Calcaftor, a CFTR stabilizer for Cystic Fibrosis treatment

描述(申请人提供)：Calista Treateutics公司发明了Calaftor，这是一种一流的多肽药物，可以治疗所有囊性纤维化(CF)患者。Calaftor在CF的黄金标准临床前模型中得到验证，该模型使用从CF移植患者采集的F508-CFTR肺组织。该模型的结果显示了25小时的作用持续时间，可以每天吸入一次雾化吸入剂量，其疗效可以预测临床效果。慢性萎缩性胃炎是一种常见的遗传性疾病，会导致肺部、消化道和其他组织产生粘液。慢性阻塞性肺疾病的预期寿命只有37.4岁，目前还没有批准的治疗方法来治疗大多数的慢性阻塞性肺疾病患者。Cf是尚未得到满足的主要医疗需求。Calaftor通过抑制CFTR运输蛋白CAL发挥作用，CAL促进上皮膜CFTR的丢失和溶酶体的过早消化。这项第一阶段的SBIR将对肺部滴注和静脉注射后Calaftor的安全性和药代动力学分布进行关键的概念验证研究，并准确地满足美国国立卫生研究院的任务，即确定“调节囊性纤维化中运输缺陷的治疗方法，稳定突变的CFTR，并增强其靶向性和细胞膜的整合”。世界一流的CF和药物开发专家与卓越的环境相结合，确保了项目目标的成功实施。目的1.生物分析方法的发展。可交付使用的1.LC-MS方法，可在体液和组织中检测到低于10 ng/ml的Calcator。里程碑1.决定继续进行目标2毒性和PK研究。目的2：探讨钙化石膏的毒理作用和PK。目的2.1：单次递增剂量的PK及IT和静脉注射钙剂的毒性。可交付成果2.1：确定IT和静脉给药中的MTD、半衰期和PK参数，以实现10μM剂量和目标器官浓度。识别PK数据和PK建模，以告知目标2.2重复给药方案和数量。里程碑2.1：决定继续重复剂量研究。目的2.2：IT炉具5天重复给药毒性研究。交付项2.2：确定5天IT剂量的未观察到的不良反应水平。里程碑2.2：决定继续进行IND促进研究。目的2.3：Calcaltor的10天比较PK研究：IT灌输。交付品2.3：它的PK分布达到并维持有效的肺、全身和CF靶器官Cssmax，无毒性。它的剂量对剂量的重复性、累积性和对每日重复剂量的PK数据进行建模。里程碑2.2：来自每日给药的10天重复剂量研究的NOAEL和MTD。决定要求与FDA召开IND前会议，并继续进行全面的IND研究，以实现临床测试。该项目将为剂量形式、毒理学、分析方法和药代动力学提供关键的临床前支持，以告知、支持和证明当前先导化合物在临床前的进展，以支持在CF中进行IND使能研究。我们的发展计划描述了在第一阶段SBIR之后5年获得NDA批准。

DESCRIPTION (provided by applicant): Calista Therapeutics has invented Calcaftor, a first-in-class peptide drug that can treat all Cystic Fibrosis (CF) patients. Calcaftor is validated in the gold standard pre-clinical model of CF using F508 -CFTR lung tissue harvested from CF transplant patients. Results from this model demonstrated a >25 hour duration of action that enables once daily inhaled nebulizer dosing and an efficacy that is predictive of clinical effect. CF is a common inherited disease that causes thick mucus in the lungs, digestive tract and other tissues. CF life expectancy is just 37.4 years and currently there is no approved treatment for the majority of CF patients. CF is a major unmet medical need. Calcaftor acts by inhibiting a CFTR trafficking protein CAL that promotes loss of CFTR from the epithelial membrane and premature lysosomal digestion. This Phase I SBIR will undertake critical proof of concept studies into the safety and pharmacokinetic distribution of Calcaftor following pulmonary instillation and intravenous injection and precisely addresses the NIH mission to identify "therapeutic approaches to modulating the transport defect in cystic fibrosis and to stabilize mutant CFTR and enhance its targeting and integration into the cell membrane". World-class experts in CF and drug development combined with an outstanding environment ensure successful execution of project aims. Aim 1. Bioanalytical Method Development. Deliverable 1. LC-MS method allowing Calcaftor detection to 10ng/ml or below in body fluids and tissues. Milestone 1. Decision to proceed to Aim 2 toxicity and PK studies. Aim 2: Exploratory Toxicology and PK of Calcaftor in rats. Aim 2.1: Single ascending dose PK and toxicity of IT and IV Calcaftor. Deliverable 2.1: Determine MTD, half-life and PK parameters in IT and IV dosing that enable 10μM dosing and target organ concentration. Identification of PK data and PK modeling that informs Aim 2.2 repeat dosing regimen and amount. Milestone 2.1: Decision to proceed to repeat dose studies. Aim 2.2: 5-Day Repeated Dose Toxicity Study of IT Calcaftor. Deliverable 2.2: Determination of no observed adverse effect level of 5 day IT dosing. Milestone 2.2: Decision to proceed to IND enabling studies. Aim 2.3: Comparative 10-day PK studies of Calcaftor: IT instillation. Deliverable 2.3: IT PK profile reaching and sustaining effective lung, systemic and CF target organ Cssmax, without toxicity. IT dose-to-dose reproducibility, accumulation, and modeling PK data from daily repeat dosing. Milestone 2.2: NOAEL and MTD from 10-day repeat dosage study with daily dosing. Decision to solicit a Pre-IND meeting with FDA and proceed with full IND studies to enable clinical testing. This project will provide critica pre-clinical enablement of the dose form, toxicology, analytical methods, and pharmacokinetics to inform, enable, and justify the preclinical progression of the current lead compound to IND-enabling studies in CF. Our development plan delineates NDA approval 5 years after this Phase I SBIR.