Comparative Efficacy of CFTR Modulators: A Network Meta-analysis.
Imran Hasan Iftikhar, Saad T Rao, Rufai Nadama, Ibrahim Janahi, Ahmed S BaHammam
Author Information
Imran Hasan Iftikhar: Department of Medicine, Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Emory University School of Medicine, 613 Michael St, NE, Atlanta, GA, USA. imran.hasan.iftikhar@emory.edu. ORCID
Saad T Rao: Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Pakistan.
Rufai Nadama: Pulmonary Division, King Khalid University Hospital, Riyadh, Kingdom of Saudi Arabia.
Ibrahim Janahi: Pediatric Pulmonology, Pediatric Medicine, Sidra Medicine, Doha, Qatar.
Ahmed S BaHammam: Department of Medicine, University Sleep Disorders Center, and Pulmonary Service, King Saud University, Riyadh, Kingdom of Saudi Arabia.
PURPOSE: The objective was to study comparative efficacies of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, vanzacaftor-tezacaftor-deutivacaftor (VTD), elexacaftor-tezacaftor-ivacaftor (ETI), tezacaftor-ivacaftor (Tez-Iva), and lumacaftor-ivacaftor (Lum-Iva) in people with cystic fibrosis (pwCF), aged ≥ 12 years, carrying at least one F508del-CFTR-allele. METHODS: Data from randomized controlled or randomized active comparator trials were included in this network meta-analysis which used frequentist approach for comparing the efficacy of drugs and ranking based on P-scores. Outcomes of interest were mean differences in percentage-predicted forced expiratory volume in one second (ppFEV), CF questionnaire-revised respiratory domain (CFQ-R) scores, sweat chloride (SwCl) levels, and odds ratios (OR) for serious adverse events (SAE). RESULTS: Data from 13 studies were analyzed. Compared to placebo, the effects of VTD and ETI on ppFEV1 were almost quadruple of Tez-Iva and Lum-Iva (VTD: 12.78 [95% confidence intervals: 6.41; 19.15] and ETI: 11.95 [7.40; 16.50]) and almost seven times of Tez-Iva and Lum-Iva for CFQ-R (VTD: 21.23 [- 28.72; 71.18] and ETI: 19.27 [10.56; 27.98]). A statistically significant difference was noted between VTD and ETI in SwCl reduction (mean difference: - 8.59 [- 15.53; - 1.65]). There were no statistically significant ORs for SAEs for any CFTR modulators but VTD, ETI, and Tez-Iva were least associated with SAEs (ORs were 0.15 [0.01; 1.79], 0.49 [0.31; 0.78], and 0.74 [0.50; 1.09], respectively, as compared to placebo). Overall, P-score ranking ranked VTD as first and ETI as second, followed by others. CONCLUSION: VTD and ETI were more efficacious than Tez-Iva and Lum-Iva in pwCF with at least one F508del-CFTR-allele.
Shteinberg M, Haq IJ, Polineni D, Davies JC (2021) Cystic fibrosis. Lancet 397:2195–2211
[DOI: 10.1016/S0140-6736(20)32542-3]
Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245:1073–1080
[DOI: 10.1126/science.2570460]
Pereira SV, Ribeiro JD, Ribeiro AF, Bertuzzo CS, Marson FAL (2019) Novel, rare and common pathogenic variants in the CFTR gene screened by high-throughput sequencing technology and predicted by in silico tools. Sci Rep 9:6234
[DOI: 10.1038/s41598-019-42404-6]
Boyle MP, De Boeck K (2013) A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med 1:158–163
[DOI: 10.1016/S2213-2600(12)70057-7]
Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, Sagel SD, Khan U, Mayer-Hamblett N, Van Dalfsen JM, Joseloff E, Ramsey BW, Network GIotCFFTD (2014) Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 190:175–184
[DOI: 10.1164/rccm.201404-0703OC]
Taylor-Cousar JL, Munck A, McKone EF, van der Ent CK, Moeller A, Simard C, Wang LT, Ingenito EP, McKee C, Lu Y, Lekstrom-Himes J, Elborn JS (2017) Tezacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med 377:2013–2023
[DOI: 10.1056/NEJMoa1709846]
Wainwright CE, Elborn JS, Ramsey BW (2015) Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 373:1783–1784
[DOI: 10.1056/NEJMoa1409547]
Uluer AZ, MacGregor G, Azevedo P, Indihar V, Keating C, Mall MA, McKone EF, Ramsey BW, Rowe SM, Rubenstein RC, Taylor-Cousar JL, Tullis E, Yonker LM, Chu C, Lam AP, Nair N, Sosnay PR, Tian S, Van Goor F, Viswanathan L, Waltz D, Wang LT, Xi Y, Billings J, Horsley A, Vx, Groups VXS (2023) Safety and efficacy of vanzacaftor-tezacaftor-deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials. Lancet Respir Med 11:550–562
[DOI: 10.1016/S2213-2600(22)00504-5]
Heijerman HGM, McKone EF, Downey DG, Van Braeckel E, Rowe SM, Tullis E, Mall MA, Welter JJ, Ramsey BW, McKee CM, Marigowda G, Moskowitz SM, Waltz D, Sosnay PR, Simard C, Ahluwalia N, Xuan F, Zhang Y, Taylor-Cousar JL, McCoy KS, Group VXT (2019) 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 394:1940–1948
[DOI: 10.1016/S0140-6736(19)32597-8]
Middleton PG, Mall MA, Drevinek P, Lands LC, McKone EF, Polineni D, Ramsey BW, Taylor-Cousar JL, Tullis E, Vermeulen F, Marigowda G, McKee CM, Moskowitz SM, Nair N, Savage J, Simard C, Tian S, Waltz D, Xuan F, Rowe SM, Jain R, Group VXS (2019) Elexacaftor-Tezacaftor-Ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 381:1809–1819
[DOI: 10.1056/NEJMoa1908639]
Sutharsan S, McKone EF, Downey DG, Duckers J, MacGregor G, Tullis E, Van Braeckel E, Wainwright CE, Watson D, Ahluwalia N, Bruinsma BG, Harris C, Lam AP, Lou Y, Moskowitz SM, Tian S, Yuan J, Waltz D, Mall MA, Group VXS (2022) Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial. Lancet Respir Med 10:267–277
[DOI: 10.1016/S2213-2600(21)00454-9]
Taylor-Cousar JL, Mall MA, Ramsey BW, McKone EF, Tullis E, Marigowda G, McKee CM, Waltz D, Moskowitz SM, Savage J, Xuan F, Rowe SM (2019) Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles. ERJ Open Res. https://doi.org/10.1183/23120541.00082-2019
[DOI: 10.1183/23120541.00082-2019]
Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP, Mulrow C, Catala-Lopez F, Gotzsche PC, Dickersin K, Boutron I, Altman DG, Moher D (2015) The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med 162:777–784
[DOI: 10.7326/M14-2385]
Schwarzer GCJ, Rücker G (2015) Meta-Analysis with R. Springer, Cham
[DOI: 10.1007/978-3-319-21416-0]
Nikolakopoulou A, Higgins JPT, Papakonstantinou T, Chaimani A, Del Giovane C, Egger M, Salanti G (2020) CINeMA: an approach for assessing confidence in the results of a network meta-analysis. PLoS Med 17:e1003082
[DOI: 10.1371/journal.pmed.1003082]
Barry PJ, Mall MA, Alvarez A, Colombo C, de Winter-de Groot KM, Fajac I, McBennett KA, McKone EF, Ramsey BW, Sutharsan S, Taylor-Cousar JL, Tullis E, Ahluwalia N, Jun LS, Moskowitz SM, Prieto-Centurion V, Tian S, Waltz D, Xuan F, Zhang Y, Rowe SM, Polineni D, Group VXS (2021) Triple therapy for cystic fibrosis Phe508del-gating and -residual function genotypes. N Engl J Med 385:815–825
[DOI: 10.1056/NEJMoa2100665]
Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, Huang X, Waltz D, Patel NR, Rodman D, Group VXS (2014) A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med 2:527–538
[DOI: 10.1016/S2213-2600(14)70132-8]
Keating C YL, Vermeulen F, Prais D, Linnemann R, Trimble A, Kotsimbos T, Mermis J, Braun A, O’Carroll M, Sutharsan S, Ramsey B, Mall M, Taylor-Cousar J, McKone E, Tullis E, Floreth T, Michelson P, Nair N, Yi B, Martin H, Ahluwalia N, Lam A, Horsley A., editor Vanzacaftor/tezacaftor/deutivacaftor in adolescents and adults with cystic fibrosis: results from two randomized, active-controlled phase 3 trials. J Cyst Fibros. 23S2 (2024) S1–S505. North American Cystic Fibrosis Conference (September 2024); 2024; Boston, Massachusetts: Journal of Cystic Fibrosis. 23S2 (2024) S1–S505.
Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, Ramsey BW, Rowe SM, Sass LA, Tullis E, McKee CM, Moskowitz SM, Robertson S, Savage J, Simard C, Van Goor F, Waltz D, Xuan F, Young T, Taylor-Cousar JL, Group VXS (2018) VX-445-Tezacaftor-Ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 379:1612–1620
[DOI: 10.1056/NEJMoa1807120]
Konstan MW, McKone EF, Moss RB, Marigowda G, Tian S, Waltz D, Huang X, Lubarsky B, Rubin J, Millar SJ, Pasta DJ, Mayer-Hamblett N, Goss CH, Morgan W, Sawicki GS (2017) Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): a phase 3, extension study. Lancet Respir Med 5:107–118
[DOI: 10.1016/S2213-2600(16)30427-1]
McKone EF, DiMango EA, Sutharsan S, Barto TL, Campbell D, Ahluwalia N, Higgins M, Owen CA, Tullis E (2021) A phase 3, randomized, double-blind, parallel-group study to evaluate tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for F508del-CFTR and a gating mutation. J Cyst Fibros 20:234–242
[DOI: 10.1016/j.jcf.2020.11.003]
Munck A, Kerem E, Ellemunter H, Campbell D, Wang LT, Ahluwalia N, Owen CA, Wainwright C (2020) Tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for minimal function CFTR mutations. J Cyst Fibros 19:962–968
[DOI: 10.1016/j.jcf.2020.04.015]
Rowe SM, McColley SA, Rietschel E, Li X, Bell SC, Konstan MW, Marigowda G, Waltz D, Boyle MP, Group VXS (2017) Lumacaftor/ivacaftor treatment of patients with cystic fibrosis heterozygous for F508del-CFTR. Ann Am Thorac Soc 14:213–219
[DOI: 10.1513/AnnalsATS.201609-689OC]
Fidler MC, Beusmans J, Panorchan P, Van Goor F (2017) Correlation of sweat chloride and percent predicted FEV(1) in cystic fibrosis patients treated with ivacaftor. J Cyst Fibros 16:41–44
[DOI: 10.1016/j.jcf.2016.10.002]
McKone EF, Velentgas P, Swenson AJ, Goss CH (2015) Association of sweat chloride concentration at time of diagnosis and CFTR genotype with mortality and cystic fibrosis phenotype. J Cyst Fibros 14:580–586
[DOI: 10.1016/j.jcf.2015.01.005]
Burgel PR, Sermet-Gaudelus I, Durieu I, Kanaan R, Macey J, Grenet D, Porzio M, Coolen-Allou N, Chiron R, Marguet C, Douvry B, Dufeu N, Danner-Boucher I, Foucaud P, Lemonnier L, Girodon E, Da Silva J, Martin C, French CFRNsg (2023) The French Compassionate Program of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis with advanced lung disease and no F508del CFTR variant. Eur Respir J. https://doi.org/10.1183/13993003.02437-2022
[DOI: 10.1183/13993003.02437-2022]
McCoy KS, Blind J, Johnson T, Olson P, Raterman L, Bai S, Eisner M, Sheikh SI, Druhan S, Young C, Pasley K (2023) Clinical change 2 years from start of elexacaftor-tezacaftor-ivacaftor in severe cystic fibrosis. Pediatr Pulmonol 58:1178–1184
[DOI: 10.1002/ppul.26318]
Dittrich AM, Sieber S, Naehrlich L, Burkhart M, Hafkemeyer S, Tummler B, Registry Working Group of the German CFR (2024) Use of elexacaftor/tezacaftor/ivacaftor leads to changes in detection frequencies of Staphylococcus aureus and Pseudomonas aeruginosa dependent on age and lung function in people with cystic fibrosis. Int J Infect Dis 139:124–131
[DOI: 10.1016/j.ijid.2023.11.013]
Duehlmeyer S, Elson EC, Oermann CM (2024) Effect of Elexacaftor/Tezacaftor/Ivacaftor on Pseudomonas aeruginosa acquisition and chronic infection at a single pediatric cystic fibrosis care center. J Pediatr Pharmacol Ther 29:135–139
[PMID: 38596420]
Bower JK, Volkova N, Ahluwalia N, Sahota G, Xuan F, Chin A, Weinstock TG, Ostrenga J, Elbert A (2023) Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: Interim results of a long-term registry-based study. J Cyst Fibros 22:730–737
[DOI: 10.1016/j.jcf.2023.03.002]
Wiesel V, Aviram M, Mei-Zahav M, Dotan M, Prais D, Cohen-Cymberknoh M, Gur M, Bar-Yoseph R, Livnat G, Goldbart A, Hazan G, Hazan I, Golan-Tripto I (2024) Eradication of nontuberculous mycobacteria in people with cystic fibrosis treated with Elexacaftor/Tezacaftor/Ivacaftor: a multicenter cohort study. J Cyst Fibros 23:41–49
[DOI: 10.1016/j.jcf.2023.05.003]
Lopez A, Daly C, Vega-Hernandez G, MacGregor G, Rubin JL (2023) Elexacaftor/tezacaftor/ivacaftor projected survival and long-term health outcomes in people with cystic fibrosis homozygous for F508del. J Cyst Fibros 22:607–614
[DOI: 10.1016/j.jcf.2023.02.004]
Mayer-Hamblett N, Clancy JP, Jain R, Donaldson SH, Fajac I, Goss CH, Polineni D, Ratjen F, Quon BS, Zemanick ET, Bell SC, Davies JC, Jain M, Konstan MW, Kerper NR, LaRosa T, Mall MA, McKone E, Pearson K, Pilewski JM, Quittell L, Rayment JH, Rowe SM, Taylor-Cousar JL, Retsch-Bogart G, Downey DG (2023) Advancing the pipeline of cystic fibrosis clinical trials: a new roadmap with a global trial network perspective. Lancet Respir Med 11:932–944
[DOI: 10.1016/S2213-2600(23)00297-7]
Zampoli M, Kashirskaya N, Karadag B, Filho L, Paul GR, Noke C (2022) Global access to affordable CFTR modulator drugs: time for action! J Cyst Fibros 21:e215–e216
[DOI: 10.1016/j.jcf.2022.03.006]
