AN ERYTHROPOIETIN-MIMETIC PEPTIDE (pHBSP) FOR TREATMENT OF TBI

说明(申请人提供)：促红细胞生成素(EPO)是目前正在研究的改善脑外伤预后的最有吸引力的药物之一。在实验模型中，EPO改善了脑外伤和许多其他中枢神经系统疾病的预后。EPO已被证明在损伤后早期给予具有神经保护作用，即使在损伤后的较晚时间给予也具有促进神经恢复的效果。神经保护机制可能是复杂的，涉及抗炎、抗凋亡和血管作用。EPO诱导的神经保护的时间窗至少在损伤后6小时。尽管在实验室观察到了这些积极的特征，但将促红细胞生成素转化为 创伤性脑损伤的临床环境，因为用于神经保护和促进神经恢复所需的EPO剂量对患者有不良影响。几乎所有危重患者、创伤患者和术后患者的EPO研究都表明，使用EPO会增加血栓形成的风险。然而，EPO的造血和组织保护作用是可以分离的。Araim制药公司已经开发出一种短的、合成的EPO模拟肽(焦谷氨酸螺旋B表面肽[pHBSP])，它保留了EPO的神经保护活性，但不保留导致EPO不良反应的造血活性。初步数据表明，在脑损伤模型中，pHBSP改善神经恢复的作用类似于促红细胞生成素。该项目的目标是完成必要的临床前工作，以便在授权期结束时将pHBSP从实验室转移到II期临床试验。阿拉姆制药公司(纽约州奥西宁)已经完成了第一阶段的人体安全性/毒性研究。完成脑外伤临床前工作的具体目标包括：1-确定pHBSP治疗脑损伤的最佳剂量水平、有效时间窗和最佳剂量方案，2-在一系列损伤严重程度中确认pHBSP最佳剂量方案的疗效，3-在第二个脑损伤模型中确认pHBSP最佳剂量方案的疗效，4-研究pHBSP最佳剂量方案对pHBSP最佳剂量方案的反应，5-提交IND申请进行II期临床试验。

DESCRIPTION (provided by applicant): Erythropoietin (EPO) is one of the most attractive agents currently being studied to improve outcome from TBI. In experimental models, EPO has improved outcome after TBI, and many other central nervous system disorders. EPO has been shown to have neuroprotective effects when given early post-injury, and to have effects that enhance neurological recovery even when given at later times after injury. The neuroprotective mechanisms are probably complex, involving anti-inflammatory, anti-apoptotic, and vascular actions. The time window for EPO-induced neuroprotection is at least 6 hr post-injury. Despite these positive features observed in the laboratory, it has been difficult to translate EPO into the clinical setting for TBI because the doses of EPO required for neuroprotection and enhancement of neurological recovery have adverse effects in patients. Almost all studies of EPO in critically ill, trauma, and post-operative patients have shown an increased risk of thrombosis with EPO administration. The hematopoietic and tissue protective effects of EPO, however, can be separated. Araim Pharmaceuticals has developed a short, synthetic EPO-mimetic peptide (pyroglutamate Helix B surface peptide [pHBSP]) that retains EPO's neuroprotective activities, but not the hematopoietic activities responsible for the adverse effect of EPO. Preliminary data demonstrates in a TBI model that pHBSP improves neurological recovery similar to EPO. The goal of this project is to perform the preclinical work necessary to move pHBSP from the laboratory to a phase II clinical trial by the end of the grant period. Araim Pharmaceuticals (Ossining, NY) has already completed phase I safety/toxicity studies in humans. The specific aims to accomplish the preclinical work in TBI include the following: 1-To determine the optimal dose level, effective time window, and optimal dose regimen for acute dosing of pHBSP for treatment of TBI, 2-To confirm efficacy of optimal dosing regimen of pHBSP in a spectrum of injury severities, 3-To confirm efficacy of optimal dosing regimen of pHBSP in a second TBI injury model, 4-To study gender and age differences in response to optimal dosing regimen of pHBSP, 5-To submit an IND application for phase II clinical trial.