Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a phase 2 randomised, parallel group, placebo-controlled trial

Abstract

PurposeThis phase 2 study was designed to assess the efficacy, safety and tolerability of immediate-release orally administered ralinepag, a selective, non-prostanoid prostacyclin receptor agonist with a 24-h terminal half-life, compared to placebo in adult patients with symptomatic pulmonary arterial hypertension (PAH).Methods61 PAH patients who were receiving standard care, including mono or dual PAH-targeted background therapy were randomised 2:1 to ralinepag (n=40) or placebo (n=21). The starting dose of ralinepag was 10 μg twice daily. Dosage was then up-titrated as tolerated over the course of the 9-week dose-titration period, to a maximum total daily dose of 600 μg (300 μg twice daily). The primary efficacy end-point was the absolute change in pulmonary vascular resistance (PVR) from baseline to week 22. Additional end-points included percentage change in PVR from baseline, other haemodynamic parameters, 6-min walk distance (6MWD) and safety and tolerability.ResultsRalinepag significantly decreased PVR by 163.9 dyn·s·cm−5 compared to an increase of 0.7 dyn·s·cm−5 with placebo (p=0.02); the least-squares mean change from baseline PVR was −29.8% compared with placebo (p=0.03). 6MWD increased from baseline by 36.2 m with ralinepag and 29.4 m with placebo (p=0.90). Serious adverse events occurred in 10% of ralinepag patients and 29% of placebo patients. Study discontinuations occurred in 13% of ralinepag patients and 10% of placebo patients.SummaryRalinepag reduced PVR compared with placebo in PAH patients on mono (41%) or dual combination (59%) background therapy.

Management of Pulmonary Arterial Hypertension

“…Ralinepag is another selective IP receptor agonist currently undergoing phase 3 clinical trials (https://clinicaltrials.gov/ ct2/show/NCT03626688). In the phase 2 clinical trial, ralinepag significantly reduced PVR in PAH patients on background PAH-specific therapies [73]. The extendedrelease formulation being tested in the ongoing phase 3 trial provides the advantage of once daily dosing.…”

Advances in the management of pulmonary arterial hypertension

“…sec/ cm 5 and an increase in 6MWD by 36.2 m in patients receiving ralinepag monotherapy or combination therapy compared with placebo. 62 Currently, ADVANCE CAPACITY, ADVANCE OUTCOMES, and ADVANCE ENDURANCE are three major phase 3 trials studying the safety, efficacy, clinical outcomes, and survival benefit of extended-release ralinepag in symptomatic PAH patients 63 (NCT03626688, NCT04084678).…”

Transcriptomic analysis of pulmonary artery smooth muscle cells identifies new potential therapeutic targets for idiopathic pulmonary arterial hypertension

“…In PASMCs, activation of GPCRs that couple to the G s protein enhances activity of AC to produce cAMP, which activates PKA and thereby can reduce contraction and proliferation (Iyinikkel & Murray, 2018). This is evident with the prostacyclin (IP) receptor, a GPCR for which several drugs have long been approved (Del Pozo, Hernandez Gonzalez, & Escribano-Subias, 2017) and are in clinical trial (Torres et al, 2019) for PAH treatment. A key goal of this study was to determine if we might identify previously unrecognized GPCRs in PASMCs that could be potentially new therapeutic targets for idiopathic pulmonary arterial hypertension (IPAH).…”