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Safety and pharmacokinetics of ralinepag (APD811) in healthy adult subjects

Ioana Preston


John Adams

Stewart Turner

Ronald Christopher

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Conference: 2017 PH Professional Network Symposium

Release Date: 10.06.2017

Presentation Type: Abstracts

File Download: 2017 PHPN Abstract 1041

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Abstract presented at the 2017 PH Professional Network Symposium held in Bethesda, MD on October 5-7, 2017

Purpose

To study the safety, tolerability, and pharmacokinetics (PK) of ralinepag in two Phase 1 placebo-controlled clinical studies. 

Background

Ralinepag is a novel, next-generation, oral, selective, and potent prostacyclin receptor agonist in development for the treatment of pulmonary arterial hypertension, that has demonstrated potent activity on human vascular smooth muscle cells and platelets. The safety, tolerability and PK needs to be determined in clinical studies. 

Methods

In a single-dose escalation study, four cohorts (n=8/cohort; 6 on ralinepag; 2 on placebo) of healthy adults received ralinepag 0.03, 0.05, 0.1 or 0.2 mg in a fasted state. In a multiple ascending dose study in healthy volunteers, Cohort A (ralinepag n=20; placebo n=10) received ralinepag 0.05 mg once-daily (q.d.), increasing every sixth day to 0.1, 0.2, 0.3 and 0.4 mg for up to 27 days. Cohort B (ralinepag n=20; placebo n=5) received ralinepag 0.01 mg twice-daily (b.i.d.), increasing every sixth day to 0.03, 0.04, 0.05 and 0.07 b.i.d for up to 30 days.

Results

In the single-dose study, all 32 subjects completed. Ralinepag was tolerated at 0.03, 0.05 and 0.1 mg. Dose escalation was discontinued at 0.2 mg due to treatment-emergent adverse events (AEs), most commonly vomiting, headache and nausea (6/6, 5/6 and 3/6, respectively); nausea and vomiting were moderate-to-severe. AEs were similar for male and female subjects. There were no clear dose-dependent changes in blood pressure and no clinically significant changes in ECG or laboratory tests. There were increases in mean heart rate from 0.05 mg upwards, most evident at 0.2 mg. In the PK analysis, the median tmax (time to maximum plasma levels) and estimated mean terminal half-life across dose groups were approximately 1.25 hrs. and 23 hours, respectively.
In the multiple ascending dose study, 26/30 subjects in Cohort A and 24/25 subjects in Cohort B completed the study. Most subjects on ralinepag reported moderate AEs, most commonly headache, nausea and jaw pain. Most common AEs with placebo were constipation and headache. Four subjects withdrew due to AEs (0.05 mg q.d., vomiting, headache; 0.1 mg q.d., nausea, headache, palpitations; 0.05 mg q.d., atrial fibrillation; 0.01 mg b.i.d., ECG wave changes). The highest tolerated doses were 0.3 mg q.d. and 0.07 mg b.i.d. Exposure of ralinepag was dose proportional, independent of q.d. or b.i.d. administration, and there was no appreciable accumulation of ralinepag after multiple dosing.

Conclusion

The tolerability of ralinepag in healthy adults varied across doses, with the observed AEs being consistent with prostacyclin agonists. AEs were generally dose-related, but not associated with plasma concentration. Individual dose titration is needed to determine the optimal individual dose level. These results support progress into clinical studies evaluating ralinepag in patients with pulmonary arterial hypertension.