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• W2058814112 abstract "Cystic fibrosis (CF) is a life-shortening inherited disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR), which encodes for the CF transmembrane conductance regulator (CFTR) ion channel that regulates chloride and water transport across the surface of epithelial cells. Ivacaftor, a drug recently approved by the US Food and Drug Administration, represents the first mutation-specific therapy for CF. It is a CFTR channel modulator and improves CFTR function in patients with CF who have a G551D mutation. A clinical trial performed to support ivacaftor dose selection demonstrated a dose-response relationship between improvement in FEV1 and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV1 and sweat chloride would facilitate development of new drugs that target the defective CFTR. Subsequently, in phase 3 studies, ivacaftor 150 mg bid resulted in significant improvements in FEV1 (10%–12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV1, nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV1 was apparent. The lack of correlation of sweat chloride with improvement in FEV1 speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity. Future clinical trials of drugs that are directed to the defective CFTR will need take into account the uncertainty of using even established measurements, such as sweat chloride, as clinical end points. Cystic fibrosis (CF) is a life-shortening inherited disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR), which encodes for the CF transmembrane conductance regulator (CFTR) ion channel that regulates chloride and water transport across the surface of epithelial cells. Ivacaftor, a drug recently approved by the US Food and Drug Administration, represents the first mutation-specific therapy for CF. It is a CFTR channel modulator and improves CFTR function in patients with CF who have a G551D mutation. A clinical trial performed to support ivacaftor dose selection demonstrated a dose-response relationship between improvement in FEV1 and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV1 and sweat chloride would facilitate development of new drugs that target the defective CFTR. Subsequently, in phase 3 studies, ivacaftor 150 mg bid resulted in significant improvements in FEV1 (10%–12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV1, nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV1 was apparent. The lack of correlation of sweat chloride with improvement in FEV1 speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity. Future clinical trials of drugs that are directed to the defective CFTR will need take into account the uncertainty of using even established measurements, such as sweat chloride, as clinical end points. cystic fibrosis cystic fibrosis transmembrane conductance regulator cystic fibrosis transmembrane conductance regulator gene Cystic fibrosis (CF) is a multisystem autosomal recessive genetic disease that results from mutations in the CF transmembrane regulator gene (CFTR).1Gibson RL Burns JL Ramsey BW Pathophysiology and management of pulmonary infections in cystic fibrosis.Am J Respir Crit Care Med. 2003; 168: 918-951Crossref PubMed Scopus (1294) Google Scholar The gene encodes for a protein that regulates transport of chloride, sodium, and other electrolytes across epithelial cell membranes and also appears to be involved in the immune response of the lung to bacteria such as Pseudomonas aeruginosa. Loss of CF transmembrane regulator (CFTR) function results in aberrant ion transport and dehydration of secretions, with subsequent mucosal obstruction of exocrine glands and an altered pulmonary inflammatory response. The severity of disease is highly variable, but in most patients these defects result in pathologic abnormalities in multiple organ systems, most notably in the respiratory and GI systems, which subsequently lead to early death.Ivacaftor, a drug indicated for the treatment of CF in patients aged ≥ 6 years who have a G551D mutation in CFTR, was approved by the US Food and Drug Administration on January 31, 2012.2Center for Drug Evaluation and Research. Kalydeco (ivacaftor) Approval package. Silver Spring, MD: US Food and Drug Administration.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000Approv.pdfGoogle Scholar It represents a breakthrough for a subset of patients with CF with a specific CFTR mutation in at least one allele, as it is the first approved therapy for CF that targets the abnormal CFTR chloride channel, the fundamental defect that is the cause of CF.Since medieval times, when folklore predicted death for any infant who tasted salty when kissed, abnormal transit of electrolytes across sweat gland epithelial cells has been recognized as a “biomarker” of disease.3Busch R On the history of cystic fibrosis.Acta Univ Carol [Med] (Praha). 1990; 36: 13-15PubMed Google Scholar In more modern times, di Sant'Agnese, in 1953, determined that excessive loss of salt was able to be detected in the sweat of patients with CF, a finding that led to the development of the pilocarpine iontophoresis method of sweat testing.4Di Sant'Agnese PA Darling RC Perera GA Shea E Abnormal electrolyte composition of sweat in cystic fibrosis of the pancreas; clinical significance and relationship to the disease.Pediatrics. 1953; 12: 549-563PubMed Google Scholar Since that time, the determination of sweat chloride levels became and still is the gold standard for the diagnosis of CF in the appropriate clinical setting. Typically, normal individuals have sweat chloride levels < 40 mmol/L, whereas patients with CF have elevated values, usually > 60 mmol/L.5Farrell PM Rosenstein BJ White TB Cystic Fibrosis Foundation et al.Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report.J Pediatr. 2008; 153: S4-S14Abstract Full Text Full Text PDF PubMed Scopus (800) Google ScholarAs a result of the diagnostic relationship between the determination of an elevation in sweat chloride in symptomatic patients and CF, change in sweat chloride was used as a measure of CFTR function and included as an important pharmacodynamic end point in the ivacaftor development program. This makes much sense for a drug that affects CFTR function, and demonstration of a positive effect of ivacaftor on the CFTR channel, as evidenced by a decrease in sweat chloride, would be suggestive of meaningful clinical activity. Subsequent validation of such a pharmacodynamic end point by being able to correlate change in sweat chloride with meaningful clinical benefits would be a major step forward for CF drug clinical development programs that target the CFTR protein. This is especially true in that CF itself is a relatively rare disease, and subpopulations of patients with CF based on genotype may be extremely small, thus precluding or making the conduct of conventional clinical efficacy trials difficult.The initial proof of principle and dose-ranging trial for the ivacaftor clinical program was a two-part, randomized, double-blind, placebo-controlled trial in 39 adults with CF and at least one copy of the G551D mutation in CFTR.6Accurso FJ Rowe SM Clancy JP et al.Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.N Engl J Med. 2010; 363: 1991-2003Crossref PubMed Scopus (621) Google Scholar Twenty patients received ivacaftor 25, 75, or 150 mg or placebo every 12 h for 14 days, and 19 patients received ivacaftor 150 or 250 mg or placebo every 12 h for 28 days. In this study, changes in sweat chloride after 14 days of treatment with 25, 75, or 150 mg of ivacaftor or placebo were −32.9, −40.4, −42.30, and +4.4 mmol/L, respectively. Of interest, although the number of patients was small, the sweat chloride results paralleled those of the clinical end point, FEV1, in which patients treated with ivacaftor 25, 75, or 150 mg every 12 h demonstrated improvements in FEV1 of 4.9%, 10.0%, and 10.5%, respectively, while those treated with placebo had little change (0.7%). The 250-mg dose did not provide any additional improvement in FEV1 or change in sweat chloride over the 150-mg dose. Change in potential difference across the nasal mucosa, another pharmacodynamic end point that has been used as a surrogate measure of CFTR function and used in the study, demonstrated similar results.Based on these results, the efficacy of the 150-mg every-12-h dose was evaluated in two randomized, double-blind, placebo-controlled clinical trials in 213 clinically stable patients with CF who have a G551D mutation in CFTR. Trial 1 evaluated 161 patients with CF who were ≥ 12 years of age (mean age, 26 years) with baseline FEV1 between 40% to 90% predicted (mean FEV1, 64% predicted),7Ramsey BW Davies J McElvaney NG VX08-770-102 Study Group et al.A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.N Engl J Med. 2011; 365: 1663-1672Crossref PubMed Scopus (1551) Google Scholar and trial 2 evaluated 52 patients who were 6 to 11 years of age (mean age, 9 years) with baseline FEV1 between 40% to 105% predicted (mean FEV1, 84% predicted).8Center for Drug Evaluation and Research Kalydeco (ivacaftor). Labeling. Silver Spring, MD: US Food and Drug Administration.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000Lbl.pdfGoogle Scholar The primary efficacy end point in both studies was the mean change from baseline in percent predicted predose FEV1 through 24 weeks of treatment. Sweat chloride was assessed at several time points throughout the trials, and change in sweat chloride at 24 weeks was designated as a key secondary end point.In both studies, treatment with ivacaftor resulted in a significant improvement in FEV1. The treatment difference between ivacaftor and placebo for the mean absolute change in % predicted FEV1 from baseline through week 24 was 10.6% (P < .0001) in trial 1 and 12.5% (P < .0001) in trial 2.7Ramsey BW Davies J McElvaney NG VX08-770-102 Study Group et al.A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.N Engl J Med. 2011; 365: 1663-1672Crossref PubMed Scopus (1551) Google Scholar, 8Center for Drug Evaluation and Research Kalydeco (ivacaftor). Labeling. Silver Spring, MD: US Food and Drug Administration.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000Lbl.pdfGoogle Scholar Similar to the results from the dose-ranging study, for both trials there were large decreases in mean sweat chloride values in patient groups treated with ivacaftor for 24 weeks: −47.9 mmol/L in trial 1 and −54.3 mmol/L in trial 2 (Table 1).9Center for Drug Evaluation and Research Kalydeco (ivacaftor). Cross-discipline team leader review. Silver Spring, MD: US Food and Drug Administration.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000CrossR.pdfGoogle ScholarTable 1Changes in Sweat Chloride Measurements Through Wk 24Adapted from the Center for Drug Evaluation and Research.9Center for Drug Evaluation and Research Kalydeco (ivacaftor). Cross-discipline team leader review. Silver Spring, MD: US Food and Drug Administration.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000CrossR.pdfGoogle ScholarResultNo.Baseline Value, mmol/LPostbaseline ValueAbsolute Change From Baseline LS MeanaEstimates from mixed effects model for repeated measurements.Difference Between Treatment Groups95% CIP ValueTrial 1 Placebo74100.1100.9−0.8……… Ivacaftor78100.450.8−48.7−47.9−51.3, −44.5< .0001Trial 2 Placebo23105.0104.7−1.2……… Ivacaftor23104.447.9−55.5−54.3−61.8, −46.8< .0001LS = least squares.a Estimates from mixed effects model for repeated measurements. Open table in a new tab As mentioned previously, an elevated sweat chloride (regarded as a measure of CFTR function), along with the expected clinical constellation of symptoms, has historically been the means by which CF is diagnosed. In this vein of thought, a marked and sustained decrease in sweat chloride by approximately one-half, as was demonstrated in ivacaftor phase 3 trials, would indicate improved CFTR function, which, in turn, should result in improved pulmonary function. To evaluate this concept, analyses were conducted on data from both ivacaftor phase 3 clinical trials determining the correlation of sweat chloride concentration with changes in FEV1. Somewhat surprisingly, as Figure 1 demonstrates, there was little to no correlation between a decrease in sweat chloride levels and FEV1 in patients treated with ivacaftor, nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV1 could be observed. Therefore, for the ivacaftor program, change of sweat chloride, while of interest, was not predictive of an improvement in lung function in individual patients with CF, as determined by FEV1. Although disappointing, the example described is not the only study in which there was a lack of correlation between a change in sweat chloride and lung function. For example, in a separate CF drug development program, treatment of patients with CF with VX-809, an experimental drug termed as a CFTR “corrector,” demonstrated dose-dependent decreases in sweat chloride; however, no changes in FEV1 were observed.10Clancy JP Rowe SM Accurso FJ et al.Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.Thorax. 2012; 67: 12-18Crossref PubMed Scopus (430) Google Scholar A lack of correlation between sweat chloride and lung function may also exist in patients with CF with the 3849+10kb C→T mutation who have low, even normal, sweat chloride values but pulmonary function similar to that of patients with CF and CFTR mutations that are generally associated with more severe pulmonary disease.11Augarten A Kerem BS Yahav Y et al.Mild cystic fibrosis and normal or borderline sweat test in patients with the 3849 + 10 kb C—>T mutation.Lancet. 1993; 342: 25-26Abstract PubMed Scopus (119) Google ScholarThe answer(s) to the question as to why there is a lack of correlation between a pharmacodynamic parameter, sweat chloride, so well established that it is diagnostic of CF, and the established lung function clinical end point, FEV1, is unknown, but there are several possible explanations. In the ivacaftor program, change in sweat chloride was used as a surrogate for CFTR activity. However, it must be remembered that sweat chloride is reflective only of sweat gland CFTR activity, and it may not be reflective of similar CFTR activity in a complex organ like the lung, which is composed of many types of cells known to be heterogeneous regarding CFTR expression.12Jiang Q Engelhardt JF Cellular heterogeneity of CFTR expression and function in the lung: implications for gene therapy of cystic fibrosis.Eur J Hum Genet. 1998; 6: 12-31Crossref PubMed Scopus (62) Google Scholar Another factor is the existence of genetic modifiers, such as polymorphisms in genes other than CFTR, that may modify the severity of lung disease and disrupt any potential correlation between sweat chloride and clinical outcome (FEV1).13Drumm ML Konstan MW Schluchter MD Gene Modifier Study Group et al.Genetic modifiers of lung disease in cystic fibrosis.N Engl J Med. 2005; 353: 1443-1453Crossref PubMed Scopus (391) Google ScholarIn addition to differences in CFTR gene expression and protein activity, the clinical end point(s) being measured may be important. For instance, although FEV1 is the most common clinical end point used to assess lung function in obstructive lung diseases, it is a surrogate end point in and of itself. This could lead to questioning whether use of FEV1 as a clinical surrogate of lung function in patients with CF is the best approach or whether there is a better lung function or other clinical end point that more accurately predicts treatment effects in patients with CF. Whatever the reason(s), the overall lack of direct correlation of sweat chloride levels with the commonly used CF clinical lung function end point, FEV1, speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity.In summary, although clinically meaningful improvements in several disease parameters have been demonstrated in patients with CF and a G551D mutation in the CFTR treated with ivacaftor, the hypothesis that decrease in sweat chloride, in and of itself, could be used to predict improvement in pulmonary function, or that there is a threshold for change in sweat chloride that would be predictive of an FEV1 clinical response, could not be substantiated. Potential reasons likely include the heterogeneity in CFTR expression and regulation in different organs, environmental factors, and/or the choice of end point in and of itself. Future CF clinical trials for novel therapies that directly address the defective CFTR protein will need take into account the uncertainty of using even established pharmacodynamic measurements, such as sweat chloride, as a means for dose selection or as clinical end points in such CF trials. Cystic fibrosis (CF) is a multisystem autosomal recessive genetic disease that results from mutations in the CF transmembrane regulator gene (CFTR).1Gibson RL Burns JL Ramsey BW Pathophysiology and management of pulmonary infections in cystic fibrosis.Am J Respir Crit Care Med. 2003; 168: 918-951Crossref PubMed Scopus (1294) Google Scholar The gene encodes for a protein that regulates transport of chloride, sodium, and other electrolytes across epithelial cell membranes and also appears to be involved in the immune response of the lung to bacteria such as Pseudomonas aeruginosa. Loss of CF transmembrane regulator (CFTR) function results in aberrant ion transport and dehydration of secretions, with subsequent mucosal obstruction of exocrine glands and an altered pulmonary inflammatory response. The severity of disease is highly variable, but in most patients these defects result in pathologic abnormalities in multiple organ systems, most notably in the respiratory and GI systems, which subsequently lead to early death. Ivacaftor, a drug indicated for the treatment of CF in patients aged ≥ 6 years who have a G551D mutation in CFTR, was approved by the US Food and Drug Administration on January 31, 2012.2Center for Drug Evaluation and Research. Kalydeco (ivacaftor) Approval package. Silver Spring, MD: US Food and Drug Administration.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000Approv.pdfGoogle Scholar It represents a breakthrough for a subset of patients with CF with a specific CFTR mutation in at least one allele, as it is the first approved therapy for CF that targets the abnormal CFTR chloride channel, the fundamental defect that is the cause of CF. Since medieval times, when folklore predicted death for any infant who tasted salty when kissed, abnormal transit of electrolytes across sweat gland epithelial cells has been recognized as a “biomarker” of disease.3Busch R On the history of cystic fibrosis.Acta Univ Carol [Med] (Praha). 1990; 36: 13-15PubMed Google Scholar In more modern times, di Sant'Agnese, in 1953, determined that excessive loss of salt was able to be detected in the sweat of patients with CF, a finding that led to the development of the pilocarpine iontophoresis method of sweat testing.4Di Sant'Agnese PA Darling RC Perera GA Shea E Abnormal electrolyte composition of sweat in cystic fibrosis of the pancreas; clinical significance and relationship to the disease.Pediatrics. 1953; 12: 549-563PubMed Google Scholar Since that time, the determination of sweat chloride levels became and still is the gold standard for the diagnosis of CF in the appropriate clinical setting. Typically, normal individuals have sweat chloride levels < 40 mmol/L, whereas patients with CF have elevated values, usually > 60 mmol/L.5Farrell PM Rosenstein BJ White TB Cystic Fibrosis Foundation et al.Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report.J Pediatr. 2008; 153: S4-S14Abstract Full Text Full Text PDF PubMed Scopus (800) Google Scholar As a result of the diagnostic relationship between the determination of an elevation in sweat chloride in symptomatic patients and CF, change in sweat chloride was used as a measure of CFTR function and included as an important pharmacodynamic end point in the ivacaftor development program. This makes much sense for a drug that affects CFTR function, and demonstration of a positive effect of ivacaftor on the CFTR channel, as evidenced by a decrease in sweat chloride, would be suggestive of meaningful clinical activity. Subsequent validation of such a pharmacodynamic end point by being able to correlate change in sweat chloride with meaningful clinical benefits would be a major step forward for CF drug clinical development programs that target the CFTR protein. This is especially true in that CF itself is a relatively rare disease, and subpopulations of patients with CF based on genotype may be extremely small, thus precluding or making the conduct of conventional clinical efficacy trials difficult. The initial proof of principle and dose-ranging trial for the ivacaftor clinical program was a two-part, randomized, double-blind, placebo-controlled trial in 39 adults with CF and at least one copy of the G551D mutation in CFTR.6Accurso FJ Rowe SM Clancy JP et al.Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.N Engl J Med. 2010; 363: 1991-2003Crossref PubMed Scopus (621) Google Scholar Twenty patients received ivacaftor 25, 75, or 150 mg or placebo every 12 h for 14 days, and 19 patients received ivacaftor 150 or 250 mg or placebo every 12 h for 28 days. In this study, changes in sweat chloride after 14 days of treatment with 25, 75, or 150 mg of ivacaftor or placebo were −32.9, −40.4, −42.30, and +4.4 mmol/L, respectively. Of interest, although the number of patients was small, the sweat chloride results paralleled those of the clinical end point, FEV1, in which patients treated with ivacaftor 25, 75, or 150 mg every 12 h demonstrated improvements in FEV1 of 4.9%, 10.0%, and 10.5%, respectively, while those treated with placebo had little change (0.7%). The 250-mg dose did not provide any additional improvement in FEV1 or change in sweat chloride over the 150-mg dose. Change in potential difference across the nasal mucosa, another pharmacodynamic end point that has been used as a surrogate measure of CFTR function and used in the study, demonstrated similar results. Based on these results, the efficacy of the 150-mg every-12-h dose was evaluated in two randomized, double-blind, placebo-controlled clinical trials in 213 clinically stable patients with CF who have a G551D mutation in CFTR. Trial 1 evaluated 161 patients with CF who were ≥ 12 years of age (mean age, 26 years) with baseline FEV1 between 40% to 90% predicted (mean FEV1, 64% predicted),7Ramsey BW Davies J McElvaney NG VX08-770-102 Study Group et al.A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.N Engl J Med. 2011; 365: 1663-1672Crossref PubMed Scopus (1551) Google Scholar and trial 2 evaluated 52 patients who were 6 to 11 years of age (mean age, 9 years) with baseline FEV1 between 40% to 105% predicted (mean FEV1, 84% predicted).8Center for Drug Evaluation and Research Kalydeco (ivacaftor). Labeling. Silver Spring, MD: US Food and Drug Administration.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000Lbl.pdfGoogle Scholar The primary efficacy end point in both studies was the mean change from baseline in percent predicted predose FEV1 through 24 weeks of treatment. Sweat chloride was assessed at several time points throughout the trials, and change in sweat chloride at 24 weeks was designated as a key secondary end point. In both studies, treatment with ivacaftor resulted in a significant improvement in FEV1. The treatment difference between ivacaftor and placebo for the mean absolute change in % predicted FEV1 from baseline through week 24 was 10.6% (P < .0001) in trial 1 and 12.5% (P < .0001) in trial 2.7Ramsey BW Davies J McElvaney NG VX08-770-102 Study Group et al.A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.N Engl J Med. 2011; 365: 1663-1672Crossref PubMed Scopus (1551) Google Scholar, 8Center for Drug Evaluation and Research Kalydeco (ivacaftor). Labeling. Silver Spring, MD: US Food and Drug Administration.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000Lbl.pdfGoogle Scholar Similar to the results from the dose-ranging study, for both trials there were large decreases in mean sweat chloride values in patient groups treated with ivacaftor for 24 weeks: −47.9 mmol/L in trial 1 and −54.3 mmol/L in trial 2 (Table 1).9Center for Drug Evaluation and Research Kalydeco (ivacaftor). Cross-discipline team leader review. Silver Spring, MD: US Food and Drug Administration.http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000CrossR.pdfGoogle Scholar LS = least squares. As mentioned previously, an elevated sweat chloride (regarded as a measure of CFTR function), along with the expected clinical constellation of symptoms, has historically been the means by which CF is diagnosed. In this vein of thought, a marked and sustained decrease in sweat chloride by approximately one-half, as was demonstrated in ivacaftor phase 3 trials, would indicate improved CFTR function, which, in turn, should result in improved pulmonary function. To evaluate this concept, analyses were conducted on data from both ivacaftor phase 3 clinical trials determining the correlation of sweat chloride concentration with changes in FEV1. Somewhat surprisingly, as Figure 1 demonstrates, there was little to no correlation between a decrease in sweat chloride levels and FEV1 in patients treated with ivacaftor, nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV1 could be observed. Therefore, for the ivacaftor program, change of sweat chloride, while of interest, was not predictive of an improvement in lung function in individual patients with CF, as determined by FEV1. Although disappointing, the example described is not the only study in which there was a lack of correlation between a change in sweat chloride and lung function. For example, in a separate CF drug development program, treatment of patients with CF with VX-809, an experimental drug termed as a CFTR “corrector,” demonstrated dose-dependent decreases in sweat chloride; however, no changes in FEV1 were observed.10Clancy JP Rowe SM Accurso FJ et al.Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation.Thorax. 2012; 67: 12-18Crossref PubMed Scopus (430) Google Scholar A lack of correlation between sweat chloride and lung function may also exist in patients with CF with the 3849+10kb C→T mutation who have low, even normal, sweat chloride values but pulmonary function similar to that of patients with CF and CFTR mutations that are generally associated with more severe pulmonary disease.11Augarten A Kerem BS Yahav Y et al.Mild cystic fibrosis and normal or borderline sweat test in patients with the 3849 + 10 kb C—>T mutation.Lancet. 1993; 342: 25-26Abstract PubMed Scopus (119) Google Scholar The answer(s) to the question as to why there is a lack of correlation between a pharmacodynamic parameter, sweat chloride, so well established that it is diagnostic of CF, and the established lung function clinical end point, FEV1, is unknown, but there are several possible explanations. In the ivacaftor program, change in sweat chloride was used as a surrogate for CFTR activity. However, it must be remembered that sweat chloride is reflective only of sweat gland CFTR activity, and it may not be reflective of similar CFTR activity in a complex organ like the lung, which is composed of many types of cells known to be heterogeneous regarding CFTR expression.12Jiang Q Engelhardt JF Cellular heterogeneity of CFTR expression and function in the lung: implications for gene therapy of cystic fibrosis.Eur J Hum Genet. 1998; 6: 12-31Crossref PubMed Scopus (62) Google Scholar Another factor is the existence of genetic modifiers, such as polymorphisms in genes other than CFTR, that may modify the severity of lung disease and disrupt any potential correlation between sweat chloride and clinical outcome (FEV1).13Drumm ML Konstan MW Schluchter MD Gene Modifier Study Group et al.Genetic modifiers of lung disease in cystic fibrosis.N Engl J Med. 2005; 353: 1443-1453Crossref PubMed Scopus (391) Google Scholar In addition to differences in CFTR gene expression and protein activity, the clinical end point(s) being measured may be important. For instance, although FEV1 is the most common clinical end point used to assess lung function in obstructive lung diseases, it is a surrogate end point in and of itself. This could lead to questioning whether use of FEV1 as a clinical surrogate of lung function in patients with CF is the best approach or whether there is a better lung function or other clinical end point that more accurately predicts treatment effects in patients with CF. Whatever the reason(s), the overall lack of direct correlation of sweat chloride levels with the commonly used CF clinical lung function end point, FEV1, speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity. In summary, although clinically meaningful improvements in several disease parameters have been demonstrated in patients with CF and a G551D mutation in the CFTR treated with ivacaftor, the hypothesis that decrease in sweat chloride, in and of itself, could be used to predict improvement in pulmonary function, or that there is a threshold for change in sweat chloride that would be predictive of an FEV1 clinical response, could not be substantiated. Potential reasons likely include the heterogeneity in CFTR expression and regulation in different organs, environmental factors, and/or the choice of end point in and of itself. Future CF clinical trials for novel therapies that directly address the defective CFTR protein will need take into account the uncertainty of using even established pharmacodynamic measurements, such as sweat chloride, as a means for dose selection or as clinical end points in such CF trials. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: The views expressed in this commentary are those of the authors and do not necessarily reflect the views or policies of the US Food and Drug Administration." @default.
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• W2058814112 title "Change in Sweat Chloride as a Clinical End Point in Cystic Fibrosis Clinical Trials" @default.
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