Browsing by Author "Sawicki, Gregory S."

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    Long-term safety and efficacy of tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study
    (Elsevier, 2021) Flume, Patrick A.; Biner, Reta Fischer; Downey, Damian G.; Brown, Cynthia; Jain, Manu; Fischer, Rainald; De Boeck, Kris; Sawicki, Gregory S.; Chang, Philip; Paz-Diaz, Hildegarde; Rubin, Jaime L.; Yang, Yoojung; Hu, Xingdi; Pasta, David J.; Millar, Stefanie J.; Campbell, Daniel; Wang, Xin; Ahluwalia, Neil; Owen, Caroline A.; Wainwright, Claire E.; VX14-661-110 study group; Medicine, School of Medicine
    Background: Tezacaftor-ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8-24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor-ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor-ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods: Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor-ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor-ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914). Findings: Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor-ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor-ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor-ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation: Tezacaftor-ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor-ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor-ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes.
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    Predictors of pulmonary exacerbation treatment in cystic fibrosis
    (Elsevier, 2020-05) Sanders, Don B.; Ostrenga, Joshua S.; Rosenfeld, Margaret; Fink, Aliza K.; Schechter, Michael S.; Sawicki, Gregory S.; Flume, Patrick A.; Morgan, Wayne J.; Pediatrics, School of Medicine
    Background: Most studies of pulmonary exacerbations (PEx) in cystic fibrosis (CF) focus on intravenous (IV)-treated PEx, though most PEx are treated with oral antibiotics. Our objectives were to describe predictors of antibiotic choice and outcomes for PEx initially identified in clinic. Methods: For each patient in the U.S. CF Foundation Patient Registry, we selected the first PEx recorded at a clinic visit in 2013-14 following a clinic visit without a PEx. We used multivariable logistic regression to determine associations between clinical characteristics and antibiotic treatment choice. We determined outcomes in the 90 days after the first PEx. Results: Among 14,265 patients with a PEx initially identified in clinic, 21.4% received no antibiotics, 61.5% received new oral and/or inhaled antibiotics, and 17.0% had IV antibiotics within 14 days. Compared to IV antibiotics, patients more likely to receive new oral and/or inhaled antibiotics: were male, <13 years old, had BMI >10th percentile or 18.5 kg/m2, >90 days between clinic visits, FEV1 > 70% predicted at the PEx, no prior-year IV-treated PEx, FEV1 decline <10% predicted, and private insurance. Following the PEx, 30.3% of patients had no clinical encounters within 90 days. Treatment with IV antibiotics within 90 days occurred for 23.7% treated without antibiotics, 22.8% of new oral and/or inhaled antibiotics, and 27.1% of IV antibiotics. Conclusion: Most PEx identified in clinic are treated with new oral and/or inhaled antibiotics. Markers of disease severity are associated with antibiotic treatment choice. Many patients had no follow-up evaluation within 90 days of treatment.
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    The Frequency and Potential Implications of HFE Genetic Variants in Children With Cystic Fibrosis
    (Wiley, 2025) Huang, Leslie; Lai, HuiChuan J.; Furuya, Katryn N.; Antos, Nicholas J.; Asfour, Fadi; Boyne, Kathleen L.; Howenstine, Michelle; Rock, Michael J.; Sawicki, Gregory S.; Gaffin, Jonathan M.; Worthey, Elizabeth A.; Farrell, Philip M.; Pediatrics, School of Medicine
    Background: Genetic modifiers have been identified that increase the risks of lung disease and other complications, such as diabetes in people with cystic fibrosis (CF). Variants in the hemochromatosis gene (HFE) were reported in a study of adults to be associated with worse lung disease. Objectives: To ascertain the frequency of HFE variants, particularly C282Y (c.845G > A) and H63D (c.187C > G) and to determine if they are associated with variations in the onset and early severity of CF lung disease as well as abnormalities in iron status. Design: We studied with whole genome sequencing and clinical outcome measures in a cohort of 104 children with CF at 5-6 years old who were previously found to show an association between aggregated genetic modifiers and an earlier onset and a more severe lung disease phenotype. Results: In our cohort, 23% have H63D and 11% have C282Y. Lung function at age 6 years and Pseudomonas aeruginosa infections did not differ by HFE variants, but having C282Y was associated with more pulmonary exacerbations in the first 6 years of life. Three patients have H63D/C282Y genotype, and all showed phenotypic expression of hemochromatosis with abnormal iron indices. Conclusion: Our study revealed that the presence of HFE variant C282Y in people with CF may lead to more severe lung disease manifestations beginning in early childhood. There is a risk of hemochromatosis in CF patients with two HFE variants, and thus they should be followed for evidence of iron overload.