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Correlation of sweat chloride and percent predicted FEV1 in cystic fibrosis patients treated with ivacaftor www elsevier com/locate/jcf Journal of Cystic Fibrosis xx (2016) xxx–xxx JCF 01390; No of Pa[.]
JCF-01390; No of Pages Journal of Cystic Fibrosis xx (2016) xxx – xxx www.elsevier.com/locate/jcf Short Communication Correlation of sweat chloride and percent predicted FEV1 in cystic fibrosis patients treated with ivacaftor☆ Meredith C Fidler a,⁎, Jack Beusmans b , Paul Panorchan b , Fredrick Van Goor a a Vertex Pharmaceuticals LLC, 11010 Torreyanna Road, San Diego, CA 92121,USA Vertex Pharmaceuticals Incorporated, 50 Northern Ave, Boston, MA 02210, USA b Received August 2016; revised 30 September 2016; accepted October 2016 Abstract Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations Several previous analyses have reported no statistical correlation between change from baseline in ppFEV1 and reduction in sweat chloride levels for individuals treated with ivacaftor The objective of the post hoc analysis described here was to expand upon previous analyses and evaluate the correlation between sweat chloride levels and absolute ppFEV1 changes across multiple cohorts of patients with different CF-causing mutations who were treated with ivacaftor The goal of the analysis was to help define the potential value of sweat chloride as a pharmacodynamic biomarker for use in CFTR modulator trials For any given study, reductions in sweat chloride levels and improvements in absolute ppFEV1 were not correlated for individual patients However, when the data from all studies were combined, a statistically significant correlation between sweat chloride levels and ppFEV1 changes was observed (p b 0.0001) Thus, sweat chloride level changes in response to potentiation of the CFTR protein by ivacaftor appear to be a predictive pharmacodynamic biomarker of lung function changes on a population basis but are unsuitable for the prediction of treatment benefits for individuals © 2016 The Authors Published by Elsevier B.V on behalf of European Cystic Fibrosis Society This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Keywords: Cystic fibrosis; Ivacaftor; Sweat chloride; FEV1 Cystic fibrosis (CF) is an autosomal recessive hereditary multi-organ disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene [1,2] CFTR regulates ion flux at the surface of certain epithelial cells, and the decreased Abbreviations: CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator; CI, confidence interval; ppFEV1, percent predicted forced expiratory volume in s; q12h, every 12 h ☆ Previous Presentations: A portion of the data in this manuscript was presented previously at the 2015 NACFC annual meeting and is cited as: Fidler M, Beusmans J, Panorchan P, Van Goor F Correlation of sweat chloride and percent predicted FEV1 in cystic fibrosis patients treated with ivacaftor Pediatr Pulmonol 2015:50, S41, S193–S453 ⁎ Corresponding author at: Human Biology, Vertex Pharmaceuticals Incorporated, 11010 Torreyanna Road, San Diego, CA 92121, USA E-mail address: Meredith_fidler@vrtx.com (M.C Fidler) CFTR-mediated ion transport in CF results in a wide range of symptoms, including abnormal electrolyte concentrations in the sweat of patients with CF [3] Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations [4–8] In a Phase study of patients carrying the G551D mutation on at least one allele, administration of ivacaftor resulted in an early and substantial mean decrease in sweat chloride levels, as well as early improvements in lung function as measured by percent predicted forced expiratory volume in s (ppFEV1) [9,10] A dose-dependent effect was seen on sweat chloride levels with ivacaftor treatment (25 mg to 250 mg) in this trial [10], suggesting that sweat chloride may also correlate with ppFEV1 Seliger et al conducted a post hoc analysis of two double-blind, multicenter studies to investigate the value of sweat http://dx.doi.org/10.1016/j.jcf.2016.10.002 1569-1993/© 2016 The Authors Published by Elsevier B.V on behalf of European Cystic Fibrosis Society This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Please cite this article as: Fidler MC, et al, Correlation of sweat chloride and percent predicted FEV1 in cystic fibrosis patients treated with ivacaftor, J Cyst Fibros (2016), http://dx.doi.org/10.1016/j.jcf.2016.10.002 M.C Fidler et al / Journal of Cystic Fibrosis xx (2016) xxx–xxx chloride level changes in predicting improvements in pulmonary function in individuals with CF carrying at least one copy of the G551D–CFTR mutation treated with ivacaftor [4,5,11] The analysis showed no statistical correlation between change from baseline in ppFEV1 and reduction in sweat chloride levels for individuals [11], thus confirming data previously published by Durmowitz et al [12] The efficacy of ivacaftor has also been evaluated in patients harboring numerous other mutations [7,8] who were predicted to respond to ivacaftor therapy based on in vitro data [13] and in patients homozygous for the F508del mutation [6] who were not expected to show a clinically meaningful response based on in vitro response data [13] The objective of the post hoc analysis described here was to expand upon previous analyses and evaluate the correlation between sweat chloride levels and absolute ppFEV1 changes across multiple cohorts of patients with different CF-causing mutations who were treated with ivacaftor The goal of the analysis was to help define the potential value of sweat chloride as a pharmacodynamic biomarker for use in CFTR modulator trials Eight Phase and clinical studies contributed data to this analysis of the relationship between sweat chloride levels and ppFEV1 among patients with CF treated for at least 14 days with ivacaftor monotherapy Trial information and treatment details for the eight studies are shown in Table For any given study, reductions in sweat chloride levels and improvements in absolute ppFEV1 were not correlated for individual patients [6] However, when the data from all studies were combined, a statistically significant correlation between sweat chloride levels and ppFEV1 changes was observed (p b 0.0001) In Fig 1, each data point corresponds to a particular study and dose and marks the mean absolute change from baseline (and 95% confidence interval [CI]) Only patients with complete data, i.e, who had baseline and end-of-treatment values for ppFEV1 and sweat chloride were included in the analyses For study 110 (R117H) [7] patients aged b 18 years were excluded since baseline FEV1 values were considered normal; the remaining patients were stratified according to their confirmed 5T/7T status and plotted separately in the graph Patients in study 111 had a mixed group of non-G551D gating CFTR mutations [8] Responses in patients with the G970R mutation, excluded from the analyses, were not consistent with those seen in the other gating mutations and research into this mutation type is ongoing Each data point corresponds to a particular study and shows the mean absolute change (and its 95% CI) from baseline in percentage points for FEV1 In all studies, patients were treated with ivacaftor 150 mg q12h, except for study 101 in which patients were treated with one of four doses of ivacaftor (25, 75, 150, or 250 mg) q12h plotted individually Relative sample size is indicated by symbol size in the figure Solid line shows the fit of the weighted linear model (weighted by number of patients in each study); r2 = 0.889, p b 0.0001, slope = − 0.168 [95% CI: − 0.21, − 0.13], intercept = 0.95 [95% CI: − 0.56, 2.51] Dashed lines show the 95% CI of the fit CF, cystic fibrosis; CI, confidence interval; ppFEV1, percent predicted forced expiratory volume in s; q12h, every 12 h Fig depicts the absolute changes from baseline in ppFEV1 and sweat chloride levels for each individual patient enrolled in the eight clinical trials analyzed The statistically significant correlation between sweat chloride levels and ppFEV1 changes observed for mean values across the full dataset of studies was also observed for individual changes (p b 0.0001, for both) Each data point corresponds to an individual study participant and shows the absolute change from baseline in percentage points for FEV1 plotted against absolute change in sweat chloride Straight lines show fit obtained by linear regression Contours correspond to levels of data density and show consistent correlation and reinforce the observed trend line The red line represents the LOESS regression In all studies, patients were treated with ivacaftor 150 mg q12h, except for study 101 in which patients were treated with four doses of ivacaftor (25, 75, 150, or 250 mg) q12h Pearson correlation: − 0.339 [95% CI: − 0.429, − 0.241]; linear fit: slope = − 0.115, intercept = 2.48, p b 0.0001 Table Study-level features of the post hoc analysis describing the correlation between sweat chloride levels and absolute ppFEV1 changes in patients with CF who received ivacaftor in clinical studies Na Mutation Treatment regimen VX770-101 [10] ≥18 42 G551D VX770-102 [4] VX770-103 [5] VX770-104 [6] VX770-106 [14] VX770-110 [7] ≥12 6–11 ≥12 ≥6 ≥6 Patients aged b18 years were excluded from analysis c ≥6 ≥12 78 23 107 17 18 G551D G551D F508del homozygous G551D R117H Part A: ivacaftor 25, 50, 75, or 150 mg q12h for 14 d Part B: ivacaftor 150 or 250 mg q12h for 28 d Ivacaftor 150 mg q12h for 48 wks Ivacaftor 150 mg q12h for 48 wks Ivacaftor 150 mg q12h for 16 wks b Ivacaftor 150 mg q12h for 28 days Ivacaftor 150 mg q12h for 24 wks b 32 21 All non-G551D gating mutations except G970R Ivacaftor 150 mg q12h for wks b Clinical evidence of CFTR residual function Ivacaftor 150 mg q12h Trial identification number Age (y) VX770-111 [8] VX770-113 [14] CF, cystic fibrosis; ppFEV1, percent predicted forced expiratory volume in s; q12h, every 12 h a Of the 353 patients identified, 338 patients had baseline and end-of-treatment values for ppFEV1 and sweat chloride and were included in the analyses Four patients with G970R were excluded, as were patients with R117H who did not have confirmed 5T or 7T status b Eligible patients had the opportunity to participate in an open-label extension study c Remaining patients were stratified according to confirmed 5T/7T status One outlying patient with an immediate and continuing decrease of N20% in ppFEV1 who discontinued after week was excluded Please cite this article as: Fidler MC, et al, Correlation of sweat chloride and percent predicted FEV1 in cystic fibrosis patients treated with ivacaftor, J Cyst Fibros (2016), http://dx.doi.org/10.1016/j.jcf.2016.10.002 M.C Fidler et al / Journal of Cystic Fibrosis xx (2016) xxx–xxx G551D (Study 101) G551D (Study 102) G551D (Study 103) G551D (Study 106) non-G551D (Study 111) 20 ppFEV1, absolute change (%) 15 F508del (Study 104) R117H 5T (Study 110) R117H 7T (Study 110) Residual Function (Study 113) 10 -70 -60 -50 -40 -30 -20 -10 Sweat chloride, absolute change (mmol/L) Fig Correlation between absolute change from baseline of ppFEV1 and sweat chloride level (mmol/L) in patients with CF treated with ivacaftor to the multiplicity of factors affecting lung function, including (but not limited to) irreversible lung tissue damage, pulmonary exacerbation rates, and long-term treatment adherence Unlike the lung, CFTR dysfunction in the sweat gland does not lead to tissue damage, and sweat chloride levels remain relatively constant, with small increases possible from birth through age 12, followed by decreases thereafter [15] A recent analysis of twins/siblings with CF concluded that while CFTR mutation was the predominant contributor to variability in sweat chloride, environmental factors and test variability contributed up to 23% of the variability observed [16] Furthermore, sweat chloride level changes are very sensitive to short-term treatment adherence, and missed doses prior to testing have been shown to affect testing results [17] In conclusion, sweat chloride level changes in response to potentiation of the CFTR protein by ivacaftor appear to be a predictive pharmacodynamic biomarker of lung function changes on a population basis but are unsuitable for the prediction of treatment benefits for individuals Conflicts of interest CF, cystic fibrosis; CI, confidence interval; ppFEV1, percent predicted forced expiratory volume in s; q12h, every 12 h A combined analysis of data from eight clinical trials evaluating ivacaftor monotherapy in patients with CF showed that, over a wide range of sweat chloride responses to treatment, a statistically significant association can be detected with absolute percentage point changes in ppFEV1 This correlation may be useful for predicting mean treatment effects in clinical trials based on mean sweat chloride changes However, more experimental and real-world data would be required to provide guidance on the utility of sweat chloride changes for clinical practice Sweat chloride level changes not appear to predict improvements in ppFEV1 for an individual, presumably due G551D (Study 101) G551D (Study 102) G551D (Study 103) G551D (Study 106) non-G551D (Study 111) 40 F508del (Study 104) R117H 5T (Study 110) R117H 7T (Study 110) Residual Function (Study 113) Funding The post hoc analysis was sponsored by Vertex Pharmaceuticals Incorporated Author contributions All authors were involved with the conception of the post hoc analysis and interpretation of the data JB conducted the data analysis MCF wrote the draft of the manuscript All authors were involved with the critical revision of the manuscript and approved the final version Acknowledgments 30 ppFEV1, absolute change (%) MCF, JB, PP, and FVG are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company Editorial support was provided by Dhrupad Patel, PharmD, and Dena McWain DM is an employee of Ashfield Healthcare Communications, which received funding from Vertex Pharmaceuticals Incorporated DP, MCF, JB, PP, and FVG are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company 20 10 References -10 -20 -100 -80 -60 -40 -20 20 Sweat chloride, absolute change (mmol/L) Fig Correlation between individual absolute change from baseline of ppFEV1 and sweat chloride level (mmol/L) in patients with CF treated with ivacaftor [1] Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, et al Identification of the cystic fibrosis gene: genetic analysis Science 1989;245:1073–80 [2] Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA Science 1989;245:1066–73 [3] Rowe SM, Miller S, Sorscher EJ Cystic fibrosis N Engl J Med 2005;352: 1992–2001 Please cite this article as: Fidler MC, et al, Correlation of sweat chloride and percent predicted FEV1 in cystic fibrosis patients treated with ivacaftor, J Cyst Fibros (2016), http://dx.doi.org/10.1016/j.jcf.2016.10.002 M.C Fidler et al / Journal of Cystic Fibrosis xx (2016) xxx–xxx [4] Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, et al A CFTR potentiator in patients with cystic fibrosis and the G551D mutation N Engl J Med 2011;365:1663–72 [5] Davies JC, Wainwright CE, Canny GJ, Chilvers MA, Howenstine MS, Munck A, et al Efficacy and safety of ivacaftor in patients aged to 11 years with cystic fibrosis with a G551D mutation Am J Respir Crit Care Med 2013;187:1219–25 [6] Flume PA, Liou TG, Borowitz DS, Li H, Yen K, Ordonez CL, et al Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation Chest 2012;142:718–24 [7] Moss RB, Flume PA, Elborn JS, Cooke J, Rowe SM, McColley 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Barry PJ, Jones AM, Webb AK, Horsley AR Sweat chloride is not a useful marker of clinical response to ivacaftor Thorax 2014;69:586–7 Please cite this article as: Fidler MC, et al, Correlation of sweat chloride and percent predicted FEV1 in cystic fibrosis patients treated with ivacaftor, J Cyst Fibros (2016), http://dx.doi.org/10.1016/j.jcf.2016.10.002 ... baseline in percentage points for FEV1 In all studies, patients were treated with ivacaftor 150 mg q12h, except for study 101 in which patients were treated with one of four doses of ivacaftor. .. -20 20 Sweat chloride, absolute change (mmol/L) Fig Correlation between individual absolute change from baseline of ppFEV1 and sweat chloride level (mmol/L) in patients with CF treated with ivacaftor. .. -30 -20 -10 Sweat chloride, absolute change (mmol/L) Fig Correlation between absolute change from baseline of ppFEV1 and sweat chloride level (mmol/L) in patients with CF treated with ivacaftor