Calcaftor, a CFTR stabilizer for Cystic Fibrosis treatment

Calcaftor，一种用于囊性纤维化治疗的 CFTR 稳定剂

• 批准号: 8648258
• 负责人: Ronald Wolff
• 金额: $ 22.46万
• 依托单位: CALISTA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648258
• 关键词: Address; Adverse effects; Affect; Age; Autopsy; Body Fluids; Breathing; Cell membrane; Cells; Cessation of life; Chloride Ion; Chlorides; Clinical; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Detection; Development Plans; Digestion; Disease; Distress; Dose; Dose-Limiting; Drug Exposure; Drug Formulations; Drug Kinetics; Ensure; Environment; Epithelial; Epithelial Cells; Future; Gastrointestinal tract structure; Gold; Half-Life; Health; Hereditary Disease; Histology; Hour; Inherited; Intestines; Intravenous; Ion Channel; Lead; Life Expectancy; Ligands; Liver; Lung; Maximum Tolerated Dose; Medical; Membrane; Methods; Mission; Modeling; Mucous body substance; Mutation; Nebulizer; No-Observed-Adverse-Effect Level; Organ; PDZ protein; Pancreas; Patients; Peptides; Pharmaceutical Preparations; Phase; Plasma; Pre-Clinical Model; Rattus; Regimen; Reproducibility; Research; Safety; Sampling; Small Business Innovation Research Grant; Solutions; Structure of parenchyma of lung; Testing; Therapeutic; Thick; Time; Tissue Harvesting; Tissues; Toxic effect; Toxicology; Transplant Recipients; United States National Institutes of Health; Validation; analytical method; clinical effect; comparative; cystic fibrosis patients; design; dosage; drug development; intravenous injection; meetings; method development; mortality; mutant; novel; pharmacokinetic characteristic; pharmacokinetic model; pre-clinical; premature; prevent; protein transport; public health relevance; research clinical testing; respiratory

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.

描述（申请人提供）：Calista Therapeutics 发明了 Calcaftor，这是一种一流的肽药物，可以治疗所有囊性纤维化 (CF) 患者。 Calcaftor 使用从 CF 移植患者身上采集的 F508 -CFTR 肺组织在 CF 黄金标准临床前模型中进行了验证。该模型的结果表明，作用持续时间大于 25 小时，可实现每日一次吸入雾化器给药，且功效可预测临床效果。 CF是一种常见的遗传性疾病，会导致肺部、消化道和其他组织出现粘稠粘液。 CF 的预期寿命仅为 37.4 年，目前大多数 CF 患者尚无批准的治疗方法。 CF 是一个重大的未满足的医疗需求。 Calcaftor 通过抑制 CFTR 运输蛋白 CAL 发挥作用，CAL 会促进上皮膜上 CFTR 的丢失和过早的溶酶体消化。该 I 期 SBIR 将对 Calcaftor 肺滴注和静脉注射后的安全性和药代动力学分布进行关键的概念验证研究，并精确解决 NIH 的使命，即确定“调节囊性纤维化转运缺陷和稳定突变 CFTR 并增强其靶向和整合到细胞膜中的治疗方法”。世界一流的 CF 和药物开发专家与卓越的环境相结合，确保项目目标的成功执行。目标 1. 生物分析方法开发。可交付成果 1. LC-MS 方法允许在体液和组织中检测到 10ng/ml 或更低的 Calcaftor。里程碑 1. 决定继续进行 Aim 2 毒性和 PK 研究。目标 2：探索 Calcaftor 在大鼠体内的毒理学和 PK。目标 2.1：IT 和 IV Calcaftor 的单次递增剂量 PK 和毒性。可交付成果 2.1：确定 IT 和 IV 给药中的 MTD、半衰期和 PK 参数，以实现 10μM 给药和靶器官浓度。确定 PK 数据和 PK 模型，为 Aim 2.2 重复给药方案和剂量提供信息。里程碑 2.1：决定继续进行重复剂量研究。目标 2.2：IT Calcaftor 的 5 天重复剂量毒性研究。可交付成果 2.2：确定 5 天 IT 给药未观察到不良反应的水平。里程碑 2.2：决定进行 IND 授权研究。目标 2.3：Calcaftor 的 10 天 PK 比较研究：IT 滴注。可交付成果 2.3：IT PK 曲线达到并维持有效的肺、全身和 CF 靶器官 Cssmax，且无毒性。 IT 剂量间的重现性、累积和每日重复给药的 PK 数据建模。里程碑 2.2：每日给药的 10 天重复剂量研究中的 NOAEL 和 MTD。决定与 FDA 召开 IND 前会议并进行全面的 IND 研究以进行临床测试。该项目将为剂型、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 CF 中的 IND 支持研究的临床前进展。我们的开发计划描绘了第一阶段 SBIR 后 5 年后 NDA 的批准。