A single dose of RT234, vardenafil inhaled via the AOS DPI acutely improves exercise capacity and reduces dyspnea in PAH patients

A single dose of RT234, vardenafil inhaled via the Axial Oscillating Sphere Dry Powder Inhaler (AOS DPI), acutely improves exercise capacity and reduces dyspnea in PAH patients (WHO Group 1 PH) – Results from the open-label Phase 2b CPET (Cardiopulmonary Exercise Testing) study (NCT04266197) R. Benza1), P. Staehr2), V. Franco3), M. Aras4), L. Spikes5), D. Grinnan6), H. B. Rossiter7), C. Ferguson7), E. Parsley2), K. Feldkircher2), T. Marmon2), I. Preston8) on behalf of Study Participants, Investigators and Study Personnel Background Methods References: 1. FDA: Pulmonary arterial hypertension: the voice of the patient. 2014. 2. Ross et al. 2010, Circulation. 2016;134:e653-e699, 3. Moutchia et al. 2013, Am J Respir Crit Care Med. 15;207(8):1070-1079: 6MWD and peak VO2 are correlated, and an increase in 6MWD of 30 meters (the minimal clinically important difference in 6MWD for PAH patients) corresponds to an improvement in peak VO2 of ~0.7 mL/min/kg. 4. Swank et al. 2012, Circ Heart Fail. 5(5):579-585: Every ~6% increase in peak VO2 is associated with a 5% lower risk of all-cause mortality or all-cause hospitalization in patients with CHF. 5. Ainsworth BE, et al. 2000, Med Sci Sports Exerc;32(9):S498-504. Figure 1: AOS DPI • Despite multiple chronic therapies, most PAH patients remain highly symptomatic, exhibiting profound exercise intolerance, dyspnea and fatigue,(1) which limit activities of daily living. • The objective of the Phase 2b study (CL202) was to determine the effects of a single-dose RT234 treatment on exercise capacity (’function’) and exertional symptoms (‘feel’) in PAH patients. • The Per-Protocol-Population (PPP, N=39) comprised the ITT, less three subjects due to missing CPET data, a right-left intra-atrial shunt, or insufficient exercise effort. • Increase of peak VO2 and decrease in VE/VCO2 slope were dose- dependent with statistically significant effects observed in the 2.0 mg cohort (Figs. 3 & 4) • The responder fraction (i.e. those with increased peak VO2) rose with dose (0.5 mg: 40%, 1.0 mg: 55%, 2.0 mg: 64%). • Most responders increased peak VO2 by at least 0.7 mL/min/kg or 6% (Fig. 5), which is considered clinically meaningful. (2,3,4) • Over all cohorts, modified Borg Dyspnea score at peak decreased independent of dose (Mean -1.3±2.07, p=0.0005, Fig. 6). • RT234 (vardenafil inhalation powder) is a novel drug-device combination incorporating a dry-powder inhaler (AOS DPI)* designed to maximize drug delivery to the distal lung (Fig 1). • RT234 aims address the unmet need for an on-demand (PRN) treatment that acutely improves exercise tolerance and reduces exertional symptoms, e.g., dyspnea. *AOS DPI: Axial Oscillating Sphere Dry Powder Inhaler Figure 2: CL202 Study Design Results • A total of 42 subjects (Intent-To-Treat Population, ITT) were enrolled (Table 1). Figure 3: RT234 increased peak V̇O2 Figure 4: RT234 decreased V̇E/V̇CO2 slope Figure 5: Peak V̇O2 Responders (PPP) Figure 6: RT234 reduced dyspnea (PPP) • CL202 was an open-label study of a single RT234 dose in 0.5 mg, 1.0 mg, and 2.0 mg cohorts, sequentially (Fig.2). • Participants underwent a baseline incremental cycling cardiopulmonary exercise test (CPET) without treatment, and, after 2-14 days, a repeat CPET initiated 30 min after RT234. • Participants maintained background therapy throughout. • The primary endpoint was the change from baseline in oxygen uptake at peak exercise (peak VO2) • Secondary endpoints included the change in VE/VCO2 slope (ventilatory efficiency) and the change in dyspnea (modified Borg Dyspnea score, 0-10 scale). • For PAH patients, incremental increases in peak V̇O2 could translate to meaningful increase in daily activities (Fig. 7). (5) Figure 7: Activities of daily living and V̇O2 uptake • RT234 demonstrated favorable safety and tolerability (Table 2). Change in V̇E/V̇CO2 slope (PPP) *p<0.05 by 2-sided t-test (Mean) or Wilcoxon signed-rank test (Median) Change in V̇E/V̇CO2 slope (PPP) *p<0.05 by 2-sided t-test (Mean) or Wilcoxon signed-rank test (Median) Conclusions* • A single dose of RT234 acutely increased exercise capacity in a dose-dependent manner, reduced exercise-induced dyspnea and demonstrated favorable safety and tolerability. For most responders, the increase in peak V̇O2 was clinically meaningful. • RT234 is a novel, on-demand treatment that may be added to chronic PAH therapy to increase function in daily activities and reduce dyspnea i.e., improve “feel and function”. • Further clinical studies for RT234 development are warranted. *Respira Therapeutics is the sponsor of study CL202. RT234 is an investigational product that has not been approved by the FDA or any other regulatory authority. Affiliations: 1) Icahn School of Medicine, Mount Sinai Heart, New York, NY, USA. 2) Employee of or consultant to Respira Therapeutics, Inc., Palo Alto, CA, USA. 3) Division of Cardiovascular Medicine, The Ohio State University Wexner Medical, Columbus, OH, USA. 4) Division of Cardiology, University of California San Francisco, San Francisco, CA, USA. 5) University of Kansas Medical Center, Kansas City, KS, USA. 6) Virginia Commonwealth University School of Medicine, Richmond, VA, USA. 7) Institute of Respiratory Medicine and Exercise Physiology, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA. 8) Lahey Hospital and Medical Center, Burlington, MA, USA. Lower modified Borg Dyspnea score = Reduced dyspnea Objective

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