Selonsertib fails to reduce pulmonary vascular resistance, improve outcomes in PAH

In the phase 2 ARROW trial, selonsertib for 24 weeks failed to significantly reduce pulmonary vascular resistance or achieve clinical improvement in patients with pulmonary arterial hypertension.

“Selonsertib is a first-in-class small-molecule [apoptosis signal-regulating kinase 1] inhibitor that has been developed for the treatment of diseases with a high burden of oxidative stress, including PAH,” Stephan Rosenkranz, MD, interventional cardiologist at the Heart Center and the Cologne Cardiovascular Research Center and head of the Pulmonary Hypertension Center at the University of Cologne, Germany, and colleagues wrote in Lancet Respiratory Medicine. “The results from non-clinical pharmacology studies show that selonsertib is a potent and selective inhibitor of [apoptosis signal-regulating kinase 1] with the potential to ameliorate disease via multiple mechanism, including modulation of inflammation and oxidative stress and inhibitor of reversal of maladaptive remodeling processes.”

The randomized, double-blind, placebo-controlled, phase 2 ARROW trial included 151 patients at 46 centers. All were aged 18 to 75 years and had a diagnosis of idiopathic or hereditary PAH or PAH-associated with connective tissue disease, drugs or toxins, human immunodeficiency virus or repaired congenital heart defects. From December 2014 to November 2015, patients were stratified by PAH etiolgy and background therapy and underwent random assignment to selonsertib 2 mg (Gilead; n = 39), selonsertib 6 mg (n = 37), selonsertib 18 mg (n = 37) or placebo (n = 37) administered once daily via tablet.

The primary outcome was change in pulmonary vascular resistance from baseline to 24 weeks, as measured by right heart catheterization.

One hundred thirty-four patients completed the 24-week study. Mean baseline pulmonary vascular resistance was 772 dyns/cm⁵. All patients were on background PAH therapy, 60% had functional class II PAH and 40% had functional class III PAH.

Mean change in pulmonary vascular resistance was 6 dyns/cm⁵ in the placebo group, 35 dyns/cm⁵ in the selonsertib 2 mg group (P = .21), 28 dyns/cm⁵ in the selonsertib 6 mg group (P = .27) and –21 dyns/cm⁵ in the selonsertib 18 mg group (P = .6), according to the results.

Additionally, the researchers reported no improvement in secondary outcomes, including exercise capacity, symptom burden, NT-proBNP level or clinical worsening events.

Headache (15%), abnormal dreams (7%), nausea (6%) and diarrhea (6%) were the most frequent adverse events in the selonsertib group, and headache (16%), nausea (14%) and diarrhea (5%) were the most frequent events in the placebo group. Serious adverse events occurred in 20% of patients who received any dose of selonsertib compared with 19% of patients who received placebo.

“Despite compelling evidence for the relevance of [apoptosis signal-regulating kinase 1] in the pathobiology of PAH and a robust study design, the results of this phase 2 trial were neutral,” the researchers wrote. “Unfortunately, we are unable to explain the disconnect between preclinical data showing the efficacy of selonsertib in non-clinical models of PAH and the trial results reported herein.”