Severe Pulmonary Arterial Hypertension Treated with ABI-009, nab-Sirolimus, an mTOR Inhibitor

Purpose mTOR signaling is markedly upregulated in cells from patients with pulmonary arterial hypertension (PAH). Importantly, sirolimus at high dose both prevented and reversed smooth muscle cell proliferation in a rat model of PAH (Houssaini 2013). ABI-009, albumin-bound sirolimus nanoparticles, has improved pharmacokinetics and biodistribution compared to oral sirolimus and is a promising novel treatment approach in patients with severe PAH. Methods This ongoing phase 1 study investigates the safety and efficacy of ABI-009 given as a weekly IV infusion for 16 weeks at dose levels of 1, 2.5, 5, and 10 mg/m 2 . Patients with PAH and WHO functional class (FC) III symptoms despite treatment with ≥2 PAH-specific therapies are eligible for enrollment. Primary endpoints are dose-limiting toxicities (DLTs) and adverse events. Secondary endpoints are changes in WHO FC, 6-minute walk distance (6MWD), and hemodynamics from baseline. Exploratory endpoints include sirolimus trough levels and biomarkers. Up to 22 patients will be enrolled in the dose-finding portion, using a 3+3 design. Results Six patients have received ABI-009 and enrollment is ongoing. Four patients were treated at the original starting dose of 10 mg/m 2 : 1 without any DLT, 2 patients required dose reductions to 5 mg/m 2 due to a DLT (rash at week 5 and paresthesia at week 7, respectively), and 1 patient discontinued treatment at week 8 due to cellulitis. Due to the DLTs at 10 mg/m 2 , the next cohort of patients were enrolled at 1 mg/m 2 dose level. Thus far, 2 patients have completed 16 weeks of ABI-009 at 1 mg/m 2 without significant safety concerns. Descriptive functional measures and hemodynamics at baseline and end-of treatment (EOT) were available for 5 patients who completed the 16-week therapy. WHO FC decreased from III to II in 3/5 patients; 6MWD increased (median [range]) from baseline 318 [290 - 378] m to EOT 425 [299 - 490] m (3/5 pts increased by >130 m); PVR decreased 616 [443 - 1011] to 498 [351 - 664] dyn.sec/cm 5 (2/5 pts decreased by >30%); cardiac index increased 2.7 [1.8 -3.6] to 3.0 [2.6 - 3.8] L/min/m 2 (3/5 pts increased by >40%); NTproBNP decreased 1041 [179 -2485] to 492 [117 - 2510] pg/ml (3/5 pts decreased by >30%). Conclusion The safety and functional and hemodynamic outcomes in this preliminary analysis support the ongoing clinical investigation of ABI-009 in patients with severe PAH. NCT02587325