Safety and Pharmacokinetics of Vardenafil Inhalation Powder (RT234-PAH) Following Oral Inhalation in Healthy Adult Volunteers.

0 4 81216 0 5 10 15 20 25 30 0 24 48 72 96120144168192216 0 5 10 15 20 25 30 ““ ““““““““““““““““““““““““““““““““““ Plasma Vardenafil Concentration (ng/mL) Day 1 Days 1 through 9 Observed Concentration“ Dose Administration Time After Start of Dosing (hr) Safety And Pharmacokinetics Of Vardenafil Inhalation Powder (RT234) Following Oral Inhalation In Healthy Adult Volunteers Introduction vVardenafil hydrochloride is a phosphodiesterase type-5 inhibitor. Vardenafil is administered as an oral tablet in the treatment of erectile dysfunction (Levitra®, Bayer). vRT234 (vardenafil inhalation powder) is being developed for use as an as-needed (PRN) treatment for episodic symptoms of pulmonary arterial hypertension (PAH), to acutely improve exercise capacity, physical function, and disease-associated symptom impacts. vRT234 is specifically designed for use as a PRN therapeutic with a rapid onset of action, extended duration of action, minimal adverse events when used in addition to background PAH disease-specific therapy, and a convenient delivery system with a low daily treatment burden. vRT234-CL101 was a Phase 1 single ascending dose (SAD, N=6/dose cohort) study, followed by a multiple ascending dose (MAD, N=8) study utilizing the maximum tolerated dose from the SAD. In the MAD, subjects received the 2.4 mg dose every 4 hrfor up to 4 doses (QID) (i.e., 9.6 mg/day) for 7 consecutive days. Of the 32 healthy volunteers, 53.1% were female, 75% were white, and the mean age was 26 yr. vThe tmaxfor RT234 was observed at the first timepoint after dose administration (ca., 2 min) vVardenafil exposure (Cmax, AUC0-inf) was dose proportional from 0.2 mg to 2.4 mg vVardenafil systemic exposure for all RT234 doses was significantly less than the 20 mg oral tablet vMinor accumulation of no clinical significance was observed following dosing of RT234 every four hours QID in the MAD portion of the study E. L. Parsley, J. Weers, T. T arara, M. Eldon, J. T epper, M. Maurer RespiraTherapeutics, Inc., Albuquerque, NM, USA Materials vRT234 is comprised of an adhesive mixture of 2.0% w/w micronized vardenafil and coarse lactose carrier particles (CDMO: Hovione FarmaCiencia, Portugal). vThe dry powder was filled into Hypromellose capsules with an MG2 FlexaLaband packaged in HDPE bottles. vFor Phase 1, the dry powder was administered with the RS01 dry powder inhaler (PlastiapeS.p.A., Osnago, Italy). Vardenafil inhalation powder RS01 DPI Rapid, dose proportional systemic uptake with low systemic exposure vs. Levitra RT234 and Portable dry powder inhaler (DPI) Nonclinical vSeven nonclinical safety studies in rats and dogs, including 5-d dose range finding, 28-d and 13-w GLP toxicology, and safety pharmacology studies were performed vNOAEL values were the highest administered dose in each study vHigh safety margins relative to the RT234 Phase 2b doses vHistopathology observations were species-specific generic effects related to powder inhalation, and not related to RT234 § Nonadversemild irritation in the upper respiratory tract and trachea in rat and dog § Nonadversereverse sneezing in the dog RT234: Large safety margins in nonclinical studies, even for four times daily dosing Phase 1: Multiple Ascending Dose (MAD) Minor accumulation with QID dosing Phase 1: Single Ascending Dose (SAD) Enrollment in a Ph 2a hemodynamic study in PAH patients (ACTRN12619001178134) is complete, and a Ph 2b exercise capacity study as assessed by Cardio-Pulmonary Exercise Testing (CPET) study is underway. vNo dose limiting toxicity was observed and the maximum tolerated dose was not reached for doses up to 9.6 mg/day vNo evidence of local airway irritation (dyspnea, wheezing, bronchospasm, or spirometry changes) vBrief, asymptomatic decreases in systemic blood pressure was noted approximately ~40- 100 min post-dosing with RT234 (not clinically significant) vThe 2.4 mg dose is ~2.5 to 5-fold greater than the 0.5 and 1.0 mg doses planned for Phase 2b Safety: RT234 was generally well tolerated with TEAEs mild to moderate in intensity Treatment related Adverse Events (>6.4%) RT234 (N=31) Levitra® (N=5) Headache 10 (32.3) 4 (80.0) Dizziness 4 (12.9) 3 (60.0) Nervous Syst. Imbal. 1 (3.2) 1 (20.0) Flushing 1 (3.2) 1 (20.0) Chills 1 (3.2) 1 (20.0) Cough 3 (9.7) 0 (0.0) Nausea 3 (9.7) 0 (0.0) IH dosing: 2.4 mg (blue), 1.2 mg (pink), 0.6 mg (violet), 0.2 mg (green); PO dosing: 20mg (orange)

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