Acute Hemodynamic Improvement in Chronic Pulmonary Arterial Hypertension on Dual Therapy Following RT234-PAH Inhalation

Figure 1: The RS01 device used to deliver powdered vardenafil Figure 3: Pulmonary vascular resistance Acute Hemodynamic Improvement in Chronic Pulmonary Arterial Hypertension on Dual Therapy Following RT234 Inhalation Anne Keogh,1 Nathan Dwyer,2 Eugene Kotlyar,1 David Kaye3 1St Vincent’s Hospital, Darlinghurst, Australia; 2Royal Hobart Hospital, Hobart, Australia; 3The Alfred Hospital, Melbourne, Australia CONCLUSIONS • Study CL201 validated that RT234 has the critical design features of a PRN vasodilator – Rapid onset of action within 5 min of administration – Acute improvements in exercise tolerance of 35 m – Duration of action of ≥1–2 hrs post administration – Minimal local and systemic safety and tolerability issues when administered in addition to maintenance therapies – Noninvasive delivery system with administration over <1 min • The study results indicate that RT234 has a safety and efficacy profile suitable for continued clinical development as a PRN vasodilator METHODS RESULTS DISCLOSURES • A. Keogh, N. Dwyer, E. Kotlyar, and D. Kaye: Work at institutions that received funding to conduct the RT234 CL201 trial • This study is funded by Respira Therapeutics, Inc. Medical writing assistance was provided by Elise Laming, PhD, of ProScribe – Envision Pharma Group, and was funded by Respira Therapeutics, Inc. Table 1: Baseline demographics Characteristic Patients (N=14) Age (years) [range] 54±14 [22–80] Female (n) 11 White (n) 12 6MWD (m) 426±129 FC (n) II (8); III (5); IV (1) mPAP (mmHg) 45±16 PCWP (mmHg) 12±3 PVR (dyn·sec·cm-5) 558±350 PDE5i (n) Sildenafil 6 Tadalafil 8 ERA (n) Macitentan 10 Bosentan 2 Ambrisentan 2 Data are mean±SD unless specified otherwise. 6MWD, 6-minute walk distance; ERA, endothelin receptor antagonist; FC, WHO Group 1 PAH functional class; mPAP, mean pulmonary arterial pressure; PAH, pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; PDE5i, phosphodiesterase type-5 inhibitor; PVR, pulmonary vascular resistance; SD, standard deviation; WHO, World Health Organization. Inhaled vs oral vardenafil • Comparable pulmonary hemodynamics were observed with inhaled vs oral vardenafil at 1/33rd of the dose Cardiac output over 2 hrs (cycle ergometry) • Single inhalation of RT234 (N=1) acutely improved cardiac output over 2 hrs • Peak decreases in PVR and PVR/systemic vascular resistance ratio with the 0.6-mg dose were -55% and 39%, respectively Figure 5: Cardiac output over 2 hrs (cycle ergometry) after inhalation of RT234 by 1 patient Figure 2: Study design, CL201 Screening (including BL 6MWT) Cohort 1 Cohort 2 Cohort 3 200 μg 600 μg N=5 600 μg 1,200 μg N=5 1,200 μg 2,400 μg N=4 Study design, CL201 (NCT05343637) • Study CL201 is a hemodynamic dose-escalation study in 15 patients with PAH (3 dose cohorts containing 5 patients each) • 2-part study: – Part A: Patients received 2 doses while undergoing right heart catheterization (Day 1) – Part B: 6-minute walking test post dose at highest tolerated dose achieved in Part A (Day 15) Safety outcomes • A single dose of RT234 was well tolerated on top of maintenance therapies • No clinically or statistically significant changes in systemic blood pressure or heart rate were noted • Only 1 treatment-emergent adverse event (TEAE) related to study drug (mild headache) was observed at the highest dose (2.4 mg) • The low rate of TEAEs related to RT234 may be due to the low dose and most patients being accustomed to oral PDE5i treatment 6MWT, 6-minute walk test; BL, baseline. • RT234 (vardenafil inhalation powder) is in development for as-needed (PRN) treatment of episodic symptoms of pulmonary arterial hypertension (PAH) • RT234 is dosed up to 4 times per day to acutely improve: – Symptoms – Exercise capacity – Performance of daily activities – Quality of life • RT234 is designed to provide: – Rapid onset of action (within ~15 min) – Acceptable duration of action (~2–3 hrs) – Convenient treatment regimen (i.e., take “as needed”) – Minimal safety/tolerability issues over background therapy – Noninvasive, portable, simple-to-administer delivery system designed for patients with PAH BACKGROUND Hemodynamic outcomes • Decreases in pulmonary vascular resistance (PVR) of >10% occurred within 5 min for the 0.6- and 1.2-mg doses • RT234 has excellent pulmonary selectivity IH, inhalation; PVR, pulmonary vascular resistance. Figure 4: Pulmonary selectivity IH, inhalation; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance. Table 2: Inhaled vs oral vardenafil Hemodynamic metric % (95% CI) change from baseline Oral vardenafil (20 mg)1 (N=9) RT234 (0.6 mg)a (N=5) Pulmonary vascular effect PVR -26.3 (-29.2 to -22.8) -23.7 (-44.7 to -18.6) Improvements in pulmonary hemodynamics for the RT234 0.6 mg dose comparable with 20-mg oral tablet mPAP -12.1 (-15.8 to -7.3) -12.3 (-19.6 to -3.3) CI +18.4 (9.8 to 25.1) +11.9 (-5.0 to 31.9) Systemic vascular effect SVR -26.4 (-29.9 to -17.5) -9.3 (-22.5 to 15.7) RT234 exhibits greater pulmonary selectivity (i.e., a lower systemic hemodynamic response) than oral medication mSAP -12.1 (-16.9 to -8.1) -2.2 (-9.0 to 18.1) PVR/SVR ratio -0.1 (-8.2 to 4.2) -18.4 (-37.8 to 0.9) Oxygenation PaO2 -2.2 (-17.9 to 13.5) +8.1 (-13.3 to 22.6) RT234 improves oxygenation relative to oral administration a Measurements at peak effect in PVR (30 min); 95% CI determined using Hodges-Lehman point estimates. CI, confidence interval; mPAP, mean pulmonary arterial pressure; mSAP, mean systemic arterial pressure; PaO2, partial pressure of oxygen; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance. Acute improvements in 6MWD • Represents results for patients with PAH with a baseline 6-minute walk distance (6MWD) <450 m • Increases in mean 6MWD were observed for RT234 in the presence of phosphodiesterase type-5 inhibitor (PDE5i)/ endothelin receptor agonist dual therapy • Unlike treprostinil, significant increases in 6MWD were observed after a single dose of RT234 (36 m vs 6 m) Figure 6: Acute improvements in 6MWD Table 3: Safety outcomes RT234 dosea N Δ Heart rate (bpm),b mean (95% CI) Δ mSAP (mmHg),b mean (95% CI) TEAE (drug-related) 0.6 mg 5 -8.2 (-16.8 to 0.4) -3.0 (-6.3 to 0.3) None 1.2 mg 5 3.4 (-0.5 to 7.3) -2.1 (-10.3 to 6.2) None 2.4 mg 4 -5.8 (-11.5 to 0.0) 1.0 (-9.1 to 11.1) 1 (mild headache) a RT234 dose is on top of peak background therapy (Day 15); b Differences are reported at 60 min following RT234 administration, although patients were followed for 4 hrs; 95% CI determined using z-statistic. bpm, beats per min; CI, confidence interval; mSAP, mean systemic arterial pressure; TEAE, treatment-emergent adverse event. REFERENCES 1. Ghofrani HA, et al. J Am Coll Cardiol. 2004;44:1488-1496. 2. McLaughlin VV, et al. J Am Coll Cardiol. 2010;55:1915-1922. 0 15 30 45 60 Time (Min) ∆ PVR (%) Acceptable duration of action (≥1 hr) 0.2 mg IH (N=5) 1.2 mg IH (N=4) 0.6 mg IH (N=5) Rapid onset of action -26.5% Peak decrease 20 15 10 5 0 -5 -10 -15 -20 -25 -30 -35 -40 10 5 0 -5 -10 -15 -20 -25 -30 0 15 30 45 60 Time (Min) ∆ PVR/SVR (%) 0.2 mg IH 1.2 mg IH 0.6 mg IH -18.7% 70 60 50 30 20 10 0 0 30 60 90 120 150 180 210 240 40 Time (Min) Change in cardiac output (%) 5 min post dose 5 min post dose 15 15 30 30 45 45 60 60 75 75 90 105 120 ∆ in cardiac output sustained >2 hrs Baseline Dose 1: 0.2 mg Dose 2: 0.6 mg Initial peak exercise Peak exercise: 2× longer Patient 103-004 + 7.3% ∆ in cardiac output PDE5i ERA Total Day 1 Day 1 Week 6 Week 12 0 10 20 30 40 6 19 20 7 22 25 6 11 9 36 Change in 6MWD (m) RT234 TRIUMPH2 Inhaled treprostinil + monotherapy Please scan code to view poster or visit https://bit.ly/3lftSbO This is an encore of data originally presented at the CHEST Annual Meeting 2020 (October 18–21, 2020) 6MWD, 6-minute walk distance; ERA, endothelin receptor agonist; PDE5i, phosphodiesterase type-5 inhibitor. Poster presented at Pulmonary Hypertension Association (PHA 2022); June 9–12, 2022; Atlanta, GA, USA For more information, contact Dr Carol Satler ([email protected])

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