Arcturus Therapeutics Holdings Inc. · NASDAQ:ARCT
Arcturus Therapeutics — NACFC 2023
16 slides from Arcturus Therapeutics's conference presentation, Nov 17, 2023
Slide 1: ARCT-032 (LUNAR-CFTR) Improves Mucociliary Clearance in CF Ferrets
ARCT-032 (LUNAR®-CFTR) Improves Mucociliary Clearance in CF Ferrets Xiaoming Liu, Meihui Luo, Guy Snow, Shahab Fakhari, Yihua Pei, Shuang Wu, Jia Ma, Douglas J. Bartels, Sourabh Shukla, Stefen A. Boehme, David E. Geller, John F. Engelhardt Arcturus Therapeutics and University of Iowa
Slide 2: LUNAR-CFTR (ARCT-032)
mRNA LUNAR®-CFTR (ARCT-032) Replacement Therapy CAP- 5’UTR ORF 3’UTR Delivery vehicle: Cargo: Optimized LUNAR® Lipid Delivery format: Aerosol hCFTR mRNA Nanoparticles Arcturus Therapeutics has developed mutation-agnostic mRNA treatment for CF lung disease ARCT-032 is currently being evaluated in
Slide 3: Epithelial Cell Types in Airways
Epithelial Cell Types in Airways Major Proximal Airway Cell Types CFTR Expression (Cartilaginous Airways) Trachea (~15 to >90%) Goblet Ionocyte Bronchi Terminal Bronchiole Cell Types Human, Pig Bronchi Trans Sheep, Ferret basal Club Bronchioles AT2 Respiratory Bronchiole Cell Types Alveolus Alveoli
Slide 4: CF Ferret Models at University of Iowa
CF Ferret Models at University of Iowa +VX-770 CFTRWT CFTRKO CFTRG551D CFTRG551D Airways Airway Glands Science Translational Medicine 2019 Human Gene Therapy 2022
Slide 5: LUNAR Mediated Delivery of mRNA Payloads to Ferret ALI Cultures
LUNAR® Mediated Delivery of mRNA Payloads to Ferret ALI Cultures ROSA-TG Tomato GFP Cre Reporter Airway ALI LUNAR®- basal cells LUNAR-Cre ROSA-TG hCFTR Wild type 1 wk 2-days ROSA-TG CF Vehicle (V) KO ∆F WT CFTR (C) Short Circuit Current V C V C V C Anti- CFTR LUNAR® Vehicle LUNAR® Vehicle LUNAR®-CFT
Slide 6: LUNAR Mediated Delivery of mRNA Payloads to Ferret Airways
LUNAR® Mediated Delivery of mRNA Payloads to Ferret Airways LUNAR® ROSA-TG Sci Rep 2019 Cre mRNA + Gene Editing Intratracheal En Face Trachea Intralobar Airways Vehicle EGFP Tomato LUNAR®-Cre
Slide 7: LUNAR-CFTR and LUNAR-tdTomato Delivery to Ferret Airways
LUNAR®-CFTR and LUNAR®-tdTomato Delivery to Ferret Airways LUNAR®-Tomato mRNA LUNAR® Vehicle Act-Tubulin CFTR LUNAR® hCFTR
Slide 8: LUNAR Platform Targets Ciliated Cells
LUNAR® Platform Targets Ciliated Cells LUNAR®-tdTomato tdTomato FOXJ1 MUC5AC tdTomato FOXJ1 tdTomato tdTomato tdTomato FOXJ1 MUC5AC tdTomato FOXJ1
Slide 9: Pulmonary Ionocytes in the Proximal Airway
Pulmonary Ionocytes in the Proximal Airway Major Proximal Airway Cell Types Human (Cartilaginous Airways) Ferret Human Ferret Trachea Other Trachea Ferret Whole Mount PNEC ~1% Yuan et al. Tuft Basal Nature 2023 Transitional Goblet Ionocyte Ciliated Hillock Bronchi Basal ~30% CFTR-KO Bronchi FOXI1-KO
Slide 10: LUNAR Platform Predominantly Targets Non-Ionocytes in the Ferret Proximal Airways
LUNAR® Platform Predominantly Targets Non-Ionocytes in the Ferret Proximal Airways LUNAR® Vehicle LUNAR®-CFTR LUNAR®-CFTR ATP6V1G3 CFTR LUNAR® -tdTomato ATP6V1G3 Tomato
Slide 11: LUNAR-Cre Transfection in ROSA-TG Ferrets
LUNAR®-Cre Transfection in ROSA-TG Ferrets EGFP EGFPMUC5AC BSND FOXJ1 P63 EGFP BSND BSND +? +? EGFP MUC5AC MUC5AC BSND EGFP - - LUNAR® platform efficiently delivered mRNA payloads to multiple epithelial cell types including ciliated cells and some ionocytes in ferret airways.
Slide 12: Mucociliary Clearance (MCC) Endpoints in CF Ferrets
Mucociliary Clearance (MCC) Endpoints in CF Ferrets Gallium-68-albumin SPECT/CT (Trachea) PET-CT WT CF On-VX CF Off-VX Proximal Distal
Slide 13: Airway clearance in the CF ferret model is CFTR-dependent
G551D/G551D Ferrets Rate of Clearance (First 6 min) Clearance Rate (Counts/min) 100 16 (9) (11) On/Off VX-770 WT CF (6)(N) Percent Cleared 80 12 (9) (5) Time off VX-770 (9) 60 8 (9) 40 (6) 4 20 0 WT Base 1 2 3 4 1 On 2 wk2On WT Baseline 1 wk Off 2 wk Off 3 wk Off 4 wk Off 1 wk (On) 0 Wks Off VX-770
Slide 14: ARCT-032 (LUNAR-hCFTR) Improved MCC in CF Ferrets
ARCT-032 (LUNAR®-hCFTR) Improved MCC in CF Ferrets • G551D ferrets were removed from VX-770 to achieve a MCC defect (20-40% of WT) • MCC evaluated 24 hr post-dosing with LUNAR®-hCFTR or LUNAR®-TdTomato Baseline Off VX LUNAR-hCFTR Baseline Off VX LUNAR-Tomato 100 100 (N=8) (N=6) 80 80 % Clearance % C
Slide 15: ARCT-032 (LUNAR-hCFTR) Improved MCC in CF Ferrets
ARCT-032 (LUNAR®-hCFTR) Improved MCC in CF Ferrets Rate of Clearance (First 6 min) P=0.0044 20 P =0.0001 P=0.0001 LUNAR®- hCFTR 16 (N=8) Clearance Rate (Counts/min) One-way ANOVA 12 P=0.9979 Paired P=0.9151 Analysis 8 P=0.8133 4 LUNAR®- tdTomato 0 (N=6) Baseline hCFTR LUNAR-hCFTR Baseline Tomato LUN
Slide 16: Conclusions
Conclusions • LUNAR® platform demonstrates efficient delivery of mRNA payloads and transfection in various cell types in ferret airways. • ARCT-032 (LUNAR®-CFTR) improved CFTR activity in CF ferret model as demonstrated by significantly improved MCC. • These in vivo results complement findings from