Rowe, S. M.Zuckerman, J. B.Dorgan, D.Lascano, J.McCoy, K.Jain, M.Schechter, M. S.Lommatzsch, S.Indihar, V.Lechtzin, N.McBennett, K.Callison, C.Brown, C.Liou, T. G.MacDonald, K. D.Nasr, S. Z.Bodie, S.Vaughn, M.Meltzer, E. B.Barbier, A. J.2024-09-192024-09-192023Rowe SM, Zuckerman JB, Dorgan D, et al. Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study. J Cyst Fibros. 2023;22(4):656-664. doi:10.1016/j.jcf.2023.04.008https://hdl.handle.net/1805/43440Background: 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.en-USPublisher PolicyAerosolCystic fibrosisGene therapymRNA therapyArticle