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、使人衰弱的、致命的疾病，目前尚无治愈方法。PAH的特征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。血管损失减少了肺血管系统的总横截面积，导致肺血管阻力逐渐增加。最终，右心室的适应能力不堪重负，导致右心衰竭和死亡。虽然目前的PAH血管扩张剂治疗可改善运动能力并延迟至临床恶化的时间，但其并未显著延长生存期。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样本和临床前动物模型的翻译工作）表明，雷帕霉素（一种别构哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂）可以预防和逆转PAH。mTOR信号传导在PAH中被激活，抑制该途径是一种有前景的新型治疗方法。本研究的意义在于用nab-雷帕霉素特异性靶向疾病生物学的新的抗增殖方法解决衰弱性疾病（ABI-009，Aadi Biosciences Inc.，太平洋帕利塞德，CA），一种新的白蛋白结合的纳米颗粒形式的雷帕霉素。ABI-009在肿瘤异种移植模型中显示出优异的抗增殖活性，并在肺中具有高蓄积性。最近在实体瘤患者中进行的I期临床试验显示了临床活性、低毒性和有利的药代动力学特征的证据。 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名受试者已入组，包括两名在NIH临床中心。NIH临床中心PAH项目正在与MedStar华盛顿医院中心肺动脉高压诊所合作，积极筛选PAH患者入组。

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.