Rechallenge of Elexacaftor/Tezacaftor/Ivacaftor After Skin Rash in Two Pediatric Patients.
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ABSTRACT:
SUBMITTER: Diseroad ER
PROVIDER: S-EPMC9268115 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Rechallenge of Elexacaftor/Tezacaftor/Ivacaftor After Skin Rash in Two Pediatric Patients.
Diseroad Emily R ER Mogayzel Peter J PJ Pan Alice A
The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG 20220706 5
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have revolutionized care for patients with cystic fibrosis (CF). The triple combination product elexacaftor/tezacaftor/ivacaftor is a highly effective CFTR modulator that is generally well tolerated. However, in clinical trials of pediatric and adult patients, 4% to 12% developed rash after initiation of therapy. Few reports have described approaches to management of this adverse effect. In this report, we describe 2 children ...[more]
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Project description:BackgroundMany individuals with cystic fibrosis (CF) have chronic rhinosinusitis resulting in nasal obstruction, sinus infections, and repeated surgeries. Elexacaftor-tezacaftor-ivacaftor is a highly effective modulator therapy approved for individuals aged 6 years or older with CF who have at least one F508del allele or other responsive mutation. The current study tests the hypothesis that ELX/TEZ/IVA improves sinonasal disease in CF.MethodsThe study was a pre/post, observational cohort study conducted at two sites. Participants underwent a study visit prior to starting ELX/TEZ/IVA and a second visit at a median of 9 months on therapy. Each visit included sinus CT scan, rigid nasal endoscopy, and sweat chloride measurement. Symptoms were measured with the 22 item Sinonasal Outcome Test at scheduled intervals during the study. Regression models were used to test for improvement in symptoms, endoscopy, and CT scales.ResultsThe study enrolled 34 individuals, with a median age of 27 years (range 12-60). Symptoms improved within 7 days of therapy and plateaued by day 28. Endoscopic crusting resolved and nasal polyposis improved, with a decrease in size or resolution of polyps. Sinus opacification and mucosal thickening improved on CT radiographs with treatment.ConclusionsSinonasal symptoms improved rapidly and durably for at least 180 days on ELX/TEZ/IVA therapy. Objective measures of disease including endoscopic and CT findings improved with ELX/TEZ/IVA.
| S-EPMC9470769 | biostudies-literature
Project description:BackgroundThis study aimed to assess how Elexacaftor/Tezacaftor/Ivacaftor (ETI) influences lung function, Body Mass Index (BMI), Sweat Test (ST) and mental health of Cystic Fibrosis (CF) patients, emphasizing on depression and anxiety.MethodsWe conducted an observational, prospective, multicentre study including 108 patients over 18 years old who initiated ETI therapy between December 2019 and December 2023. Patients underwent regular evaluations, including clinical, functional, and microbiological assessments, alongside completion of quality of life, anxiety, and depression questionnaires. We evaluated whether there was a difference in anxiety and depression levels over time.ResultsAfter 12 months of treatment, significant improvements were noted in BMI, lung function (FEV1%), ST and various aspects of quality of life (CFQ-R). However, anxiety and depression levels did not differ significantly during the follow-up. When we stratified our sample by key groups, we observed that younger patients (under 28 years) and those with homozygous Phe508del mutations experienced significant higher anxiety with no differences on depression. Furthermore, anxiety and depression demonstrated a moderate correlation, strengthening over time.ConclusionsTreatment with ETI establishes significant improvements in lung function, BMI, ST and quality of life in patients with CF. However, despite these positive outcomes, there were no significant changes observed in levels of anxiety and depression, except for individuals with homozygous mutation type and those younger than 28 years old, who exhibited significant higher levels of anxiety.
| S-EPMC11831831 | biostudies-literature
Project description:Elexacaftor/tezacaftor/ivacaftor (ETI) has had a substantial positive impact for people living with cystic fibrosis (pwCF). However, there can be substantial variability in efficacy, and we lack adequate biomarkers to predict individual response. We thus aimed to identify transcriptomic profiles in nasal respiratory epithelium that predict clinical response to ETI treatment. We obtained nasal epithelial samples from pwCF before ETI initiation and performed a transcriptome-wide analysis of baseline gene expression to predict changes in forced expiratory volume in 1 second (ΔFEV1), year's best FEV1 (ΔybFEV1), and body mass index (ΔBMI). Using the top differentially expressed genes, we generated transcriptomic risk scores (TRSs) and evaluated their predictive performance. The study included 40 pwCF ≥6 years of age (mean, 27.7 [SD, 15.1] years; 40% female). After ETI initiation, FEV1 improved by ≥5% in 22 (61.1%) participants, and ybFEV1 improved by ≥5% in 19 (50%). TRSs were constructed using top overexpressed and underexpressed genes for each outcome. Adding the ΔFEV1 TRS to a model with age, sex, and baseline FEV1 increased the area under the receiver operating characteristic curve (AUC) from 0.41 to 0.88, the ΔybFEV1 TRS increased the AUC from 0.51 to 0.88, and the ΔBMI TRS increased the AUC from 0.46 to 0.92. Average accuracy was thus ∼85% in predicting the response to the three outcomes. Results were similar in models further adjusted for F508del zygosity and previous CFTR modulator use. In conclusion, we identified nasal epithelial transcriptomic profiles that help accurately predict changes in FEV1 and BMI with ETI treatment. These novel TRSs could serve as predictive biomarkers for clinical response to modulator treatment in pwCF.
| S-EPMC11622631 | biostudies-literature
Project description:BackgroundCystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.MethodsWe conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.ResultsA total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group.ConclusionsElexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).
| S-EPMC7282384 | biostudies-literature
Project description:BackgroundAbnormal macrophage function caused by dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is a critical contributor to chronic airway infections and inflammation in people with cystic fibrosis (PWCF). Elexacaftor/tezacaftor/ivacaftor (ETI) is a new CFTR modulator therapy for PWCF. Host-pathogen and clinical responses to CFTR modulators are poorly described. We sought to determine how ETI impacts macrophage CFTR function, resulting effector functions and relationships to clinical outcome changes.MethodsClinical information and/or biospecimens were obtained at ETI initiation and 3, 6, 9 and 12 months post-ETI in 56 PWCF and compared with non-CF controls. Peripheral blood monocyte-derived macrophages (MDMs) were isolated and functional assays performed.ResultsETI treatment was associated with increased CF MDM CFTR expression, function and localisation to the plasma membrane. CF MDM phagocytosis, intracellular killing of CF pathogens and efferocytosis of apoptotic neutrophils were partially restored by ETI, but inflammatory cytokine production remained unchanged. Clinical outcomes including increased forced expiratory volume in 1 s (+10%) and body mass index (+1.0 kg·m-2) showed fluctuations over time and were highly individualised. Significant correlations between post-ETI MDM CFTR function and sweat chloride levels were observed. However, MDM CFTR function correlated with clinical outcomes better than sweat chloride.ConclusionETI is associated with unique changes in innate immune function and clinical outcomes.
| S-EPMC10066828 | biostudies-literature
Project description:BackgroundA decrease in the lumacaftor-mediated increase in F508del-CFTR function and expression upon prolonged exposure to ivacaftor (VX-770) has previously been described. However, the efficacy observed with ivacaftor-containing CFTR modulator therapies in vivo is in conflict with these reports. We hypothesized that a portion of the apparent decrease in CFTR function observed after prolonged ivacaftor exposure in vitro was due to an increase in constitutive CFTR-mediated ion transport.MethodsHuman nasal epithelial (HNE) cells were obtained by brushings from three CF individuals homozygous for the F508del CFTR mutation. Differentiated epithelia were pre-treated with prolonged (24 h) exposure to either lumacaftor (VX-809; 3 µM), tezacaftor (VX-661; 3 µM), elexacaftor (VX-445; 3 µM), and/or ivacaftor (0.1-6.4 µM) or DMSO (vehicle control), and CFTR function was assayed by Ussing chamber electrophysiology.ResultsIn cells treated with lumacaftor, constitutive CFTR activity was not increased at any concentration of co-treatment with ivacaftor. Constitutive CFTR activity was also unchanged in cells treated with the combination of tezacaftor and elexacaftor. An increase in constitutive CFTR activity above the DMSO controls was only observed in cells treated with the combination of tezacaftor and elexacaftor and co-treated with at least 0.1 µM ivacaftor.ConclusionsThese results demonstrate that ivacaftor is a critical component in the triple combination therapy along with tezacaftor and elexacaftor to increase constitutive CFTR function. This work further elucidates the mechanism of action of the effective triple combination therapeutic that is now the primary clinical tool in treating CF.
| S-EPMC9329187 | biostudies-literature
Project description:ImportanceCystic fibrosis (CF) is a multiorgan genetic disease with progressive upper and lower airway involvement. The effects of CF transmembrane conductance regulator (CFTR) modifier therapies on CF-related upper airway disease, specifically chronic rhinosinusitis (CRS), are not characterized.ObjectiveTo determine the outcome of elexacaftor-tezacaftor-ivacaftor (ETI) on CRS as measured by changes in sinus computed tomography (CT) metrics and on clinical parameters in individuals with CF.Design, setting, and participantsThis prospective longitudinal cohort study was conducted at the CF center of a tertiary care hospital between October 1, 2019, and July 31, 2021. A total of 64 participants with CF were included in the analysis.InterventionSinus CT was obtained within 1 month of initiation of ETI therapy (baseline), and within 1 month of 1 year of ETI therapy. Images were independently analyzed by pulmonology, radiology, and otolaryngology physicians, using the Lund-Mackay and Sheikh-Lind scoring systems. Percent predicted forced expiratory volume in 1 second (ppFEV1), body mass index (BMI), and microbiologic data collected at initiation of ETI therapy and 3-month intervals for 1 year were also measured.Main outcomes and measuresThe study hypothesis was that ETI therapy will improve CRS as measured by changes in sinus CT at initiation and 1 year after ETI therapy and clinical parameters in individuals with CF.ResultsAmong the 64 participants (39 [60.9%] female; median age, 18.5 [IQR, 16.0-28.5] years; 64 [100%] White), improvement in CRS was noted by improvements in sinus CT scans using both sinus CT scoring systems after 1 year of ETI therapy. The reduction in the median total score using the Lund-Mackay sinus CT scoring system (from 5.8 [IQR, 5.0-7.0] to 3.3 [IQR, 2.6-4.2]) and the Sheikh-Lind scoring system (from 3.8 [IQR, 3.0-5.0] to 2.2 [IQR, 2.0-2.5]) was noted. Increases in ppFEV1 and BMI were also observed by 3 months of ETI therapy with persistent improvement through 1 year of treatment. Similarly, after 1 year of ETI therapy, participants with CF had reductions in positivity for Pseudomonas aeruginosa and Staphylococcus aureus in oropharyngeal cultures.Conclusion and relevanceThis cohort study found that use of ETI therapy was associated with improved CRS outcomes in participants with CF as quantified by improved sinus CT scans measured by 2 radiographic scoring systems and was also associated with improved clinical outcomes. Despite improvement in CT scan scores, most people with CF continue to have scores that indicate severe sinus disease.
| S-EPMC10485743 | biostudies-literature
Project description:BackgroundCystic fibrosis (CF) lung transplant (LT) recipients may warrant treatment with elexacaftor/tezacaftor/ivacaftor (ETI) to improve extrapulmonary manifestations of CF. Our objectives were to identify reasons for prescribing ETI after LT and evaluate changes in body mass index (BMI), hemoglobin A1c, hemoglobin, and liver enzymes.MethodsThis was an electronic health record-based cohort study, October 2019-September 2020, at 14 CF LT Consortium sites in North America. The study included CF LT recipients prescribed ETI after transplant. Differences in BMI, A1c, and hemoglobin were assessed with paired t-tests.ResultsThere were 94 patients prescribed ETI; indications included sinus disease (68%), GI symptoms (39%), or low BMI (19%). Prescriptions were written by CF physicians (34%), LT physicians (27%), or physicians who practice both CF and LT (39%). Forty patients (42%) stopped ETI at a median of 56 days [IQR 26, 139] after start/prescription date. ETI was not associated with a significant change in BMI (0.2 kg/m2, 95% CI [-0.1, 0.6], p = 0.150), but was associated with decreased A1c (0.4%, 95% CI 0.2, 0.7, p = 0.003), and increased hemoglobin for patients with anemia (0.6 g/dL, 95% CI 0.2, 1.0, p = 0.007). Three people (3%) stopped ETI due to elevated transaminases.ConclusionsETI is rarely prescribed for non-pulmonary indications after LT for CF. Further study is needed to determine the risks and benefits of ETI in the CF lung transplant population given the potential for drug interactions, side effects leading to discontinuation of ETI, and the possible mechanisms for ETI to positively impact long-term post-transplant outcomes.
| S-EPMC9509406 | biostudies-literature
Project description:The combination of medication containing elexacaftor, ivacaftor, and tezacaftor (EIT) has dramatically impacted the treatment and prognosis for patients with cystic fibrosis (CF). Lung function, weight, and self-reported quality of life have improved for many of these patients, but little is known about whether this treatment will have a beneficial effect in preventing morbidity and/or mortality from respiratory infections such as COVID-19. EIT received Food and Drug Administration (FDA) approval shortly before the first cases of COVID-19 appeared in the United States. We performed an analysis using the TriNetX (Cambridge, MA, USA) research database to determine if patients being treated with EIT who became infected with COVID-19 experienced significantly different outcomes compared to patients who were not receiving it.
| S-EPMC9578654 | biostudies-literature
Project description:BackgroundCFTR modulator therapies have positive clinical outcomes, yet chronic inflammation and bacterial infections persist in people with CF (pwCF). How elexacaftor-tezacaftor-ivacaftor (ETI) fails to improve innate immune signaling responsible for bacterial clearance and inflammation resolution remains unknown.MethodsWe used an unbiased proteomics approach to measure the effect of ETI on inflammatory proteins. Plasma from 20 pediatric pwCF and 20 non-CF (NCF) was collected during routine examination and 3 months after ETI initiation. Protein screening was performed with an inflammation panel (Target 96, Olink®). Bioinformatics analysis was used to determine changes in protein expression.ResultsThere were significantly fewer pulmonary exacerbations after ETI initiation, along with sustained improvement in lung function and reduced bacterial colonization. Unpaired analysis of CF pre-ETI and NCF resulted in 34 significantly different proteins. Of these, CCL20, MMP-10, EN-RAGE, and AXIN1 had a log2 fold change of 1.2 or more. There was a modest shift in overall CF protein profiles post-ETI toward the NCF cluster. Unpaired analysis of protein differential expression between NCF and CF post-ETI identified a total of 24 proteins significantly impacted by ETI therapy (p-value ≤ 0.05), with only CCL20 having a log2 fold change higher than 1.2. Paired analysis (CF pre- and CF post-ETI) of differential protein expression demonstrated significant expression changes of MMP-10, EN-RAGE, and IL-17A. Pathway analysis identified significantly impacted pathways such as the NF-κB pathway.ConclusionThis study showed that ETI in a pediatric cohort had a modest effect on several inflammatory proteins with potential as biomarkers. Pathways significantly impacted by ETI can be further studied for future therapies to combat persistent inflammation and dysregulated immunity.
| S-EPMC11811078 | biostudies-literature