Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study

被引:48
作者
Rowe, S. M. [1 ]
Zuckerman, J. B. [2 ]
Dorgan, D. [3 ]
Lascano, J. [4 ]
Mccoy, K. [5 ]
Jain, M. [6 ]
Schechter, M. S. [7 ]
Lommatzsch, S. [8 ]
Indihar, V. [9 ]
Lechtzin, N. [10 ]
McBennett, K. [11 ]
Callison, C. [12 ]
Brown, C. [13 ]
Liou, T. G. [14 ]
MacDonald, K. D. [15 ]
Nasr, S. Z. [16 ]
Bodie, S. [17 ]
Vaughn, M. [17 ]
Meltzer, E. B. [17 ]
Barbier, A. J. [17 ]
机构
[1] Univ Alabama Birmingham, Birmingham, AL USA
[2] Tufts Univ, Maine Med Ctr, Medford, MA 02155 USA
[3] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA
[4] Univ Florida, Gainesville, FL 32611 USA
[5] Ohio State Univ, Nationwide Childrens Hosp, Columbus, OH 43210 USA
[6] Northwestern Univ, Feinberg Sch Med, Evanston, IL 60208 USA
[7] Virginia Commonwealth Univ, Childrens Hosp Richmond, Richmond, VA 23284 USA
[8] Natl Jewish Hlth, Denver, CO USA
[9] Univ Cincinnati, Cincinnati, OH 45221 USA
[10] Johns Hopkins Univ, Baltimore, MD 21218 USA
[11] Cleveland Med Ctr, Univ Hosp, Cleveland, OH USA
[12] Univ Tennessee, Knoxville, TN 37996 USA
[13] Indiana Univ Sch Med, Indiana, PA USA
[14] Univ Utah, Salt Lake City, UT USA
[15] Oregon Hlth & Sci Univ, Portland, OR 97201 USA
[16] Univ Michigan, Ann Arbor, MI 48109 USA
[17] Translate Bio Inc, Lexington, MA USA
关键词
Cystic fibrosis; Aerosol; mRNA therapy; Gene therapy;
D O I
10.1016/j.jcf.2023.04.008
中图分类号
R56 [呼吸系及胸部疾病];
学科分类号
摘要
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.
引用
收藏
页码:656 / 664
页数:9
相关论文
共 31 条
  • [1] Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial
    Alton, Eric W. F. W.
    Armstrong, David K.
    Ashby, Deborah
    Bayfield, Katie J.
    Bilton, Diana
    Bloomfield, Emily V.
    Boyd, A. Christopher
    Brand, June
    Buchan, Ruaridh
    Calcedo, Roberto
    Carvelli, Paula
    Chan, Mario
    Cheng, Seng H.
    Collie, D. David S.
    Cunningham, Steve
    Davidson, Heather E.
    Davies, Gwyneth
    Davies, Jane C.
    Davies, Lee A.
    Dewar, Maria H.
    Doherty, Ann
    Donovan, Jackie
    Dwyer, Natalie S.
    Elgmati, Hala I.
    Featherstone, Rosanna F.
    Gavino, Jemyr
    Gea-Sorli, Sabrina
    Geddes, Duncan M.
    Gibson, James S. R.
    Gill, Deborah R.
    Greening, Andrew P.
    Griesenbach, Uta
    Hansell, David M.
    Harman, Katharine
    Higgins, Tracy E.
    Hodges, Samantha L.
    Hyde, Stephen C.
    Hyndman, Laura
    Innes, J. Alastair
    Jacob, Joseph
    Jones, Nancy
    Keogh, Brian F.
    Limberis, Maria P.
    Lloyd-Evans, Paul
    Maclean, Alan W.
    Manvell, Michelle C.
    McCormick, Dominique
    McGovern, Michael
    McLachlan, Gerry
    Meng, Cuixiang
    [J]. LANCET RESPIRATORY MEDICINE, 2015, 3 (09) : 684 - 691
  • [2] Cationic lipid-mediated CFTR gene transfer to the lungs and nose of patients with cystic fibrosis:: a double-blind placebo-controlled trial
    Alton, EWFW
    Stern, M
    Farley, R
    Jaffe, A
    Chadwick, SL
    Phillips, J
    Davies, J
    Smith, SN
    Browning, J
    Davies, MG
    Hodson, ME
    Durham, SR
    Li, D
    Jeffery, PK
    Scallan, M
    Balfour, R
    Eastman, SJ
    Cheng, SH
    Smith, AE
    Meeker, D
    Geddes, DM
    [J]. LANCET, 1999, 353 (9157) : 947 - 954
  • [3] Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia
    An, Ding
    Schneller, Jessica L.
    Frassetto, Andrea
    Liang, Shi
    Zhu, Xuling
    Park, Ji-Sun
    Theisen, Matt
    Hong, Sue-Jean
    Zhou, Jenny
    Rajendran, Raj
    Levy, Becca
    Howell, Rebecca
    Besin, Gilles
    Presnyak, Vladimir
    Sabnis, Staci
    Murphy-Benenato, Kerry E.
    Kumarasinghe, E. Sathyajith
    Salerno, Timothy
    Mihai, Cosmin
    Lukacs, Christine M.
    Chandler, Randy J.
    Guey, Lin T.
    Venditti, Charles P.
    Martini, Paolo G. V.
    [J]. CELL REPORTS, 2017, 21 (12): : 3548 - 3558
  • [4] [Anonymous], 2022, Cystic fibrosis foundation patient registry highlights
  • [5] Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine
    Baden, Lindsey R.
    El Sahly, Hana M.
    Essink, Brandon
    Kotloff, Karen
    Frey, Sharon
    Novak, Rick
    Diemert, David
    Spector, Stephen A.
    Rouphael, Nadine
    Creech, C. Buddy
    McGettigan, John
    Khetan, Shishir
    Segall, Nathan
    Solis, Joel
    Brosz, Adam
    Fierro, Carlos
    Schwartz, Howard
    Neuzil, Kathleen
    Corey, Larry
    Gilbert, Peter
    Janes, Holly
    Follmann, Dean
    Marovich, Mary
    Mascola, John
    Polakowski, Laura
    Ledgerwood, Julie
    Graham, Barney S.
    Bennett, Hamilton
    Pajon, Rolando
    Knightly, Conor
    Leav, Brett
    Deng, Weiping
    Zhou, Honghong
    Han, Shu
    Ivarsson, Melanie
    Miller, Jacqueline
    Zaks, Tal
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2021, 384 (05) : 403 - 416
  • [6] Barbier A, 2018, PEDIATR PULM, V53, P253
  • [7] Barbier A, 2022, patent application publication, Patent No. 2021021988
  • [8] The future of cystic fibrosis care: a global perspective
    Bell, Scott C.
    Mall, Marcus A.
    Gutierrez, Hector
    Macek, Milan
    Madge, Susan
    Davies, Jane C.
    Burgel, Pierre-Regis
    Tullis, Elizabeth
    Castaos, Claudio
    Castellani, Carlo
    Byrnes, Catherine A.
    Cathcart, Fiona
    Chotirmall, Sanjay H.
    Cosgriff, Rebecca
    Eichler, Irmgard
    Fajac, Isabelle
    Goss, Christopher H.
    Drevinek, Pavel
    Farrell, Philip M.
    Gravelle, Anna M.
    Havermans, Trudy
    Mayer-Hamblett, Nicole
    Kashirskaya, Nataliya
    Kerem, Eitan
    Mathew, Joseph L.
    McKone, Edward F.
    Naehrlich, Lutz
    Nasr, Samya Z.
    Oates, Gabriela R.
    O'Neill, Ciaran
    Pypops, Ulrike
    Raraigh, Karen S.
    Rowe, Steven M.
    Southern, Kevin W.
    Sivam, Sheila
    Stephenson, Anne L.
    Zampoli, Marco
    Ratjen, Felix
    [J]. LANCET RESPIRATORY MEDICINE, 2020, 8 (01) : 65 - 124
  • [9] Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA
    Diebold, SS
    Kaisho, T
    Hemmi, H
    Akira, S
    Sousa, CRE
    [J]. SCIENCE, 2004, 303 (5663) : 1529 - 1531
  • [10] Leveraging Rational Protein Engineering to Improve mRNA Therapeutics
    Farelli, Jeremiah D.
    Asrani, Kirtika H.
    Isaacs, Cleo
    deBear, Joanna S.
    Stahley, Mary R.
    Shah, Anumeha
    Lasaro, Melissa A.
    Cheng, Christopher J.
    Subramanian, Romesh R.
    [J]. NUCLEIC ACID THERAPEUTICS, 2018, 28 (02) : 74 - 85