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Current Reviews in Clinical and Experimental Pharmacology

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ISSN (Print): 2772-4328
ISSN (Online): 2772-4336

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Meta-Analysis

Cystic Fibrosis Transmembrane Conductance Regulator Protein Modulators in Children and Adolescents with Different CF Genotypes - Systematic Review and Meta-Analysis

Author(s): Alaa Hassan Yousif Hamdan, Faiza Zakaria, Maria Kezia Lourdes Pormento, Odunayo Susan Lawal, Adaugo Opiegbe, Samina Zahid, Prathima Guntipalli, Ujala Nasr and Syed Asad Hasan Rizvi*

Volume 19, Issue 1, 2024

Published on: 24 February, 2023

Page: [93 - 110] Pages: 18

DOI: 10.2174/2772432818666230201094115

Price: $65

Abstract

Objective: To determine the efficacy of the first triple CFTR protein modulators in children and adolescents with cystic fibrosis.

Methods: Systematic review and meta-analysis were conducted, following PRISMA guidelines. The following databases were searched extensively: PubMed/Medline, Clinical trials.gov, Google Scholar, Scopus, Embase, and Europe PMC using the keywords: “Ivacaftor”, “Elexacaftor”, “Tezacaftor”, VX_661”, VX_770”, “VX_445”, “cystic fibrosis”. A total of ten randomized clinical trials were included in our analysis. Primary outcomes included: Absolute change in predicted FEV1 from baseline, Absolute change in sweat chloride test from baseline, Absolute change in BMI from baseline, Absolute change in CF-QR from baseline, and Adverse Events.

Results: Among primary findings, significant absolute change in predictive FEV1 from baseline through 4 weeks favoured the triple CFTR protein modulators. (MD = 11.80, 95% CI = 8.47_15.12, p value = <0.00001); as well as CF_QR score (MD = 0.00, 95% CI = -2.50_2.50, p value= 1.00), and BMI kg/m² change (MD = 16.90, 95% CI = 12.73_21.06, p value= <0.00001). No significant change was noted for CFTR channels activity in the treatment group when compared to placebo or VX_770/VX_661 (MD = -12.57, 95% CI = -94.46_69.32, p value= 0.76).

Conclusion: In children aged ≥ 6 y old and adolescents with F508del_CFTR mutation, Elexacaftor- Tezacaftor-Ivacaftor tend to be more effective than first-generation therapy, demonstrating promising results by exhibiting significant improvement in lung function, body weight, and respiratory-related quality of life.

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[1]
Brown SD, White R, Tobin P. Keep them breathing. JAAPA 2017; 30(5): 23-7.
[http://dx.doi.org/10.1097/01.JAA.0000515540.36581.92] [PMID: 28441669]
[2]
Elborn JS. Cystic fibrosis. Lancet 2016; 388(10059): 2519-31.
[http://dx.doi.org/10.1016/S0140-6736(16)00576-6] [PMID: 27140670]
[3]
Yu E, Sharma S. Cystic Fibrosis. StatPearls Publishing: Treasure Island, FL 2021.
[4]
Keiser NW, Birket SE, Evans IA, et al. Defective innate immunity and hyperinflammation in newborn cystic fibrosis transmembrane conductance regulator-knockout ferret lungs. Am J Respir Cell Mol Biol 2015; 52(6): 683-94.
[http://dx.doi.org/10.1165/rcmb.2014-0250OC] [PMID: 25317669]
[5]
Mathew HR, Choi MY, Parkins MD, Fritzler MJ. Systematic review: Cystic fibrosis in the SARS-CoV-2/COVID-19 pandemic. BMC Pulm Med 2021; 21(1): 173.
[http://dx.doi.org/10.1186/s12890-021-01528-0] [PMID: 34016096]
[6]
Swahn H, Harris A. Cell-selective regulation of CFTR gene expression: Relevance to gene editing therapeutics. Genes 2019; 10(3): 235.
[http://dx.doi.org/10.3390/genes10030235] [PMID: 30893953]
[7]
Dawson KP, Frossard PM. The geographic distribution of cystic fibrosis mutations gives clues about population origins. Eur J Pediatr 2000; 159(7): 496-9.
[http://dx.doi.org/10.1007/s004310051317] [PMID: 10923221]
[8]
Lopes-Pacheco M. CFTR modulators: The changing face of cystic fibrosis in the era of precision medicine. Front Pharmacol 2020; 10: 1662.
[http://dx.doi.org/10.3389/fphar.2019.01662] [PMID: 32153386]
[9]
De Boeck K, Zolin A, Cuppens H, Olesen HV, Viviani L. The relative frequency of CFTR mutation classes in European patients with cystic fibrosis. J Cyst Fibros 2014; 13(4): 403-9.
[http://dx.doi.org/10.1016/j.jcf.2013.12.003] [PMID: 24440181]
[10]
Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: A double-blind, randomised, phase 3 trial. Lancet 2019; 394(10212): 1940-8.
[http://dx.doi.org/10.1016/S0140-6736(19)32597-8] [PMID: 31679946]
[11]
Farinha CM, Canato S. From the endoplasmic reticulum to the plasma membrane: Mechanisms of CFTR folding and trafficking. Cell Mol Life Sci 2017; 74(1): 39-55.
[http://dx.doi.org/10.1007/s00018-016-2387-7] [PMID: 27699454]
[12]
AbdulWahab A. AlNaimi A, Habra B, Janahi I. First report of the cystic fibrosis transmembrane conductance regulator mutation c.1521_1523delCTT (p. Phe508del) in two Qatari patients with cystic fibrosis. Qatar Med J 2021; 2021(2): 24.
[http://dx.doi.org/10.5339/qmj.2021.24] [PMID: 34377682]
[13]
Jih KY, Li M, Hwang TC, Bompadre SG. The most common cystic fibrosis-associated mutation destabilizes the dimeric state of the nucleotide-binding domains of CFTR. J Physiol 2011; 589(11): 2719-31.
[http://dx.doi.org/10.1113/jphysiol.2010.202861] [PMID: 21486785]
[14]
Gramegna A, Contarini M, Aliberti S, Casciaro R, Blasi F, Castellani C. From ivacaftor to triple combination: A systematic review of efficacy and safety of CFTR modulators in people with cystic fibrosis. Int J Mol Sci 2020; 21(16): 5882.
[http://dx.doi.org/10.3390/ijms21165882] [PMID: 32824306]
[15]
Keating D, Marigowda G, Burr L, et al. VX-445–Tezacaftor–ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018; 379(17): 1612-20.
[http://dx.doi.org/10.1056/NEJMoa1807120] [PMID: 30334692]
[16]
Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor–ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med 2017; 377(21): 2024-35.
[http://dx.doi.org/10.1056/NEJMoa1709847] [PMID: 29099333]
[17]
Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013; 187(11): 1219-25.
[http://dx.doi.org/10.1164/rccm.201301-0153OC] [PMID: 23590265]
[18]
Moss RB, Flume PA, Elborn JS, et al. Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: A double-blind, randomised controlled trial. Lancet Respir Med 2015; 3(7): 524-33.
[http://dx.doi.org/10.1016/S2213-2600(15)00201-5] [PMID: 26070913]
[19]
Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019; 381(19): 1809-19.
[http://dx.doi.org/10.1056/NEJMoa1908639] [PMID: 31697873]
[20]
Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365(18): 1663-72.
[http://dx.doi.org/10.1056/NEJMoa1105185] [PMID: 22047557]
[21]
Laselva O, Bartlett C, Gunawardena TNA, et al. Rescue of multiple class II CFTR mutations by elexacaftor+tezacaftor+ivacaftor mediated in part by the dual activities of elexacaftor as both corrector and potentiator. Eur Respir J 2021; 57(6): 2002774.
[http://dx.doi.org/10.1183/13993003.02774-2020] [PMID: 33303536]
[22]
Veit G, Roldan A, Hancock MA, et al. Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination. JCI Insight 2020; 5(18): e139983.
[http://dx.doi.org/10.1172/jci.insight.139983] [PMID: 32853178]
[22a]
Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 2018; 27(6): 1785-805.
[http://dx.doi.org/10.1177/0962280216669183]
[22b]
Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014; 14: 1-3.
[http://dx.doi.org/10.1186/1471-2288-14-135]
[23]
Rowe SM, Miller S, Sorscher EJ. Cystic Fibrosis. N Engl J Med 2005; 352(19): 1992-2001.
[http://dx.doi.org/10.1056/NEJMra043184] [PMID: 15888700]
[24]
Flume PA, Liou TG, Borowitz DS, et al. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 2012; 142(3): 718-24.
[http://dx.doi.org/10.1378/chest.11-2672] [PMID: 22383668]
[25]
Taylor-Cousar JL, Mall MA, Ramsey BW, et al. Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles. ERJ Open Res 2019; 5(2): 00082-2019.
[http://dx.doi.org/10.1183/23120541.00082-2019] [PMID: 31218221]
[26]
Munck A, Kerem E, Ellemunter H, et al. Tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for minimal function CFTR mutations. J Cyst Fibros 2020; 19(6): 962-8.
[http://dx.doi.org/10.1016/j.jcf.2020.04.015] [PMID: 32546431]
[27]
Rink S. Janić M, Lunder M, Šabovič M, Salobir B. Effect of elexacaftor-tezacaftor-ivacaftor on pulmonary and endothelial function in a patient with advanced cystic fibrosis. ERJ Open Res 2021; 7(S6)
[http://dx.doi.org/10.1183/23120541.LSC-2021.104]
[28]
Bermingham B,A R, G R, et al. Short-term effect of elexacaftor-tezacaftor-ivacaftor on lung function and transplant planning in cystic fibrosis patients with advanced lung disease. J Cyst Fibros 2021; 20(5): 768-71.
[http://dx.doi.org/10.1016/j.jcf.2021.05.009] [PMID: 34162524]
[29]
Rowe SM, McColley SA, Rietschel E, et al. Lumacaftor/ivacaftor treatment of patients with cystic fibrosis heterozygous for F508del-CFTR. Ann Am Thorac Soc 2017; 14(2): 213-9.
[http://dx.doi.org/10.1513/AnnalsATS.201609-689OC] [PMID: 27898234]
[30]
Clancy JP. Rapid therapeutic advances in CFTR modulator science. Pediatr Pulmonol 2018; 53(S3): S4-S11.
[http://dx.doi.org/10.1002/ppul.24157] [PMID: 30289627]
[31]
Donaldson SH. Tezacaftor/ivacaftor in subjects with cystic fibrosis and F508del/F508del-CFTR or F508del/G551D-CFTR. Am J Respir Crit Care Med 2018; 197(2): 214-24.
[http://dx.doi.org/10.1164/rccm.201704-0717OC]
[32]
Bell SC, Mall MA, Gutierrez H, et al. The future of cystic fibrosis care: A global perspective. Lancet Respir Med 2020; 8(1): 65-124.
[http://dx.doi.org/10.1016/S2213-2600(19)30337-6] [PMID: 31570318]
[33]
Schwarz C, Sutharsan S, Epaud R, et al. Tezacaftor/ivacaftor in people with cystic fibrosis who stopped lumacaftor/ivacaftor due to respiratory adverse events. J Cyst Fibros 2021; 20(2): 228-33.
[http://dx.doi.org/10.1016/j.jcf.2020.06.001] [PMID: 32586736]
[34]
Burgel PR, Durieu I, Chiron R, Ramel S, Danner-Boucher I, Prevotat A, et al. Rapid improvement after starting elexacaftor–tezacaftor–ivacaftor in patients with cystic fibrosis and advanced pulmonary disease. Am J Respir Crit Care Med 2021; 204(1): 64-73.
[http://dx.doi.org/10.1164/rccm.202011-4153OC]
[35]
Davies JC, Sermet-Gaudelus I, Naehrlich L, Harris RS, Campbell D, Ahluwalia N, et al. A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation. J Cyst Fibros 2021; 20(1): 68-77.
[http://dx.doi.org/10.1016/j.jcf.2020.07.023]

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