D96-09 Safety and Effect on Mucociliary Clearance of RCT1100, an Inhaled Lipid Nanoparticle DNAI1 MRNA, in Patients With Primary Ciliary Dyskinesia Due to Disease Causing DNA Variants in the DNAI1 Gene: An Open-label, Multiple-dose, Phase 1b Trial
C M Nygaard, J Raidt, K N Olivier, T Qvist, J Mortensen, S H Donaldson, R Wiewrodt, L Stegger, R Hjeij, N T Loges, M R Loebinger, J A Couch, J G Matthews, V M Daryani, S Bradley, P Ryali, V Kharitonov, L E Ostrowski, P Sears, H Omran, K G Nielsen,Abstract
Rationale
Primary ciliary dyskinesia (PCD) is a rare genetic, progressively destructive pulmonary disease associated with impaired mucociliary clearance (MCC). Disease causing variants in the dynein axonemal intermediate chain-1 gene (DNAI1) cause PCD associated with absent or abnormal outer dynein arms, resulting in impaired ciliary motility. RCT1100, an inhaled DNAI1 mRNA encapsulated in a novel selective organ targeting lipid nanoparticle formulation, is designed for delivery and restoration of DNAI1 expression in airway cells ultimately aiming for improved MCC. Thus, we explored the safety and biological activity of RCT1100 in patients with PCD (pwPCD) due to disease causing variants in DNAI1.
Methods
RCT1100-103 was an open-label, multiple-dose, Phase 1b trial, conducted across a total of 3 tertiary PCD clinics located in Denmark, Germany, and the United States. PwPCD and genetic defects in DNAI1 were recruited and given 5 mg orally nebulized RCT1100 3 times weekly for 12 weeks. Safety was evaluated by adverse events (AEs) in all who received at least one partial dose, while change in MCC was assessed by pulmonary radio-aerosol studies conducted at baseline, Weeks (W) 4, 12, and optionally 16. Changes in immunofluorescence (IF) for DNAI1, ciliary activity by high-speed video microscopy (HSVM), and FEV1 were additionally explored.
Results
Fourteen pwPCD (10 [71·4%] male; 4 [28·6] female; median age 35 [range 19 to 51] yrs; median ppFEV1 71 [range 54 to 113]%) were enrolled between Oct 10 2024 and Jun 30 2025, 13 completed the trial. All 14 pwPCD had at least one MCC assessment while one dropped out after W4 MCC. At Week 12, 3 (21·4%) achieved an absolute ≥5% increase from baseline MCC, and 8 (57·1%) achieved an absolute ≥2% increase. Mean (SD) changes from baseline MCC were 2·1% (4·28) at W4, 1·8% (4·99) at W12, and -1·4% (3·06) at W16. All 14 participants (100%) experienced mild or moderate AEs. No serious AEs or AEs of Grade ≥3 were considered treatment related. Furthermore, positive changes of IF-stained DNAI1 and ciliary activity in bronchial brushings were shown. FEV1 was unchanged at W12.
Conclusion
Preliminary evidence of biological activity of RCT1100 in pwPCD due to disease causing variants in DNAI1 was reflected by improved whole-lung MCC in a subset of participants and positive changes in IF DNAI1 expression and ciliary activity in bronchial epithelial cells. This represents the first clinical indication of successful delivery and translation of an mRNA therapeutic in the human airway.
This abstract is funded by: ReCode Therapeutics