TY - JOUR
T1 - Inhaled mRNA therapy for treatment of cystic fibrosis
T2 - Interim results of a randomized, double‐blind, placebo‐controlled phase 1/2 clinical study
AU - Rowe, S. M.
AU - Zuckerman, J. B.
AU - Dorgan, D.
AU - Lascano, J.
AU - McCoy, K.
AU - Jain, M.
AU - Schechter, M. S.
AU - Lommatzsch, S.
AU - Indihar, V.
AU - Lechtzin, N.
AU - McBennett, K.
AU - Callison, C.
AU - Brown, C.
AU - Liou, T. G.
AU - MacDonald, K. D.
AU - Nasr, S. Z.
AU - Bodie, S.
AU - Vaughn, M.
AU - Meltzer, E. B.
AU - Barbier, A. J.
N1 - Funding Information:
This study was funded by Translate Bio. Infrastructure grants were funded by the Cystic Fibrosis Foundation (CFF) and NIH P30DK072482.
Publisher Copyright:
© 2023 European Cystic Fibrosis Society
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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.
KW - Aerosol
KW - Cystic fibrosis
KW - Gene therapy
KW - mRNA therapy
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UR - http://www.scopus.com/inward/citedby.url?scp=85153858705&partnerID=8YFLogxK
U2 - 10.1016/j.jcf.2023.04.008
DO - 10.1016/j.jcf.2023.04.008
M3 - Article
C2 - 37121795
AN - SCOPUS:85153858705
SN - 1569-1993
VL - 22
SP - 656
EP - 664
JO - Journal of Cystic Fibrosis
JF - Journal of Cystic Fibrosis
IS - 4
ER -