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. Loss of pulmonary arterioles 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. The protocol for this study was approved by the NIH Intramural National Heart Lung and Blood Institutional Review Board (now called General Medicine I IRB Panel) in May 2018. The Cooperative Research and Development Agreement (CRADA) with Aadi Biosciences Inc. was finalized in August 2018. Subject recruitment for the study at the NIH Clinical Center began following the site initiation at the end of September 2018. To date, across all six study centers, 11 subjects have been enrolled. One subject was enrolled and completed the study 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. The following abstracts were presented in 2018 and 2019: Simon MA, Gomberg-Maitland M, Oudiz R, Machado R, Rischard F, Elinoff JM, Grigorian B, Schmid AN, Hou S, Desai N, and Gladwin MT. Patients with Severe Pulmonary Arterial Hypertension Treated with ABI-009, nab-Sirolimus, an mTOR Inhibitor: Interim Results from a Phase 1 Clinical Trial. ACC.19 68th Annual Scientific Session of the American College of Cardiology Simon MA, Gomberg-Maitland M, Oudiz R, Machado R, Rischard F, Elinoff JM, Grigorian B, Schmid AN, Hou S, Desai N, and Gladwin MT. Severe Pulmonary Arterial Hypertension Treated with ABI-009, nab-Sirolimus, an mTOR Inhibitor. International Society of Heart and Lung Transplantation 2019 Annual Meeting and Scientific Sessions Simon MA, Gomberg-Maitland M, Oudiz R, Machado R, Rischard F, Elinoff JM, Grigorian B, Schmid AN, Hou S, Desai N, and Gladwin MT. ABI-009, nab-Sirolimus, an mTOR Inhibitor with High Lung Accumulation in Preclinical Models: Initial Results from an Ongoing Phase I/II Safety and Preliminary Efficacy Study in Severe PAH. American Thoracic Society 2019 International Conference
