠单抗治疗的患者红细胞上 C3b 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，但由于持续且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，使病原体感染的风险进一步复杂化。针对旁路途径的上游抑制似乎对于预防患有 PNH 等溶血性疾病的患者的 IVH 和 EVH 至关重要。 NovelMed 开发了一种替代途径特异性抗备解素单克隆抗体 hNM9405。这种上游抑制剂可防止 EVH 的关键分子 C3b 和 IVH 的关键分子 C5b-9 的形成。此外，hNM9405 对替代途径具有选择性，使经典途径完全发挥作用。初步的体外、离体和体内研究表明，hNM9405 可防止 a) C3a、C3b、C5a、C5b 和 C5b-9 的形成，b) PNH 和兔子红细胞的裂解，以及 c) 细胞因子和 LDH 的产生。初步结果证明了其作为一种新型的、比目前现有的治疗方法 Eculizumab 更有益的 PNH 治疗方法的有效性。该提案将在 I 期阶段对 Eculizumab 与 hNM9405 进行比较。在第二阶段，我们将生产并表征适合临床前研究的材料。我们还将进行第二阶段的兔 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。