Acute Hemodynamic Improvement in Chronic Pulmonary Arterial Hypertension on Dual Therapy Following Rt234 Inhalation

Abstract

RT234 is an inhaled formulation of the phosphodiesterase type-5 inhibitor (PDE5i) vardenafil, and is being developed for 'as-needed' use for episodic symptoms of pulmonary arterial hypertension (PAH). This study assessed the hemodynamic (HD) response to RT234. METHODS: A multicentre, open label, Phase 2a escalating dose ongoing clinical trial to evaluate acute changes in pulmonary vascular resistance (PVR) and other HD parameters in PAH patients on stable maintenance dual therapy. Three cohorts of 5 subjects each were to receive 0.2, 0.6, 1.2 mg RT234 during right heart catheterization. HD parameters were recorded at 5, 15, 30, 45, and 60-min post-inhalation. RESULTS: Of the 14 subjects enrolled, mean age was 54AE14 years (79% females). 57% of subjects were functional class (FC) II, 36% FC III, and 7% FC IV. All subjects took a long-term oral endothelin receptor antagonist combined with oral PDE5i. Mean baseline PVR was 635AE344, 469AE431, 579AE337 dyn/sec/cm-5 for the 0.2 mg, 0.6 mg and 1.2 mg cohorts respectively. RT234 administration at 0.2 mg, 0.6 mg and 1.2 mg dosages reduced PVR by-6.6% (-22.2 to 2.7),-23.7% (-44.7 to-18.6), and-16.0% (-22.7 to-10.5), respectively. With the 0.6 and 1.2 mg doses, PVR fell by >10% at 5 min, and the reduced PVR was sustained at least 60 mins. PVR/SVR 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 may offer the greatest pulmonary selectivity. No clinically significant changes in systemic blood pressure or heart rate were observed. The change in PaO2 was þ1.8% (-13.5 to 27.4), þ8.1% (-13.5 to 22.6) and þ4.3% (-1.4 to 9.9) for the three dose levels. Improvements in pulmonary HD with 0.6mg inhaled RT234 were on par with 20mg oral vardenafil, but with less systemic hypotension and higher oxygenation. The only treatment related adverse events (AE) observed were a mild headache and mild throat irritation, each in a single subject. No respiratory AEs (cough, dyspnoea, wheezing, bronchospasm) occurred. CONCLUSIONS: RT234 inhalation resulted in rapid reduction in PVR that was sustained for at least 60 min post-administration and was well tolerated. The optimally effective dose of RT234 appears to be 0.6 mg. RT234 is well-suited for further clinical development as an "as-needed" or even pre-emptive therapy in PAH. CLINICAL IMPLICATIONS: The observed acute improvements in HD should enable PAH patients to perform more of their activities of daily living, resulting in an improved quality of life.

Safety, Tolerability, and Pharmacokinetics of RT234 (Vardenafil Inhalation Powder): A First-in-Human, Ascending Single- and Multiple-Dose Study in Healthy Subjects

“…Indeed, measures of pulmonary hemodynamics following right heart catheterization in subjects with PAH demonstrated a comparable pulmonary hemodynamic effect for the 0.6 mg RT234 dose relative to a 20 mg oral Levitra tablet, although with greater pulmonary selectivity and improved oxygenation (Study ACTRN12618001077257). (14,15) A 10%-20% improvement in pulmonary vascular resistance was observed within 5 minutes following pulmonary administration of RT234, with a peak effect within 15-30 minutes. (14) The rapid PK and pharmacodynamic Compared with other PDE5i, vardenafil has an extended half-life on the catalytic receptor of the PDE5 enzyme (i.e., 1-2 hours vs. 3 and 7 minutes, for sildenafil and tadalafil, respectively).…”

“…(14,15) A 10%-20% improvement in pulmonary vascular resistance was observed within 5 minutes following pulmonary administration of RT234, with a peak effect within 15-30 minutes. (14) The rapid PK and pharmacodynamic Compared with other PDE5i, vardenafil has an extended half-life on the catalytic receptor of the PDE5 enzyme (i.e., 1-2 hours vs. 3 and 7 minutes, for sildenafil and tadalafil, respectively). (16,17) The extended receptor half-life may provide a prolonged hemodynamic effect, enabling PAH patients to complete activities away from home.…”

“…(21) The improved lung targeting of vardenafil leads to large decreases (33-fold) in nominal dose to achieve a comparable pharmacodynamic effect. (14) This leads to decreases in systemic exposure by about one order of magnitude, and gastrointestinal exposure by about two orders of magnitude relative to oral Levitra.…”

The Evolving Management and Treatment Options for Patients with Pulmonary Hypertension: Current Evidence and Challenges

“…In an open label, phase 2a escalating dose trial, inhaled vardenafil lowered PVR rapidly with the effect persisting at least 1 hour after inhalation. 227 Rodatristat ethyl is a prodrug for rodatristat which potently inhibits tryptophan hydroxylase, the rate limiting enzyme responsible for synthesis of serotonin from tryptophan. 228 As noted previously in this review, serotonin has been implicated in the vasoconstriction and vascular remodeling characteristic of PAH.…”