The ARROW Study: A Phase 2, Prospective, Randomized, Double-Blind, Placebo-Controlled Study of Selonsertib in Subjects with Pulmonary Arterial Hypertension

Purpose: The ARROW study is a Phase 2 study designed to determine the efficacy, safety, and tolerability of the apoptosis signal regulating kinase 1 (ASK-1) inhibitor Selonsertib compared to placebo in subjects with pulmonary arterial hypertension (PAH). Methods: 150 PAH patients were randomized to placebo (n=37), 2 mg (n=39), 6 mg (n=37), or 18 mg (n=37) oral Selonsertib once daily. The primary efficacy endpoint was change in pulmonary vascular resistance (PVR) from baseline to Week 24. Secondary endpoints included 6-min-walking distance (6MWD), parameters of right ventricular (RV) function and NT-proBNP levels. Results: Of the 150 patients, 56% had idiopathic PAH, 15% had hereditary PAH, 60% and 40% were in functional class (FC) II or III respectively; 79% were female; all were on background PAH therapy (92% combination therapy); mean baseline 6MWD was 437 meters (SD 103.1) and mean baseline PVR was 772 dyn*sec/cm5 (SD 334). Overall 88% of subjects completed 24 weeks on study drug. The mean change in PVR was 6.0 (SE 28.0), 35 (35.4), -28 (30.2) and -21 (37.9) dyn*sec/cm5 for placebo, 2mg, 6mg and 18mg Selonsertib respectively (p=0.36). The mean placebo corrected change in 6MWD was 19.7 (SE 10.9), 18.5 (11.9) and -0.9 (11.8) meters for 2mg, 6mg and 18mg of Selonsertib respectively (p=0.083). There were no significant changes in FC, RV function or NT-proBNP levels between groups. Serious adverse events and death occurred in 19.5% and 5.3% of Selonsertib and 18.9% and 8.1% of placebo subjects, respectively. Conclusions: Selonsertib once daily for 24 weeks did not lead to a significant reduction in PVR in patients with PAH.