A Phase 1 Clinical Trial of ABI-009, an mTOR Inhibitor, for Patients with Severe Pulmonary Arterial Hypertension (PAH)

mTOR 抑制剂 ABI-009 针对严重肺动脉高压 (PAH) 患者的 1 期临床试验

• 批准号: 10683664
• 负责人: Jason Matthew Elinoff
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683664
• 关键词: Address; Albumins; Animal Model; Area; Biological Sciences; Biology; Blood Vessels; Cells; Cessation of life; Clinic; Clinical; Correlative Study; Data; Data Set; Disease; Distal; Dose; Drug Kinetics; Enrollment; Evaluation; FDA approved; FRAP1 gene; Hospitals; Human; In Vitro; Institution; Intravenous; Lung; Maximum Tolerated Dose; Multicenter Studies; Natural History; Pathway interactions; Patients; Pharmacology Study; Phase; Phase I Clinical Trials; Publishing; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Research Personnel; Right ventricular structure; Safety; Sampling; Schedule; Signal Transduction; Sirolimus; Site; Smooth Muscle Myocytes; Solid Neoplasm; Study Subject; Time; Toxic effect; United States National Institutes of Health; University Hospitals; Vascular Endothelium; Vasodilator Agents; Washington; Work; World Health Organization; Xenograft Model; arm; clinical center; cohort; efficacy study; exercise capacity; improved; inhibitor; nanoparticle; novel; open label; patient screening; pre-clinical; prevent; programs; prospective; pulmonary arterial hypertension; right ventricular failure; safety study; tumor xenograft

Pulmonary arterial hypertension (PAH) is a rare, debilitating, and fatal disease for which there is currently no cure. PAH is characterized by vascular cell hyperproliferation leading to the progressive narrowing and even obliteration of the distal pulmonary arteries. Vessel loss reduces overall cross-sectional area of the pulmonary vasculature resulting in progressive increases in pulmonary vascular resistance. Eventually the ability of the right ventricle to adapt is overwhelmed leading to right heart failure and death. While current PAH vasodilator therapies improve exercise capacity and delay the time to clinical worsening, they do not significantly prolong survival. Importantly, none of the current FDA-approved therapies specifically target the underlying pulmonary vascular endothelial and smooth muscle cell hyperproliferation. Recent in vitro studies including translational work using human PAH samples and pre-clinical animal models suggest that rapamycin, an allosteric mammalian target of rapamycin (mTOR) inhibitor, can prevent and reverse PAH. mTOR signaling is activated in PAH and inhibiting this pathway is a promising novel treatment approach. The significance of this study lies in addressing a debilitating disease with a new anti-proliferative approach specifically targeting the disease biology with nab-Rapamycin (ABI-009, Aadi Biosciences Inc., Pacific Palisades, CA), a novel albumin-bound nanoparticle form of rapamycin. ABI-009 has shown excellent anti-proliferative activity in tumor xenograft models and high accumulation in the lung. A recent phase 1 clinical trial in patients with solid tumors showed evidence of clinical activity, low toxicity, and a favorable pharmacokinetic profile. This multi-center study includes the National Institute of Health (NIH) Clinical Center and six other institutions. In total, fifteen subjects have been enrolled including two at the NIH Clinical Center. In FY22, the NIH Clinical Center PAH Program was actively screening patients participating in our PAH Natural History Study as well as those referred by pulmonary hypertension clinics at MedStar Washington Hospital Center and Howard University Hospital. However, study enrollment at all sites was closed by the sponsor on January 27, 2022. Investigators plan to analyze and publish the results of the study once the final dataset has been completed.

肺动脉高压（PAH）是一种罕见，令人衰弱的致命疾病，目前尚无治愈方法。 PAH的特征是血管细胞的过度增殖，导致远端肺动脉的逐渐变窄甚至闭塞。血管损失减少了肺血管的总体横截面区域，导致肺血管耐药性逐渐增加。最终，右心室适应的能力被不堪重负，导致右心衰竭和死亡。虽然当前的PAH血管扩张剂可以提高运动能力并延迟临床恶化的时间，但它们并没有显着延长生存率。重要的是，当前的FDA批准疗法均未专门针对潜在的肺血管内皮和平滑肌细胞过度增殖。 最近的体外研究包括使用人类PAH样品和临床前动物模型的翻译工作，这表明雷帕霉素是雷帕霉素（MTOR）抑制剂的变构哺乳动物靶标，可以预防和逆转PAH。 MTOR信号在PAH中被激活，抑制此途径是一种有希望的新型治疗方法。这项研究的意义在于通过一种新的抗增殖方法来解决一种使人衰弱的疾病，该方法专门针对疾病生物学，用NAB-rapamycin（ABI-009，Aadi Biosciences Inc.，Pacific Palisades，CA），一种新型的白蛋白 - 蛋白 - 蛋白 - 蛋白 - 蛋白 - 蛋白 - 蛋白 - 蛋白 - 蛋白 - 蛋白质结合纳米菌的形式。 ABI-009在肿瘤异种移植模型中表现出极好的抗增殖活性，并且在肺中高积累。最近对实体瘤患者的1期临床试验显示出临床活性，低毒性和有利的药代动力学特征的证据。 这项多中心研究包括国家卫生研究院（NIH）临床中心和其他六个机构。总共有15名受试者在NIH临床中心招募了两个受试者。在22财年，NIH临床中心PAH计划正在积极筛查参加我们PAH自然史研究的患者，以及在华盛顿医院中心和霍华德大学医院的肺动脉高压诊所提到的患者。但是，赞助商于2022年1月27日关闭了所有站点的研究入学率。研究人员计划一旦完成最终数据集完成，研究人员计划分析和发布研究结果。