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

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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.