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 先导药物 AT010，该药物正在优化和开发为囊性纤维化 (CF) 的每日吸入疗法。 CF 是一种致命的遗传性遗传性疾病，会破坏氯离子通道功能，导致患者肺部和其他器官积聚粘液。CF 患者的预期寿命为 37 年，需要对慢性合并症和症状进行强化治疗干预。至关重要的是，96% 的囊性纤维化患者尚无获批的疾病缓解治疗方法，导致临床需求未得到满足。 AT010 的初步结果已证明其在恢复人 CF 支气管上皮细胞氯离子通道方面的功效。此外，AT010 可以在局部根尖给药后通过 CF 粘液递送。 PDZ1-2 是 CF 中经过充分验证的治疗靶点，它影响 CF 氯化物通道在细胞膜上的运输和锚定及其激活。我们已经通过 AT010 观察到高水平的恢复，可以预测临床疗效。 PDZ1-2 在 CF 中新颖且独特的作用机制也表明它与其他 CF 药物具有有益的相加作用。我们建立了一支世界一流的 CF 和药物开发专家团队，我们的成果证明了成功实现该项目目标的技术能力和环境： 目标 1. 合成优化的临床先导 AT010 衍生肽库：旨在具有稳定性、有效性、低成本制造、简单预测 CMC、非免疫原性、生物利用度、粘液渗透性和目标特异性的 AT010 类似物 以足够数量和纯度合成以满足目标 2。目标 2. 在人类 CF 模型中测试候选化合物的稳定性和功效。目标 2.1：我们将测试文库在人 CF 上皮内衬液中的稳定性并对其进行百分比排序。只有当肽表现出低溶解度或半衰期<30分钟时，才会在进一步开发中被淘汰，因为这将导致不可接受的生物利用度。目标 2.2：我们将使用 CF 患者组织和样本以及金标准临床前模型来评估肽药物库的功效，这些模型为临床成功提供最佳预测能力：(1) 恢复人 delta-F508-CFTR 氯化物电流 >10%，(2) 恢复正常气道表面液体 (ASL) 高度，以及 (3) 通过 CF 粘液的扩散不受损害。这将为 CF 相关的体外稳定性和功效终点提供百分比排名的肽药物库，从而确定临床先导和备用肽药物，以进行毒性评估。里程碑 2：完成后，我们将召开预 IND 会议，以便先导药物快速进入 IND 研究和临床试验。专家团队、经过充分验证的靶标、专有新药类别 (AT010)、令人信服的初步数据和出色的环境相结合，确保商业化的成功。 Calista Therapeutics 已计划开展 IND 启用研究和临床试验，预计在授予后第 4 年完成 1 期和 2a 期试验，并在新药申请批准之前进行关键的 2b/3 期试验。