ELD607 Orai1 Antagonist Increases Bacterial Clearance from the Lung

摘要 医院获得性肺炎(HAP)是美国重症监护病房最常见的死亡原因，也是美国第二大最常见的医院感染。铜绿假单胞菌、金黄色葡萄球菌(包括耐甲氧西林金黄色葡萄球菌)和其他ESKAPE病原体是引起HAP的常见病原体。包括耐甲氧西林金黄色葡萄球菌在内的耐药细菌的增加，使在这一患者群体中提供有效治疗的挑战进一步复杂化。迫切需要传统抗生素以外的新方法来改善HAP患者的预后。先天性免疫蛋白短腭肺和鼻腔上皮克隆1(SPLunc1)分泌到肺腔内，在那里它可以结合和调节离子通道。ORAI1是一种普遍表达的质膜钙通道，其激活是炎症发生所必需的。我们已经确定了SPLUN1的S Orai1抑制域，即A6区：SPLunc1和A6负性调节Orai1，调节钙信号转导，减轻炎症。然而，SPLunc1和A6肽都被中性粒细胞弹性蛋白酶迅速降解，限制了它们在减少肺炎的钙信号和炎症方面的有效性，肺炎的特征是中性粒细胞减少。Eldec Pharma已经开发出一种名为ELD607的强健的新型模拟肽药物，它重组了SPLuc1/a6‘S抑制Orai1的能力，但对中性粒细胞弹性蛋白酶的降解的抵抗力明显强于a6。在铜绿假单胞菌和金黄色葡萄球菌感染的小鼠肺炎模型中，单次吸入ELD607可将肺中性粒细胞减少90%，将肺部细菌感染减少3-5log10 cfu，减少败血症，并提高存活率。这些决定性的实验表明，在没有抗生素的情况下，通过ELD607重新平衡肺部的炎症反应可以增强肺部清除病原体的自然能力。这一能力预计将使同时使用抗生素更加有效，提供一种重要的新治疗策略，以帮助解决抗生素耐药菌株的出现。ELD607抑制Orai1和增加细菌清除的能力代表了一种改善HAP结果的革命性方法。ELD607在第一阶段的强有力验证将使Eldec Pharma能够要求与FDA举行IND前会议，以便在第二阶段进行IND使能研究，并进行后续的临床开发过渡。阶段1目的1.确认ELD607复制了SPLunc1/a6观察到的Orai1嗜性。目的2.复制ELD607‘S清除其他ESKAPE病原体的能力。第二阶段的目标是第三阶段生产GLP级ELD607，以支持下游开发活动。目的4.在小鼠模型中确定ELD607的最佳给药方案。目的5.在HAP猕猴模型中验证ELD607给药方案的有效性。

Abstract Hospital acquired pneumonia (HAP) is most common cause of mortality in intensive care units and the 2nd most common nosocomial infection in the US. P. aeruginosa, S. aureus (including MRSA) and other ESKAPE pathogens are common causes of HAP. The rise in antibiotic-resistant bacteria, including MRSA, further complicates the challenges of delivering effective treatments in this patient population. New approaches beyond traditional antibiotics are urgently need to improve outcomes in HAP patients. The innate immune protein Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1) is secreted into the lung lumen, where it can bind to and regulate ion channels. Orai1 is a ubiquitously-expressed plasma membrane Ca2+ channel, whose activation is required for the onset of inflammation. We have identified SPLUNC1’s Orai1-inhibitory domain, termed the a6 region: SPLUNC1 and a6 negatively regulate Orai1 to moderate Ca2+ signaling and reduce inflammation. However, both SPLUNC1 and the a6 peptide are rapidly degraded by neutrophil elastase, limiting their effectiveness in reducing Ca2+ signaling and inflammation in pneumonia, which is characterized by neutrophilia. Eldec Pharma has developed a robust, novel peptidomimetic called ELD607, which reconstitutes SPLUNC1/a6’s ability to inhibit Orai1, yet is significantly more resistant to degradation by neutrophil elastase than a6. In murine pneumonia models with P. aeruginosa and S. aureus, a single, inhaled dose of ELD607 reduced lung neutrophilia by 90%, decreased lung bacterial infection by 3-5 log10 CFUs, reduced sepsis, and increased survival. These definitive experiments demonstrate that rebalancing the lung’s inflammatory response via ELD607 enhances the lungs’ natural ability to clear pathogens, in the absence of antibiotics. This capacity is predicted to make concurrently-administered antibiotics more effective, providing an important new therapeutic strategy to help address the emergence of antibiotic-resistant strains of bacteria. The ability of ELD607 to inhibit Orai1 and increase bacterial clearance represents a revolutionary approach to improving HAP outcomes. Robust validation of ELD607 in Phase I will enable Eldec Pharma to request a pre-IND meeting with the FDA, in order to perform IND-enabling studies in Phase II and to make the subsequent transition to clinical development. Phase 1 Aim 1. To confirm that ELD607 replicates the Orai1-tropism observed with SPLUNC1/a6. Aim 2. To replicate ELD607’s ability to clear other ESKAPE pathogens. Phase 2 Aim 3 To produce GLP grade ELD607 to support downstream development activities. Aim 4. To determine the optimal dosing regimen of ELD607 in a murine model. Aim 5. To validate the ELD607 dosing regimen in a Rhesus macaque model of HAP.