In patients with pulmonary arterial hypertension (PAH), selonsertib does not significantly reduce pulmonary vascular resistance or lead to clinical improvement, according to results of the phase 2 ARROW trial (ClinicalTrials.gov Identifier: NCT02234141) published in The Lancet Respiratory Medicine.
Despite the availability of targeted therapies for PAH, the morbidity and mortality remain high. Because oxidative stress and elevated apoptosis signal-regulating kinase 1 (ASK1) activity appear to play a prominent role for vascular remodeling in PAH, ASK1 inhibition with selonsertib was identified as a potential novel therapeutic strategy.
ARROW, a randomized, dose-ranging, double-blind, placebo controlled study, involved 46 centers in Canada, France, Germany, Italy, the Netherlands, Spain, the United Kingdom, and the United States. Researchers evaluated the efficacy, safety, and tolerability of various doses of selonsertib compared with placebo in adults with PAH who were receiving stable background therapy for PAH. Of 150 participants who received selonsertib or placebo, 134 (89%) completed 24 weeks of the randomly assigned treatment, 90 patients (60%) were in functional class II and 60 (40%) were in functional class III; mean baseline pulmonary vascular resistance was 772 dyn·s/cm⁵.
The researchers found that the change in pulmonary vascular resistance was 6.0 dyn·s/cm⁵ (n=31) for placebo, 35.0 dyn·s/cm⁵ (n=35; P =.21 vs placebo) for 2 mg selonsertib, –28.0 dyn·s/cm⁵ (n=34; P =.27 vs placebo) for 6 mg selonsertib, and –21.0 dyn·s/cm⁵ (n=36; P =.60 vs placebo) for 18 mg selonsertib. Treatment-emergent adverse events for patients treated with selonsertib were similar to those who received placebo.
The authors concluded, “Selonsertib once daily for 24 weeks did not lead to a significant reduction in pulmonary vascular resistance or to clinical improvement in patients with PAH, but appeared to be safe and well tolerated.” They added, “Although these data do not support the clinical use of selonsertib in PAH, further study of the potential of targeting the ASK1–p38 pathway in PAH is warranted.”
Disclosure: This research was supported by Gilead Sciences. Please see the original reference for a full list of disclosures.
Rosenkranz S, Feldman J, McLaughlin VV, et al; ARROW Study Group. Selonsertib in adults with pulmonary arterial hypertension (ARROW): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. Published online August 20, 2021. doi:10.1016/S2213-2600(21)00032-1