Therapeutic correction of deltaF508-CFTR cystic fibrosis by a novel PDZ12 drug.

通过新型 PDZ12 药物治疗 deltaF508-CFTR 囊性纤维化。

• 批准号: 8592140
• 负责人: Andrew Peter Mallon
• 金额: $ 22.5万
• 依托单位: CALISTA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592140
• 关键词: Apical; Award; Back; Binding; Biological Availability; Breathing; Capital; Cell membrane; Cells; Cessation of life; Chloride Channels; Chloride Ion; Chlorides; Chronic; Clinical; Clinical Research; Clinical Trials; Comorbidity; Competence; Custom; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Development; Diffuse; Diffusion; Disease; Dose; Ensure; Environment; Epithelial; Epithelial Cells; Epithelium; Exhibits; Foundations; Funding; Future; Gold; Grant; Half-Life; Height; Hereditary Disease; Human; In Vitro; Inherited; Investigation; Investments; Ion Channel; Lead; Libraries; Life Expectancy; Liquid substance; Lung; Marketing; Membrane; Modeling; Modification; Mucous body substance; Mutation; Organ; Patients; Penetration; Peptide Library; Peptides; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Powder dose form; Pre-Clinical Model; Property; Proteins; Research; Research Project Grants; Respiratory physiology; Safety; Scaffolding Protein; Series; Site; Small Business Innovation Research Grant; Sodium Chloride; Solubility; Solutions; Specificity; Structure of parenchyma of lung; Surface; Symptoms; Technology; Testing; Therapeutic; Therapeutic Intervention; Thick; TimeLine; Tissue Sample; Toxic effect; Toxicity Tests; Treatment Protocols; Triage; Validation; Water; Work; airway surface liquid; analog; apical membrane; base; bronchial epithelium; caucasian American; clinical efficacy; clinically significant; commercialization; comparative; cost; cystic fibrosis patients; design; drug candidate; drug development; efficacy testing; experience; follow-up; functional improvement; innovation; meetings; novel; preclinical study; prevent; public health relevance; research study; restoration; risk mitigation; sodium-hydrogen exchanger regulatory factor; stability testing; success; therapeutic target; trafficking

DESCRIPTION (provided by applicant): Calista Therapeutics has discovered a first-in-class, proprietary PDZ1-2 lead drug, AT010, that is being optimized and developed as an inhaled daily therapy for cystic fibrosis (CF). CF is a deadly inherited genetic disorder that disrupts chloride channel function, resulting in the buildup of sticky mucus in patient's lungs and other organs.CF patients have a life expectancy of 37 years and need intensive therapeutic interventions for chronic co-morbidities and symptoms. Critically, there are no approved disease-modifying treatments for 96% of CF patients, resulting in a very high unmet clinical need. Preliminary AT010 results already show proof of efficacy in the restoration of the chloride channel in human CF bronchial epithelium. In addition, AT010 can be delivered through CF mucus following topical apical dosing. PDZ1-2 is a well-validated therapeutic target in CF that influences both the CF chloride channels trafficking and anchoring at the cell membrane, and its activation. The high level of restoration we have already observed with AT010 is established to be predictive of clinical efficacy. The novel and distinct PDZ1-2 mechanism of action in CF also suggests it will have a beneficial additive effect with other CF drugs. We have built a world-class team of CF and drug development experts and our results demonstrate technical competence and the environment to successfully achieve the project's aims: Aim 1. Synthesis of an optimized clinical lead AT010-derived peptide library: AT010 analogs designed to have stability, efficacy, low cost of manufacture, simple predicted CMC, non-immunogenicity, bioavailability, mucus penetration and target specificity will be synthesized in sufficient quantity and purity for Aim 2. Aim 2. Stability and efficacy testing of candidate compounds in human CF models. Aim 2.1: We will test and percentage rank the library for stability in human CF epithelial lining fluid. Peptides wil be eliminated from further development only if they show low solubility or a half-life <30 minutes because this will lead to unacceptable bioavailability. Aim 2.2: We will assess efficacy of the peptide drug library using CF patient tissues and samples and gold standard pre-clinical models that provide the best predictive power for clinical success: (1) Restoration of human delta-F508-CFTR chloride current >10%, (2) Restoration of normal airway surface liquid (ASL) height and (3) Unimpaired diffusion through CF mucus. This will provide a percentage ranked peptide drug library for CF-relevant in vitro stability and efficacy endpoints that will identify clinical lead nd back-up peptide drugs ready for toxicity assessments. Milestone 2: Upon completion we will solicit a Pre-IND meeting to allow rapid lead drug progression to IND studies and clinical trials. An expert team, substantially validated target, proprietary novel drug class (AT010), compelling preliminary data and an outstanding environment combine to ensure successful commercialization. Calista therapeutics has planned IND enabling studies and clinical trials that project completion of Phase1 and 2a trials in Year 4 post-grant award with a pivotal Phase 2b/3 trial prior to New Drug Application for approval.

描述（由申请人提供）：Calista Therapeutics发现了一种一流的专有PDZ1-2铅药AT010，该药物正在优化和开发为囊性纤维化（CF）的吸入每日治疗。 CF是一种致命遗传的遗传疾病，可破坏氯化物通道功能，导致患者肺部和其他器官的粘性粘液堆积。CF患者的预期寿命为37年，需要进行密集的治疗干预措施来慢性综合性和症状。至关重要的是，96％的CF患者没有经过认可的疾病改良治疗，导致临床需求很高。初步AT010结果已经显示出在人CF支气管上皮的氯化物通道恢复中的功效证明。此外，局部顶端给药后可以通过CF粘液传递AT010。 PDZ1-2是CF中有验证的治疗靶标，它两者都影响 CF氯化物在细胞膜及其激活上运输和锚定。我们已经在AT010上观察到的高恢复水平是可以预测临床功效的。 CF中新型且独特的PDZ1-2作用机理还表明，它将与其他CF药物具有有益的添加剂作用。我们已经建立了一个由CF和药物开发专家组成的世界一流团队，我们的结果证明了技术能力和成功实现该项目目标的环境：AIM 1。综合优化的临床铅AT010衍生的肽库：AT010类似物：稳定性，功效，低成本，简单预测的CMC，非免疫原性，生物利用度，粘液渗透率和目标特异性将以足够数量和纯度合成，以实现AIM 2。AIM 2。稳定性和在人类CF模型中的稳定性和效率测试。 AIM 2.1：我们将测试和百分比对库的稳定性排名为人类CF上皮衬里流体的稳定性。只有在溶解度较低或半衰期<30分钟的半衰期时，才能从进一步的开发中消除肽，因为这将导致不可接受的生物利用度。 AIM 2.2：我们将使用CF患者组织和样品以及黄金标准前临床模型评估肽药物库的功效，从而为临床成功提供最佳的预测能力：（1）恢复人Delta-F508-CFTR氯化物> 10 ％，（2）恢复正常气道表面液体（ASL）高度和（3）通过CF粘液的未损坏扩散。这将为CF相关的体外稳定性和功效终点提供一个排名的肽库百分比，这些肽将确定临床铅ND备用替代肽药物，准备进行毒性评估。里程碑2：完成后，我们将征求预先开会的会议，以允许快速铅药物进展为IND研究和临床试验。一个专业的团队，具有实质性验证的目标，专有的新型药物类（AT010），引人注目的初步数据和出色的环境结合在一起，以确保成功的商业化。 Calista Therapeutics已计划在第4年授予后奖励中的第1阶段和2A试验的研究和临床试验中，并在新药申请批准之前，在第4年的授予后奖励中进行了2B期试验。