Proof of Principle Evaluation of IV Gallium Nitrate in Patients with CF

描述（由申请人提供）：一种新的抗感染方法是利用已经施加在体内入侵生物体上的应力。铁（Fe）代谢是感染细菌的一个关键弱点，因为生物体需要铁来生长。我们已经表明，使用金属镓（Ga）破坏细菌Fe代谢的策略有望成为抗菌方法。由于其与Fe的化学相似性，Ga可以在许多生物系统中取代Fe并抑制Fe依赖性过程。我们的数据表明，Ga杀死机会致病菌铜绿假单胞菌（包括抗生素耐药菌株），对生物膜有活性，并治疗3种不同的铜绿假单胞菌感染模型。Ga也被证明具有抗炎特性。这些数据、硝酸镓（商品名GaniteTM）被美国食品和药物管理局（FDA）批准用于静脉内（IV）给药的事实，以及开发中的新抗生素的缺乏，使Ga成为一种有希望的铜绿假单胞菌感染的新治疗剂。我们已经在患有囊性纤维化的慢性感染铜绿假单胞菌的患者中进行的初始Ib期研究中表明，IV Ga是安全的、耐受性良好的、具有良好的药代动力学特征，并且在开始IV Ga的5天输注后14天和28天与肺功能的临床上有意义的改善相关。在此，我们提出了一项概念验证的2期临床试验，以确认我们先前的疗效发现，并提供关于IV Ga在感染铜绿假单胞菌的CF受试者中的安全性和药代动力学的进一步数据。我们还提出了两个辅助项目，以进一步阐明这种新代理的作用机制。慢性铜绿假单胞菌气道感染是这些患者死亡的主要原因，并且存在很少的治疗。这种药物可以代表一种治疗这种感染的新方法，并对其他具有挑战性的感染产生影响。

DESCRIPTION (provided by applicant): A novel anti-infective approach is to exploit stresses already imposed on invading organisms in vivo. Iron (Fe) metabolism is a key vulnerability of infecting bacteria because organisms require Fe for growth. We have shown that a strategy that uses the metal gallium (Ga) to disrupt bacterial Fe, metabolism holds promise as an antimicrobial approach. Due to its chemical similarity to Fe, Ga can substitute for Fe in many biologic systems and inhibit Fe-dependent processes. Our data shows that Ga kills the opportunistic pathogen Pseudomonas aeruginosa (including antibiotic resistant strains), is active against biofilms, and treats 3 different models of P. aeruginosa infections. Ga has also been shown to have anti-inflammatory properties. These data, the fact that gallium nitrate (trade name, GaniteTM) is Food and Drug Administration (FDA) approved for intravenous (IV) administration, and the dearth of new antibiotics in development make Ga a promising new therapeutic for P. aeruginosa infections. We have shown in our initial phase 1b study in patients with cystic fibrosis chronically infected with P. aeruginosa that IV Ga is safe, well tolerated, ha a good pharmacokinetic profile and is associated with a clinically meaningful improvement in lung function 14 days and 28 days after the start of a 5 day infusion of IV Ga. Here we propose a proof of concept phase 2 clinical trial to confirm our prior findings of efficacy and provide further data regarding the safety and pharmacokinetics of IV Ga in CF subjects infected with P. aeruginosa. We also propose two ancillary projects to further delineate the mechanism of action of this new agent. Chronic P. aeruginosa airway infections are the major cause of death in these patients and few treatments exist. This drug could represent a novel approach to treating this infection and have implications for other challenging infections.