A Retrospective, Longitudinal Registry Study on the Long-Term Durability of Ivacaftor Treatment in People with Cystic Fibrosis

Overview

Journal Pulm Ther

Publisher Springer

Date 2024 Sep 12

PMID 39266929

Authors

Christian Merlo

Teja Thorat

Lisa J McGarry

Christina V Scirica

Maral DerSarkissian

Catherine Nguyen

Yuqian M Gu

Aruna Muthukumar

Joe Healy

Jaime L Rubin

M Alan Brookhart

Affiliations

Soon will be listed here.

Abstract

Introduction: Ivacaftor (IVA) has been shown to change the trajectory of cystic fibrosis (CF) disease progression by slowing the rate of lung function decline in clinical studies. Long-term real-world data help to confirm the durability of this response.

Methods: This non-interventional, longitudinal study used data from the US CF Foundation Patient Registry to describe the annualized rate of change in lung function in people with CF receiving IVA. The IVA-treated cohort included people with CF aged ≥ 6 years who had ≥ 1 CF transmembrane conductance regulator (CFTR)-gating mutation and initiated IVA between 31 January 2012 and 31 December 2018. An age-matched comparator cohort included people with CF heterozygous for the F508del-CFTR mutation and a minimal function mutation (R117H excluded) and had not received CFTR modulator therapy. Baseline characteristics were balanced using standardized mortality ratio (SMR) weights computed from estimated propensity scores. The annualized rate of change in percent predicted forced expiratory volume in 1 s (ppFEV) was estimated over 5 years and used to calculate the relative annualized rate of change in lung function in the IVA-treated versus comparator cohorts.

Results: In the 5-year follow-up period, 548 people were in the IVA-treated and 541 in the comparator cohorts after SMR weighting. The annualized rate of change in ppFEV over 5 years was -1.23 (95% CI -1.45, -1.03) and -2.03 (-2.16, -1.90) percentage points in the IVA-treated and comparator cohorts, respectively. There was a 39% reduction (95% CI: 28, 50) in the rate of lung function decline in the IVA-treated versus comparator cohort over 5 years. Findings were generally consistent with those of shorter follow-up periods.

Conclusion: IVA showed a durable clinical benefit by slowing the rate of lung function decline over 5 years. Results support a sustained and consistent impact of IVA on lung function trajectory in people with CF. Word count: 300 (limit: 300 words).

References

Davies J, Wainwright C, Canny G, Chilvers M, Howenstine M, Munck A . 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. PMC: 3734608. DOI: 10.1164/rccm.201301-0153OC. View

Merlo C, Thorat T, DerSarkissian M, McGarry L, Nguyen C, Gu Y . Long-term impact of ivacaftor on mortality rate and health outcomes in people with cystic fibrosis. Thorax. 2024; 79(10):925-933. PMC: 11503052. DOI: 10.1136/thorax-2023-220558. View

Knapp E, Fink A, Goss C, Sewall A, Ostrenga J, Dowd C . The Cystic Fibrosis Foundation Patient Registry. Design and Methods of a National Observational Disease Registry. Ann Am Thorac Soc. 2016; 13(7):1173-9. DOI: 10.1513/AnnalsATS.201511-781OC. View

Corey M, Edwards L, Levison H, Knowles M . Longitudinal analysis of pulmonary function decline in patients with cystic fibrosis. J Pediatr. 1998; 131(6):809-14. DOI: 10.1016/s0022-3476(97)70025-8. View

De Boeck K, Munck A, Walker S, Faro A, Hiatt P, Gilmartin G . Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014; 13(6):674-80. DOI: 10.1016/j.jcf.2014.09.005. View

Sawicki G, McKone E, Pasta D, Millar S, Wagener J, Johnson C . Sustained Benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data. Am J Respir Crit Care Med. 2015; 192(7):836-42. DOI: 10.1164/rccm.201503-0578OC. View

Liou T, Elkin E, Pasta D, Jacobs J, Konstan M, Morgan W . Year-to-year changes in lung function in individuals with cystic fibrosis. J Cyst Fibros. 2010; 9(4):250-6. PMC: 4102928. DOI: 10.1016/j.jcf.2010.04.002. View

Quanjer P, Stanojevic S, Cole T, Baur X, Hall G, Culver B . Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012; 40(6):1324-43. PMC: 3786581. DOI: 10.1183/09031936.00080312. View

Lee T, Sawicki G, Altenburg J, Millar S, Geiger J, Jennings M . EFFECT OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON ANNUAL RATE OF LUNG FUNCTION DECLINE IN PEOPLE WITH CYSTIC FIBROSIS. J Cyst Fibros. 2022; 22(3):402-406. DOI: 10.1016/j.jcf.2022.12.009. View

10.

Brookhart M, Wyss R, Layton J, Sturmer T . Propensity score methods for confounding control in nonexperimental research. Circ Cardiovasc Qual Outcomes. 2013; 6(5):604-11. PMC: 4032088. DOI: 10.1161/CIRCOUTCOMES.113.000359. View

11.

Austin P . Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009; 28(25):3083-107. PMC: 3472075. DOI: 10.1002/sim.3697. View

12.

Moss R, Flume P, Elborn J, Cooke J, Rowe S, McColley S . 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. PMC: 4641035. DOI: 10.1016/S2213-2600(15)00201-5. View

13.

Konstan M, Wagener J, VanDevanter D . Characterizing aggressiveness and predicting future progression of CF lung disease. J Cyst Fibros. 2009; 8 Suppl 1:S15-9. PMC: 4167362. DOI: 10.1016/S1569-1993(09)60006-0. View

14.

Bell S, Mall M, Gutierrez H, Macek M, Madge S, Davies J . The future of cystic fibrosis care: a global perspective. Lancet Respir Med. 2019; 8(1):65-124. PMC: 8862661. DOI: 10.1016/S2213-2600(19)30337-6. View

15.

Kirwan L, Fletcher G, Harrington M, Jeleniewska P, Zhou S, Casserly B . Longitudinal Trends in Real-World Outcomes after Initiation of Ivacaftor. A Cohort Study from the Cystic Fibrosis Registry of Ireland. Ann Am Thorac Soc. 2018; 16(2):209-216. DOI: 10.1513/AnnalsATS.201802-149OC. View

16.

Ramsey B, Davies J, McElvaney N, Tullis E, Bell S, Drevinek P . A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011; 365(18):1663-72. PMC: 3230303. DOI: 10.1056/NEJMoa1105185. View