ELD607 Orai1 Antagonist Increases Bacterial Clearance from the Lung

摘要 医院获得性肺炎（HAP）是重症监护病房中最常见的死亡原因，也是美国第二常见的医院感染。铜绿假单胞菌、S.金黄色葡萄球菌（包括MRSA）和其他ESKAPE病原体是HAP的常见原因。包括MRSA在内的耐药性细菌的增加，使在这一患者群体中提供有效治疗的挑战进一步复杂化。迫切需要超越传统抗生素的新方法来改善HAP患者的预后。先天免疫蛋白短腭LUng和鼻上皮克隆1（SPLUNC 1）分泌到肺腔中，在那里它可以结合并调节离子通道。Orai 1是一种普遍表达的质膜Ca 2+通道，其激活是炎症发生所必需的。我们已经确定了SPLUNC 1的Orai 1抑制结构域，称为a6区域：SPLUNC 1和a6负调节Orai 1以调节Ca 2+信号传导并减少炎症。然而，SPLUNC 1和α 6肽都被嗜中性粒细胞弹性蛋白酶快速降解，限制了它们在减少肺炎中的Ca 2+信号传导和炎症的有效性，肺炎的特征是嗜中性粒细胞。Eldec Pharma开发了一种强大的新型肽模拟物ELD 607，它重建了SPLUNC 1/a6抑制Orai 1的能力，但对中性粒细胞弹性蛋白酶降解的抗性明显高于a6。在铜绿假单胞菌和沙门氏菌感染的小鼠肺炎模型中，金黄色葡萄球菌，单次吸入剂量的ELD 607使肺嗜中性粒细胞减少90%，使肺细菌感染减少3-5 log 10 CFU，减少败血症，并增加存活。这些明确的实验表明，在没有抗生素的情况下，通过ELD 607重新平衡肺部的炎症反应增强了肺部清除病原体的自然能力。预计这种能力将使同时施用的抗生素更有效，提供一种重要的新治疗策略，以帮助解决细菌耐药菌株的出现。ELD 607抑制Orai 1和增加细菌清除的能力代表了改善HAP结局的革命性方法。ELD 607在I期的稳健验证将使Eldec Pharma能够要求与FDA进行IND前会议，以便在II期进行IND使能研究，并随后过渡到临床开发。第一阶段目标1.确认ELD 607复制了SPLUNC 1/a6观察到的Orai 1向性。目标二。复制ELD 607清除其他ESKAPE病原体的能力。第2阶段目标3生产GLP级ELD 607，以支持下游开发活动。目标4。确定ELD 607在鼠模型中的最佳给药方案。目标5。验证HAP恒河猴模型中ELD 607给药方案。

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.