DEVELOPMENT AND TESTING OF SUBCUTANEOUS CSD PEPTIDE FORMULATIONS FOR CHRONIC KIDNEY DISEASE

项目摘要 据估计，全球慢性肾病（CKD）患病率超过10%，影响 全世界约有5亿人患有II型糖尿病，由于全球II型糖尿病流行， 预计将上升。CKD特异性治疗目前尚不存在。临床管理主要侧重于 使用肾素-血管紧张素系统（RAS）抑制剂控制血压，从而减轻CKD 进展，但它不是治愈性的。肾纤维化（KF）是CKD的病理标志，并且是CKD的主要促成因素。 进展为终末期肾病的因素。因此，开发一种靶向纤维化过程的疗法， 肾脏可以减缓或停止CKD的进展，降低伴随的费用和生活质量负担。 透析和移植。Lung Therapeutics的专利LTI-03是一种7聚体肽（FTTFTVT），来源于 20-CAV-1的mer caveolin-1支架结构域（CSD）（文献中称为CSP 7）。它会减弱 在皮肤、心脏和肺纤维化（PF）的多种体内临床前模型中建立的纤维化， 在体外减弱多种促纤维化信号通路。我们已经开发了LTI-03的吸入制剂 用于治疗特发性肺纤维化（IPF），并获得监管部门批准， 2020年人体安全试验Cav 1-/-小鼠表现出增加的细胞增殖和胶原蛋白合成，导致 心肌肥大和肺动脉高压;两者都通过内皮细胞特异性再灌注恢复正常。 Cav-1的表达。此外，Cav 1-/-小鼠表现出比WT更广泛的间质纤维化， 单侧输尿管梗阻（RUUO）。最近，CSD肽被发现在治疗糖尿病中有效。 在全身性高血压的血管紧张素模型中减少心脏和肾脏纤维化。肺治疗 获得专利的可溶性抗蛋白水解肽LTI-2355甚至比CSD更有效（数据 未出版）。此外，虽然FDA批准的（非治愈性）IPF药物Nepal和吡非尼酮 在UUO模型中有效降低KF，新治疗剂PRM-151在Alport中有效 CKD综合征（AS）模型和2019年IPF II期临床试验。基于这些发现，我们建议 开发用于皮下（SC）递送的LTI-2355的简单和延长释放形式， 稳定性和药代动力学数据。接下来，在获得稳定性和PK数据后，将对电极导线进行严格评估 在快速发作AS模型中识别最佳先导候选者。将在中度发作时评估最终电极导线 AS模型（对照和使用标准治疗进行评估）。在取得有效结果之前，一名主要候选人将 将提交II期研究以支持进一步的临床开发（PK/PD，毒理学特异性， SC制定、IND支持工作）。该建议迎合了团队的总体优势，包括 肽制剂，器官纤维化生化评估的专业知识，以及纤维化的动物模型 肾病最后，该项目具有产生治疗CKD的新疗法的强大潜力。

Project Summary The global prevalence of chronic kidney disease (CKD) is estimated to be greater than 10%, affecting approximately 500 million people around the world, and due to the global type II diabetes epidemic, incidence is expected to rise. CKD-specific treatments do not currently exist. Clinical management focuses primarily on controlling blood pressure using renin–angiotensin system (RAS) inhibitors, which results in attenuated CKD progression, but it is not curative. Kidney fibrosis (KF) is a pathological hallmark of CKD and a major contributing factor to progression to end-stage renal disease. Therefore, developing a therapy that targets fibrotic processes in the kidney may slow or halt CKD progression, reducing the cost and the quality of life burdens that accompany dialysis and transplantation. Lung Therapeutics’ patented LTI-03 is a 7-mer peptide (FTTFTVT) derived from the 20-mer caveolin-1 scaffolding domain (CSD) of CAV-1 (known as CSP7 in the literature). It attenuates established fibrosis in multiple in vivo pre-clinical models of dermal, cardiac and pulmonary fibrosis (PF) and attenuates multiple pro-fibrotic signaling pathways in vitro. We have developed an inhaled formulation of LTI-03 for the treatment of Idiopathic Pulmonary Fibrosis (IPF), and regulatory approval was received to start a first in human safety trial in 2020. Cav1-/- mice demonstrate increased cell proliferation and collagen synthesis, leading to myocardial hypertrophy and pulmonary hypertension; both are normalized by endothelial cell specific re- expression of Cav-1. Furthermore, Cav1-/- mice exhibited more extensive interstitial fibrosis than WTs following release of a unilateral ureteral obstruction (RUUO). Recently, CSD peptide was found to be efficacious in reducing both heart and kidney fibrosis in an angiotensin model of systemic hypertension. Lung Therapeutics’ patented, soluble and proteolysis resistant peptide, LTI-2355, was even more efficacious than CSD (data unpublished). Furthermore, while both of the FDA-approved (non-curative) IPF drugs Nintedanib and Pirfenidone were efficacious for reducing KF in the UUO model, a new therapeutic, PRM-151, was efficacious in the Alport Syndrome (AS) model of CKD and in a 2019 Ph2 clinical trial for IPF. Based on these findings, we propose to develop both a simple and extended release form of LTI-2355 for subcutaneous (SC) delivery and to generate stability and pharmacokinetic data. Next, after obtaining stability and PK data, leads will be rigorously evaluated in a rapid onset AS model to identify the best lead candidate. The final lead will be assessed in a moderate onset AS model (evaluated both against and with standard of care). Pending efficacious results, a lead candidate will be selected, and a Phase II will be filed to support further clinical development (PK/PD, toxicology specificity of SC formulation, IND-supporting work). This proposal caters to the aggregate strengths of the team including peptide formulation, expertise in the biochemical assessment of organ fibrosis, and animal models of fibrotic kidney disease. Finally, this project has strong potential to yield a novel therapy for the treatment of CKD.