Background: MRT5005, a codon-optimized CFTR mRNA, delivered by aerosol in lipid nanoparticles, was designed as a genotype-agnostic treatment for CF lung disease. Methods: This was a randomized, double-blind, placebo-controlled Phase 1/2 study performed in the US. Adults with 2 severe class I and/or II CFTR mutations and baseline ppFEV1 values between 50 and 90% were randomized 3:1 (MRT5005: placebo). Six dose levels of MRT5005 (4, 8, 12, 16, 20, and 24 mg) or placebo (0.9% Sodium Chloride) were administered by nebulization. The single ascending dose cohort was treated over a range from 8 to 24 mg; the multiple ascending dose cohort received five weekly doses (range 8-20 mg); and the daily dosing cohort received five daily doses (4 mg). Results: A total of 42 subjects were assigned to MRT5005 [31] or placebo [11]. A total of 14 febrile reactions were observed in 10 MRT5005-treated participants, which were mild [3] or moderate [11] in severity; two subjects discontinued related to these events. Additionally, two MRT5005-treated patients experienced hypersensitivity reactions, which were managed conservatively. The most common treatment emergent adverse events were cough and headache. No consistent effects on FEV1 were noted. Conclusions: MRT5005 was generally safe and well tolerated through 28 days of follow-up after the last dose, though febrile and hypersensitivity reactions were noted. The majority of these reactions resolved within 1-2 days with supportive care allowing continued treatment with MRT5005 and careful monitoring. In this small first-in-human study, FEV1 remained stable after treatment, but no beneficial effects on FEV1 were observed. (c) 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Background: AR-501, an inhaled novel iron analog disrupts microbial iron-dependent metabolic pathways, resulting in antimicrobial activity against bacteria, NTM, and fungi. This Ph1/2a study will have data readout by mid-2023 (www.clinicaltrials.gov NCT03669614). Inhaled AR-501 in HV's was generally well tolerated once weekly for 5 weeks. Here we report the preliminary safety, PK, and exploratory efficacy results of once-weekly inhaled AR-501 for 3 doses over four weeks. Methods: A RDBPC Ph1 study in 50 HVs has been completed. Thirty-nine (39) subjects were randomized in the CF Phase 2a study, from which 30 subjects received one of the three ascending doses of AR-501, 9 received placebo. Each cohort has received a once-weekly, 3-dose regimen of inhaled active drug (6.4, 20 and 40 mg Ga) or placebo, in a 2:1 ratio and followed for 28 days after the 3rd dose. Outcome measures include safety, PK, PFTs (FEV1), microbiology, CFQ-R, and inflammatory biomarkers. Results: Phase 2a, all CF sentinel and all but 1 subject in the expanded cohort completed all 3 doses (6.4, 20 and 40 mg) in a blinded fashion. Subjects given: Low (n = 8), Medium (n = 11), High Dose (n = 11) and Placebo (n = 9). PK, efficacy and biomarker data will be reported after database lock. Safety data reviewed by an independent unblinded Data and Safety Monitoring Board (DSMB) deemed suitable for expansion to an 80 mg study group. Most AEs were mild/moderate and respiratory in nature. Nebulized AR-501 is well tolerated, with no attributable serious adverse events (SAEs). DSMB had no safety concerns. The 80 mg dosing, to include 15 subjects randomized in a 2:1 ratio. DSMB will review safety from 6 sentinel subjects prior to enrolling 9 subjects. Tabled 1Multiple Ascending Dose Adverse Event Incidence SummarySubjects with anyLow Dose Cohort (N = 5)Medium Dose Cohort (N = 3)High Dose Cohort (N = 3)Expanded Dose Cohort N = 31)AE2 (40%)1 (33.3%)2 (66.6%)24 (77.4%)Grade 3 AE1 (20%)007 (22.6%)Grade ≥4 AE0000Study drug-related AE01 (33.3%)1 (33.3%)16 (51.6%)SAE0002 (6.5%)Study drug-related SAE0000 Open table in a new tab Conclusions: AR-501 is being developed as a once-weekly aerosolized antimicrobial with broad antimicrobial activity. Inhaled AR-501 has been well tolerated when administered once weekly ×3 weeks. Ph2a safety, efficacy and biomarker data readout is due prior to ECFS meeting.

Figure 1 (A and B) Effect of DA discontinuation: (A) Between-group comparison of change in whole-lung MCC (WLAveClr90).(B) Scatter plot of baseline vs. 6-week WLAveClr90.(C and D) Effect of hypertonic saline discontinuation: (C) Betweengroup comparison of change in whole-lung MCC (WLAveClr90).(D) Scatter plot of baseline vs. 6-week WLAveClr90.Conclusions: These results suggest that PwCF on ETI with mild disease do not experience subclinical deterioration in MCC that could affect health outcomes after discontinuing hypertonic saline.Those stopping dornase alfa could benefit from better MCC after stopping this treatment.

Conclusions: In this study of people with CF who had undergone lung transplantation, ELX/TEZ/IVA did not change CFQ-R domain scores or SNOT-20 scores.SNOT-20 scores improved for most patients studied.Overall, ELX/TEZ/IVA was well tolerated and may improve certain nonpulmonary symptoms of CF.Larger studies are necessary to determine the risk-versus-benefit profile of ELX/TEZ/IVA in people with CF who have undergone lung transplantation.

A lumen /A (all p < 0.001), but not in A wt /A ( p = 0.35).Between 64% and 66% of AA pairs were defined as bronchiectasis and 59% as AWT.Conclusions: Progressive bronchiectasis can be observed in CwCF during late childhood into adolescence.AA analysis results agree with PRAGMA-CF results to monitor disease progression in CwCF.