ACUTE HEMODYNAMIC IMPROVEMENT IN CHRONIC PULMONARY ARTERIAL HYPERTENSION ON DUAL THERAPY FOLLOWING RT234 INHALATION

Abstract

SESSION TITLE: Advances in the Diagnosis and Management of Pulmonary Hypertension SESSION TYPE: Original Investigations PRESENTED ON: October 18-21, 2020 PURPOSE: 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 54±14 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 635±344, 469±431, 579±337 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 +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 0.6mg 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. DISCLOSURES: Advisory Committee Member relationship with Actelion Please note: $1001 - $5000 Added 03/22/2020 by Nathan Dwyer, source=Web Response, value=Consulting fee Advisory Committee Member relationship with GSK Please note: $1001 - $5000 Added 03/22/2020 by Nathan Dwyer, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Bayer Please note: $1001 - $5000 Added 03/22/2020 by Nathan Dwyer, source=Web Response, value=Consulting fee Institutional Funding to Conduct Study relationship with Respira Therapeutics Please note: $20001 - $100000 Added 03/22/2020 by Nathan Dwyer, source=Web Response, value=Grant/Research Support No relevant relationships by David Kaye, source=Admin input No relevant relationships by Anne Keogh, source=Web Response No relevant relationships by Eugene Kotlyar, source=Web Response Employee relationship with Respira Therapeutics, Inc. Please note: >$100000 Added 03/23/2020 by Mari Maurer, source=Web Response, value=Salary Consultant relationship with Respira Therapeutics Please note: $20001 - $100000 Added 03/26/2020 by Ed Parsley, source=Web Response, value=Consulting fee Employee relationship with Respira Therapeutics Please note: >$100000 Added 03/22/2020 by Jeffry Weers, source=Web Response, value=Salary