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

肺动脉高压(PAH)是一种罕见的、使人衰弱和致命的疾病，目前还没有治愈的方法。PAH的特点是血管细胞过度增殖，导致远端肺动脉进行性狭窄甚至闭塞。血管丢失会减少肺血管的总横截面积，导致肺血管阻力的进行性增加。最终，右心室的适应能力被压垮，导致右心衰竭和死亡。虽然目前的PAH血管扩张剂疗法提高了运动能力，延缓了临床恶化的时间，但它们并没有显著延长生存期。重要的是，目前FDA批准的治疗方法中没有一种特别针对潜在的肺血管内皮细胞和平滑肌细胞过度增殖。 最近的体外研究，包括使用人类PAH样本的翻译工作和临床前动物模型表明，雷帕霉素，一种变构的哺乳动物靶标雷帕霉素(MTOR)，可以预防和逆转PAH。MTOR信号通路在PAH中被激活，抑制这一通路是一种有前途的新的治疗方法。这项研究的意义在于用一种新的抗增殖方法来解决一种衰弱的疾病，这种方法专门针对疾病生物学与NaB-Rapamcin(ABI-009，Aadi Biosciences Inc.，Pacific Palisade，CA)，一种新的白蛋白结合的雷帕霉素纳米颗粒形式。ABI-009在肿瘤异种移植模型中表现出良好的抗增殖活性，并在肺内高度蓄积。最近在实体瘤患者中进行的一项1期临床试验显示，该药具有临床活性、低毒和良好的药代动力学特征。 这是一项多中心研究，包括美国国立卫生研究院(NIH)临床中心和其他五个机构。到目前为止，在所有六个研究中心，14名受试者已经登记，其中包括NIH临床中心的两名受试者。NIH临床中心PAH计划正在与MedStar华盛顿医院中心肺动脉高压诊所合作，积极筛查PAH患者。

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 is a multi-center study including the National Institute of Health (NIH) Clinical Center and five other institutions. To date, across all six study centers, 14 subjects have been enrolled, including two at the NIH Clinical Center. The NIH Clinical Center PAH Program is actively screening PAH patients for enrollment in collaboration with the MedStar Washington Hospital Center Pulmonary Hypertension Clinic.