Development of an oxygen delivery biotherapeutic for the preservation of myocardial function during pediatric cardiopulmonary bypass

1.项目概要/摘要 Omniox正在开发一种独特的氧气输送蛋白OMX，作为保护心肌的治疗方法。 和外周器官功能，并显着降低新生儿心肺复苏后的发病率 在先天性心脏病（CHD）的外科手术矫正期间，在出生的约4万名儿童中， 每年约有10，000名冠心病患者需要紧急手术修复心脏缺陷1，2。高达60%的婴儿 接受CPB的患者将经历可能导致外周器官功能障碍的术后并发症， 长期神经功能缺损3 -15. 心肌和外周器官组织损伤的关键驱动因素是缺氧或缺氧3 -15。 然而，目前没有或有希望的治疗方法针对CPB手术期间的缺氧， 阻止或减轻其破坏性的下游影响。Omniox的主要治疗候选药物OMX， 以恢复缺氧组织中的生理氧气水平。因此，OMX有可能解决高 与新生儿CPB手术相关的保留心肌功能和改善发病率的需求未得到满足。 与我们的合作者，新生儿和儿科护理重症监护医生Fineman博士和马尔泰佩在 加州大学，旧金山弗朗西斯科（UCSF），我们已经证明，OMX减弱缺氧- 诱发羔羊心肌功能障碍。此外，我们的初步数据表明，OMX： 1)恢复生理氧水平，特别是在缺氧组织; 2)防止脑缺血后缺氧诱导的细胞死亡; 3)在多种物种中稳定、安全且耐受性良好; 4)不增加自由基的产生或减少一氧化氮。 本快速通道SBIR I/II期提案的目标是完成OMX作为一种 通过证明其在以下方面的治疗效用，治疗接受CPB的新生儿的新型生物制剂 氧合缺氧组织并保护心肌和外周器官功能。我们建议：（1） 证明OMX在完整新生儿CPB期间和之后保护心肌和外周器官功能 羔羊（I期），然后2）证明OMX在临床相关新生羔羊CHD模型中的功效 CPB（第二阶段）。这些数据将为新生儿和儿科临床试验的IND申请提供信息。 在接受CPB的新生儿和儿科患者中获得良好的安全性和有效性数据之前，Omniox计划 将OMX的使用扩展到缺氧驱动疾病病理学的其他儿科适应症，例如持续性 肺动脉高压16、17和出生窒息18 -22。 Omniox，Inc.©2016机密-不得分发

1. PROJECT SUMMARY/ABSTRACT Omniox is developing a unique oxygen delivery protein, OMX, as a treatment to preserve myocardial and peripheral organ function and significantly reduce morbidity after neonatal cardiopulmonary bypass (CPB) during surgical correction of congenital heart disease (CHD). Of the ~40,000 children born annually with CHD, ~10,000 require urgent surgery to repair heart defects1, 2. Up to 60% of infants who undergo CPB will experience post-operative complications that can result in peripheral organ dysfunction and long-term neurological deficits3-15. A critical driver of the myocardial and peripheral organ tissue damage is oxygen deprivation, or hypoxia3-15. However, there are no current or promising therapeutic approaches that target hypoxia during CPB surgery to stem or alleviate its damaging downstream effects. Omniox' lead therapeutic candidate, OMX, is designed to restore physiologic oxygen levels in hypoxic tissues. Thus, OMX has the potential to address a high unmet need of preserving myocardial function and improving morbidity associated with neonatal CPB surgery. Together with our collaborators, neonatal and pediatric care intensivists Drs. Fineman and Maltepe at the University of California, San Francisco (UCSF), we have demonstrated that OMX attenuates hypoxia- induced myocardial dysfunction in lambs. Furthermore, our preliminary data demonstrate that OMX: 1) restores physiologic oxygen levels specifically in oxygen-deprived tissues; 2) prevents hypoxia-induced cell death after brain ischemia; 3) is stable, safe, and well tolerated in multiple species; and 4) does not increase free radical production or scavenge nitric oxide. The objective of this Fast-Track SBIR Phase I/II proposal is to complete preclinical development of OMX as a novel biologic for the treatment of neonates undergoing CPB by demonstrating its therapeutic utility in oxygenating hypoxic tissue and preserving myocardial and peripheral organ function. We propose to 1) demonstrate OMX preserves myocardial and peripheral organ function during and after CPB in intact newborn lambs (Phase I), then 2) demonstrate OMX' efficacy in a clinically relevant neonatal lamb CHD model undergoing CPB (Phase II). These data will inform an IND application for a neonatal and pediatric clinical trial. Pending good safety and efficacy data in neonatal and pediatric patients undergoing CPB, Omniox plans to expand OMX use to other pediatric indications in which hypoxia drives disease pathology such as persistent pulmonary hypertension in neonates16, 17 and birth asphyxia18-22. Omniox, Inc. ©2016 Confidential – Not for Distribution