In patients with moderately symptomatic pulmonary arterial hypertension (PAH), treatment with the next-generation, orally available, nonprostanoid, selective, potent prostacyclin receptor agonist ralinepag reduced pulmonary vascular resistance (PVR) compared with placebo, according to study results published in the European Respiratory Journal.
Investigators conducted a multicenter, international, double-blind, placebo-controlled, randomized, phase 2 study (ClinicalTrials.gov Identifier: NCT02279160) to evaluate the efficacy, safety, and tolerability of immediate-release oral ralinepag vs placebo for the treatment of adults with symptomatic PAH. A total of 61 patients with PAH who were being treated with standard of care, including monotherapy or dual PAH-targeted background therapy, were randomly assigned in a 2:1 ratio to treatment with ralinepag (n=40) or placebo (n=21). The initial ralinepag dose was 10 µg twice daily. The dosage was then uptitrated as tolerated over 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 absolute change in PVR from baseline to week 22. Other study end points included percentage change in PVR from baseline, additional hemodynamic parameters, safety, tolerability, and 6-minute walk distance (6MWD).
Results showed that treatment with ralinepag significantly decreased PVR by 163.9 dyn.sec/cm5 in contrast with an increase of 0.7 dyn.sec/cm5 with placebo (P =.02), thus meeting the primary end point. When expressed as a percent change relative to placebo, a 29.8% reduction in PVR (least-squares mean) was reported compared with placebo (P =.03), including a 20.1% decrease from baseline in the ralinepag treatment group. The reductions in PVR in the ralinepag group were observed even though the patients had already received either monotherapy (35%) or dual combination PAH-specific background therapy (65%).
Other study findings included an increase in 6MWD from baseline of 36.2 meters with ralinepag compared with 29.4 meters with placebo, but this was not statistically significant (P =.90). Serious adverse events were reported in 10% of patients treated with ralinepag and 29% of patients who received placebo. Moreover, study discontinuations were reported in 13% of patients in the ralinepag treatment group vs 10% of patients in the placebo group.
A major study limitation was the small sample size, and several imbalances existed at baseline between the 2 groups. Furthermore, the patients in the placebo group reported a substantial increase in 6MWD — an occurrence that is both “unusual and unexplained.”
The investigators concluded that compared with placebo, ralinepag reduced PVR in individuals with PAH on monotherapy (41% of patients) or dual combination therapy (59% of patients) at the time of enrollment. Additional studies are warranted, including larger and more long-term clinical trials, to confirm these results.
Disclosure: This clinical trial was supported by Arena Pharmaceuticals, Inc. Please see the original reference for a full list of authors’ disclosures.
Torres F, Farber H, Ristic A, et al. Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a Phase 2 randomized, parallel group, placebo-controlled trial [published online August 7, 2019]. Eur Respir J. doi:10.1183/13993003.01030-2019