RT234 is an inhaled formulation of the phosphodiesterase type-5 inhibitor (PDE5i) vardenafil, in development for episodic symptoms of pulmonary arterial hypertension (PAH). This phase 2a escalating-dose trial evaluated acute changes in pulmonary vascular resistance (PVR) and other hemodynamic (HD) parameters in PAH patients on stable maintenance dual therapy. Three cohorts received RT234 0.2, 0.6 or 1.2 mg during right heart catheterization. Hemodynamic parameters were recorded up to 60 min post-inhalation. Of 14 subjects enrolled, the mean ± SD age was 54 ± 14 years (79% female) and functional class was II (57%), III (36%) or IV (7%). All subjects took oral endothelin receptor antagonist and oral PDE5i. In the 0.2, 0.6 and 1.2 mg cohorts, respectively, mean PVR was 635 ± 344, 469 ± 431 and 579 ± 337 dyn/s/cm−5 at baseline and decreased by −6.6% (−22.2 to 2.7), −23.7% (−44.7 to −18.6) and −16.0% (−22.7 to −10.5) post-inhalation. With 0.6 and 1.2 mg, PVR fell >10% at 5 min, a reduction sustained for ≥60 min. The PVR/systemic vascular resistance ratio changed by −8.0% (−27.1 to 14.1), −18.4% (−37.8 to 0.9) and −11.9% (−23.9 to −0.3) for the 0.2, 0.6 and 1.2 mg doses, respectively, indicating that the 0.6 mg dose might offer the greatest pulmonary selectivity. No clinically significant changes in systemic blood pressure or heart rate were observed. Change in arterial O2 tension was +1.8% (−13.5 to 27.4), +8.1% (−13.5 to 22.6) and +4.3% (−1.4 to 9.9) for the three dose levels. Improvements in pulmonary HD with 0.6 mg inhaled RT234 were on par with 20 mg oral vardenafil, but with less systemic hypotension and higher oxygenation. The only treatment-related adverse events (AEs) were mild headache and mild throat irritation, each in a single subject. No respiratory AEs occurred. RT234 produced rapid reduction in PVR, sustained for ≥60 min, and was well tolerated. The optimally effective RT234 dose appears to be 0.6 mg. RT234 is well suited for development of as ‘as-needed’ or pre-emptive PAH therapy.
Anne Keogh, St Vincent’s Hospital, Darlinghurst, NSW, Australia Nathan Dwyer, Royal Hobart Hospital, Hobart, TAS, Australia Eugene Kotlyar, St Vincent’s Hospital, Darlinghurst, NSW, Australia David Kaye, The Alfred Hospital, Melbourne, VIC, Australia