Fibrosis Transmembrane Conductance Regulator Modulators Research Articles

In vitro activity of cefiderocol in Pseudomonas aeruginosa isolates from people with cystic fibrosis recovered during three multicentre studies in Spain.

Despite the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, Pseudomonas aeruginosa is still a major pathogen in people with cystic fibrosis (pwCF). We determine the activity of cefiderocol and comparators in a collection of 154 P. aeruginosa isolates recovered from pwCF during three multicentre studies performed in 17 Spanish hospitals in 2013, 2017 and 2021. ISO broth microdilution was performed and MICs were interpreted with CLSI and EUCAST criteria. Mutation frequency and WGS were also performed. Overall, 21.4% were MDR, 20.8% XDR and 1.3% pandrug-resistant (PDR). Up to 17% of the isolates showed a hypermutator phenotype. Cefiderocol demonstrated excellent activity; only 13 isolates (8.4%) were cefiderocol resistant by EUCAST (none using CLSI). A high proportion of the isolates resistant to ceftolozane/tazobactam (71.4%), meropenem/vaborbactam (70.0%), imipenem/relebactam (68.0%) and ceftazidime/avibactam (55.6%) were susceptible to cefiderocol. Nine out of 13 cefiderocol-resistant isolates were hypermutators (P < 0.001). Eighty-three STs were detected, with ST98 being the most frequent. Only one isolate belonging to the ST175 high-risk clone carried blaVIM-2. Exclusive mutations affecting genes involved in membrane permeability, AmpC overexpression (L320P-AmpC) and efflux pump up-regulation were found in cefiderocol-resistant isolates (MIC = 4-8 mg/L). Cefiderocol resistance could also be associated with mutations in genes related to iron uptake (tonB-dependent receptors and pyochelin/pyoverdine biosynthesis). Our results position cefiderocol as a therapeutic option in pwCF infected with P. aeruginosa resistant to most recent β-lactam/β-lactamase inhibitor combinations.

Assessment of Physical Condition in Cystic Fibrosis Patients during 12-month Treatment with Cystic Fibrosis Transmembrane Conductance Regulator Modulators

Objective − To investigate the effect of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy on physical condition in children with cystic fibrosis (CF) during a 12month period.Materials and Methods − This is a retrospective cohort study including children aged ≥5 years treated with Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) or Lumacaftor/ Ivacaftor (LUM/IVA). A six-minute walk test (6MWT) was performed at baseline and at the 3-month follow-ups. Changes in spirometry and sweat chlorides, and body mass index (BMI) were also observed. Collected data were analysed for changes in 6MWT results in correlation with other parameters. The 6MWT results were compared to those predicted for healthy peers. Missing values were replaced using imputation.Results − Study includes 34 patients (median age 14 years); 28 received ELX/TEZ/ IVA, and 6 LUM/IVA. The average 6MWT walking distance (6MWD) increased from 519.3±107.7 m at baseline to 620.0±99.5 m after 12 months (P&lt;0.0001). The 12 month 6MWD values matched those expected for healthy peers. The increase in BMI z-score (P=0.019) and ppFEV1 (P&lt;0.0001) visible at the 3-month followup was sustained throughout the rest of the year. Sweat chloride concentration decreased (P&lt; 0.0001); after 12 months 13/34 subjects had values below 60 mmol/L. No correlation between 6MWD and other parameters was observed.Conclusion − Significant improvement in 6MWT results was already visible at three months following the initiation of CFTR modulator treatment. After 12 months patients performed 6MWT at a level indistinguishable from that expected of healthy peers.

SHIFTing goals in cystic fibrosis—managing extrapulmonary disease in the era of CFTR modulator therapy; Proceedings of the International Shaping Initiatives and Future Trends (SHIFT) Symposium

AbstractBackgroundCystic fibrosis (CF) is a life‐shortening multisystem genetic disease. Although progressive pulmonary disease is the predominant cause of morbidity and mortality, improvements in treatment for CF‐related lung disease, with associated increase in longevity, have increased the prevalence of extrapulmonary manifestations1.MethodsTo discuss these issues, a multidisciplinary meeting of international leaders and experts in the field was convened in November 2021 at the Shaping Initiatives and Future Trends  Symposium with the goal of highlighting shifting management paradigms in CF. The main topics covered were: (1) nutrition and obesity, (2) exocrine pancreas, (3) CF‐related diabetes, (4) CF liver disease, (5) CF‐related bone disease, and (6) post‐lung transplant care. This document summarizes the proceedings, highlighting the key priorities and important research questions that were discussed.ResultsImproved life expectancy, the advent of cystic fibrosis transmembrane conductance regulator modulators, and the increasing appreciation of the heterogeneity or spectrum of disease are leading to a shift in management for patients with cystic fibrosis. Care should be individualized to ensure that increased longevity is accompanied by improved extra‐pulmonary care and reduced morbidity.

Persistence and evolution of Pseudomonas aeruginosa following initiation of highly effective modulator therapy in cystic fibrosis.

The highly effective cystic fibrosis transmembrane conductance regulator modulator therapy Elexakaftor/Tezacaftor/Ivacaftor (ETI) has changed cystic fibrosis (CF) disease for many people with cystic fibrosis. While respiratory symptoms are improved by ETI, we found that people with CF remain infected with Pseudomonas aeruginosa. How these persistent and evolving bacterial populations will impact the clinical manifestations of CF in the coming years remains to be seen, but the role and potentially changing face of infection in CF should not be discounted in the era of highly effective modulator therapy.

Elexacaftor/Tezacaftor/Ivacaftor use in Pediatric Cystic Fibrosis Patients with Advanced Liver Disease

BackgroundCystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy extends the life expectancy of people with cystic fibrosis (PwCF). However, CFTR modulators have not been well studied in patients with cystic fibrosis liver disease (CFLD), specifically those with advanced liver disease with portal hypertension. The purpose of this report is to describe the use of elexacaftor/tezacaftor/ivacaftor (ETI) in pediatric CF patients with advanced CFLD. MethodsThis retrospective case series included PwCF < 18 years old with baseline advanced CFLD initiated on ETI. ResultsEleven PwCF and advanced CFLD were treated with ETI; six started a reduced dose regimen. No patient required treatment interruption and four patients received dose changes related to increase in transaminase and/or bilirubin elevations. Mean (SD) change in ppFEV1 from prior to ETI to highest value during therapy was 14.27 % (4.25) (p = 0.007). When evaluating the group as whole, AST decreased from baseline to last reported –15.18 (23.23) units/L (p = 0.054) and ALT slightly increased 0.73 (39.13) units/L (p = 0.96). Bilirubin increased minimally overall for patients with mean change from baseline of 0.83 (1.33) mg/dL [range –0.5–3] (p = 0.17). A model for time on ETI showed a significant decrease in AST over time of 0.955 per month of ETI but no other liver biochemistries were significant. No patient experienced decompensation of CFLD. ConclusionETI therapy in pediatric CF patients with advanced CFLD can be beneficial in improving pulmonary and nutritional outcomes without negative impact on liver biochemistries or hepatic outcomes. Close monitoring is recommended to ensure safety and tolerability.

A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes: a pilot study.

Background People with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF. Methods We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers. Results We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA &gt;360minutes [225,&gt;360] vs. placebo 330minutes [285,&gt;360], p=0.8) or secondary outcomes. There were no adverse events. Conclusions Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators. ClinicalTrials.gov registration NCT04006873 (02/07/2019)

Impact of CFTR modulator therapy on body composition as assessed by thoracic computed tomography: A follow-up study

Treatment with cystic fibrosis transmembrane conductance regulator (CFTR) modulators in individuals with cystic fibrosis (CF) has brought a significant change in forced expiratory volume in 1 second (FEV1) and clinical parameters. However, it also results in weight gain. The aim of our study is to evaluate the effect of CFTR modulator treatment on body composition, measured by computed tomography (CT). Adult subjects with CF under follow-up at La Princesa University Hospital were recruited. All of them were on elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) treatment. Body composition analysis was conducted using CT scans and an open-source software. The results were then compared with bioimpedance estimations, as well as other clinical and spirometry data. Our sample consisted of 26 adult subjects. The fat mass compartments on CT scans correlated with similar compartments on bioimpedance, and normal-density muscle mass exhibited a strong correlation with phase angle. Higher levels of very low-density muscle prior to treatment were associated with lower final FEV1 and less improvement in FEV1 after therapy. We observed an increase in total body area (P < 0.001), driven by increases in total fat mass (P < 0.001), subcutaneous fat (P < 0.001), visceral fat (P = 0.002), and intermuscular fat (P = 0.022). The only muscle compartment that showed an increase after treatment was very low-density muscle (P = 0.032). CT scans represent an opportunity to assess body composition on CF. Combination treatment with CFTR modulators, leads to an improvement in FEV1 and to an increase in body mass in all compartments primarily at the expense of fat mass.

Evaluation of the drug-drug interaction between triazole antifungals and cystic fibrosis transmembrane conductance regulator modulators in a real-life cohort.

Limited data on the clinical management of drug-drug interactions between triazoles and Cystic Fibrosis transmembrane conductance regulator (CFTR) modulators are available. We retrospectively evaluated azole target attainment and dose adaptations in patients from two Dutch CF centres concomitantly receiving triazoles and CFTR modulators. In total, 21 patients with 59 triazole trough concentrations were evaluated. Subtherapeutic concentrations were frequently observed, especially for itraconazole and voriconazole. Of the investigated antifungal agents, posaconazole appears the most preferable option. Our results emphasize the importance of adequate management of this interaction and underpin the added value of therapeutic drug monitoring of triazoles in this population.

Impact of CFTR Modulation on Pseudomonas aeruginosa Infection in People With Cystic Fibrosis.

Pseudomonas aeruginosa is a multidrug-resistant pathogen causing recalcitrant pulmonary infections in people with cystic fibrosis (pwCF). Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been developed that partially correct the defective chloride channel driving disease. Despite the many clinical benefits, studies in adults have demonstrated that while P. aeruginosa sputum load decreases, chronic infection persists. Here, we investigate how P. aeruginosa in pwCF may change in the altered lung environment after CFTR modulation. P. aeruginosa strains (n = 105) were isolated from the sputum of 11 chronically colonized pwCF at baseline and up to 21 months posttreatment with elexacaftor-tezacaftor-ivacaftor or tezacaftor-ivacaftor. Phenotypic characterization and comparative genomics were performed. Clonal lineages of P. aeruginosa persisted after therapy, with no evidence of displacement by alternative strains. We identified commonly mutated genes among patient isolates that may be positively selected for in the CFTR-modulated lung. However, classic chronic P. aeruginosa phenotypes such as mucoid morphology were sustained, and isolates remained just as resistant to clinically relevant antibiotics. Despite the clinical benefits of CFTR modulators, clonal lineages of P. aeruginosa persist that may prove just as difficult to manage in the future, especially in pwCF with advanced lung disease.

Highly effective cystic fibrosis transmembrane conductance (regulator) modulator therapy: shifting the curve for most while leaving some further behind.

Traditional cystic fibrosis (CF) care had been focused on early intervention and symptom mitigation. With the advent of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy (HEMT), in particular, the approval of elexacaftor/tezacaftor/ivacaftor in 2019, there has been a dramatic improvement in outcomes in CF. The purpose of this article is to review the benefits, limitations, and impact of HEMT as well as discuss the new implications, challenges, and hope that modulators bring to people with CF (pwCF). HEMT has demonstrated sustained improvement in lung function, nutrition, quality of life, and survival for over 90% of pwCF. As HEMT has delivered such promise, there is a small but significant portion of pwCF who do not benefit from HEMT due to ineligible mutations, intolerance, or lack of accessibility to modulators. HEMT has significantly improved outcomes, but continued research is needed to understand the new challenges and implications the era of HEMT will bring, as well as how to provide equitable care to those who are unable to benefit from HEMT.

A grumbling concern: A survey of gastrointestinal symptoms in cystic fibrosis in the modulator era

Background Gastrointestinal symptoms in cystic fibrosis (CF) are common and intrusive to daily life. Relieving gastrointestinal symptoms was identified as an important research priority and previously explored in an international survey in 2018. However, following the widespread introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators in 2019, the landscape of CF treatment has changed. We repeated an online survey to further describe gastrointestinal symptoms and their effect on quality of life (QoL) in the CFTR modulator era. Methods An electronic survey consisting of closed questions and free text responses was distributed via social media and professional networks for a period of one month between March - April 2022. People with CF (pwCF), their family and friends, and healthcare professionals (HCPs) were invited to take part. Results There were 164 respondents: 88 pwCF (54%), 22 (13%) family, and 54 (33%) healthcare professionals (HCPs). A total of 89/110 (81%) pwCF or family members reported CFTR modulator treatment. The most commonly reported symptoms were wind / gas and rumbling stomach noises (borborygmi) in both the modulator and non-modulator groups in addition to loose motions (modulator group) and bloating (no modulator group). Abdominal pain and bloating had the greatest impact on QoL. For those on a CFTR modulator, the proportion of pwCF reporting “no change” or “worse” for all of the symptoms surveyed was greater than the proportion reporting an improvement. For some symptoms such as stomach pains and reduced appetite, improvements were perceived more commonly in HCPs than what was reported by pwCF. Following modulator introduction, dietary changes to manage GI symptoms were recommended by 28/35 (80%) of HCPs and reported by 38/76 (50%) lay respondents. Changes in medication were recommended by 19/35 (54%) HCPs and reported by 44/76 (58%) of patients and family members. Conclusion This survey has shown that gastrointestinal symptoms remain prevalent in pwCF in the CFTR modulator era, though the nature of these symptoms may have changed. A better understanding of the underlying pathophysiology of these symptoms is essential. Future clinical studies should focus on improving symptoms and QoL.

Raman Spectroscopy and Cystic Fibrosis Disease: An Alternative Potential Tool for Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Response Differentiation-A Pilot Study Based on Serum Samples.

Cystic fibrosis (CF) is a genetic disorder that alters chloride transport in mucous membranes. Recent studies have demonstrated that treatment with modulators of the chloride channel reduces inflammatory markers, restoring, among others, the imbalance of lipids. In this study, we analyzed the serum samples of treated and non-treated patients with modulators with Raman spectroscopy. Nineteen (eight treated an eleven non-treated) patients were considered. The main difference between the two groups appeared in the 3020-2800 cm-1 range. A Voigt deconvolution fit was performed, and nine sub-bands were identified. To distinguish between treated and non-treated patients, the area ratio between the CH3 and CH2 vibration modes was calculated for each patient. The results were validated using statistical analyses. In particular, receiver operating characteristic (ROC) curves and Youden index (Y) were calculated (Area Under Curve (AUC): 0.977; Y: 3.30). An ROC curve represents the performance of the classification, illustrating the diagnostic ability of Raman spectroscopy. It was demonstrated that Raman spectroscopy is able to highlight peculiar differences between elexacaftor/tezacaftor/ivacaftor (ETI)-treated and non-treated patients, in relation with lipids biomarkers.

Laboratory Tools to Predict CFTR Modulator Therapy Effectiveness and to Monitor Disease Severity in Cystic Fibrosis.

The implementation of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator drugs into clinical practice has been attaining remarkable therapeutic outcomes for CF, a life-threatening autosomal recessive genetic disease. However, there is elevated CFTR allelic heterogeneity, and various individuals carrying (ultra)rare CF genotypes remain without any approved modulator therapy. Novel translational model systems based on individuals' own cells/tissue are now available and can be used to interrogate in vitro CFTR modulator responses and establish correlations of these assessments with clinical features, aiming to provide prediction of therapeutic effectiveness. Furthermore, because CF is a progressive disease, assessment of biomarkers in routine care is fundamental in monitoring treatment effectiveness and disease severity. In the first part of this review, we aimed to focus on the utility of individual-derived in vitro models (such as bronchial/nasal epithelial cells and airway/intestinal organoids) to identify potential responders and expand personalized CF care. Thereafter, we discussed the usage of CF inflammatory biomarkers derived from blood, bronchoalveolar lavage fluid, and sputum to routinely monitor treatment effectiveness and disease progression. Finally, we summarized the progress in investigating extracellular vesicles as a robust and reliable source of biomarkers and the identification of microRNAs related to CFTR regulation and CF inflammation as novel biomarkers, which may provide valuable information for disease prognosis.

Impact of elexacaftor/tezacaftor/ivacaftor on lipid and fat-soluble vitamin levels and association with body mass index.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve gastrointestinal absorption of nutrients and may result in changes in body mass index (BMI), serum lipids, and fat-soluble vitamin levels. We hypothesized that serum lipids and vitamin levels would increase with CFTR modulator therapy and that greater increase in lipids and vitamin levels would be related to greater increase in BMI. A retrospective study was performed to evaluate the impact of elexacaftor/tezacaftor/ivacaftor (ETI) on nutritional parameters, serum lipids, and fat-soluble vitamin levels. Pre-ETI values (<2 years prior) and post-ETI values (>1 month after) were compared. Linear regression was used to evaluate whether change in BMI is associated with the change in lipid and/or vitamin levels and whether modulator duration is associated with the degree of rise in lipid and/or vitamin levels. Adults and adolescents with CF (n = 137) were evaluated before and 31-300 days after starting ETI. Median BMI (adults 21.9 vs. 23.5 kg/m2 ; adolescents 48 vs. 63 percentile) increased after initiation of ETI. Total cholesterol (126 vs. 154 mg/dL), low-density lipoprotein cholesterol (63 vs. 78 mg/dL), non-high-density lipoprotein cholesterol (84 vs. 102 mg/dL), and high density lipoprotein cholesterol (43 vs. 49 mg/dL) increased after ETI, while triglycerides and very low density lipoprotein did not change. Median values for vitamin D (34.5 vs. 38.0 ng/mL) and vitamin A (40.1 vs. 47.9 µg/dL) increased, while vitamin E did not change significantly. There was no significant correlation between BMI change or duration of modulator therapy with vitamin levels or lipid changes. After initiation of ETI therapy, serum lipids increased in our population, but most values remained within the normal range. Vitamins A and D levels increased post-ETI and no changes were noted in vitamin E. No significant correlation between the degree of BMI change and the magnitude of increase in lipids or vitamin levels was found.

Optimizing CFTR modulator therapy management for cystic fibrosis through the ReX platform.

Cystic fibrosis (CF) is a chronic multi-systemic disease that requires a complex daily treatment regimen. Therefore, there is sub-optimal adherence to CF therapies, and it was shown to impact its clinical and economic burden. Cystic fibrosis transmembrane conductance regulator modulators (CFTRm) are high-cost medications that demonstrated significant benefit in clinical trials. The aim of this study was to evaluate the safety, usability, and efficacy of the ReX platform in medication management of CFTRm for the treatment of people with CF (pwCF). ReX is a patient engagement platform consisting of a cloud-based management system and a cell-enabled handheld device intended to dispense oral medication into the patient's mouth, following a pre-programmed treatment protocol. It provides real-time adherence data to caregivers and timely, personalized reminders to patients. This is a prospective multi-center open study for pwCFs older than 12 years, who had been prescribed CFTRm [elexacaftor/tezacaftor/ivacaftor (ETI) or tezacaftor/ivacaftor (TI)], and provided consent to use ReX platform to receive CFTRm and record their health condition. Study duration was 12-24 months, with clinic visits where physical examination, body mass index (BMI), and pulmonary function tests were performed, and user experience questionnaires were filled in. Ten pwCFs from two CF centers in Israel were included. The mean age was 31.5 years (range 15-74 years); eight were taking ETI and two TI. Median adherence to CFTRm was 97.5% (range 70%-100%) in the first year and 94% (range 84%-99%) in the second year, which is higher than the previously reported CFTRm adherence of ∼80%. No adverse events related to the use of the platform were reported. Patients reported ReX to be valuable to their treatment management and user friendly. Estimated mean forced expiratory volume in 1 s (FEV1%) increased from 74.4% to 80.8% (p = 0.004) over 2 years. Similarly, estimated BMI percentile increased from 53.5 to 59.0 (p < 0.001). Using the ReX platform in medication management of pwCF treated by CFTRm is safe, easy to use, and effective in improving the adherence to treatment and the clinical outcomes. Consequently, this device may potentially reduce costs to healthcare providers. Further larger and long-term studies are required to examine the clinical benefits of the ReX platform.

2229. Impact of Elexacaftor/tezacaftor/ivacaftor on Utilization of Antibiotics at a Single Pediatric Cystic Fibrosis Center

Abstract Background Intravenous (IV) and oral (PO) antibiotics (ABX) are standard treatments for pulmonary exacerbations (PEx) in people with cystic fibrosis (pwCF). Frequent ABX use may lead to adverse events and ABX resistance. Cystic fibrosis transmembrane conductance regulator modulator treatments have significantly reduced PEx in qualifying pwCF, but impact on ABX use is unknown. The approval of elexacaftor/tezacaftor/ivacaftor (ETI) in 2019 makes these treatments accessible to the majority of pwCF. The primary objective was to examine utilization of ABX pre-and post-ETI in pwCF managed at Children’s Mercy Kansas City’s (CMKC) CF center. Methods A retrospective analysis of PO and IV ABX for CF PEx was performed at CMKC. The pre-ETI treatment period was defined as 1/1/2017-12/31/2019 and post-ETI treatment period as 1/1/2020-12/31/2022. A paired analysis including pwCF managed by CMKC during both periods was used to compare ABX courses pre- and post-ETI. Results A total of 293 pwCF and 110 pwCF received PO and IV ABX during the study period, respectively. Of these, 224 pwCF managed by CMKC during both periods were included. IV ABX were received by 25 pwCF in both periods whereas 138 pwCF did not receive IV ABX in either period. There were 43 pwCF who received IV ABX only in the pre-ETI period compared to 18 pwCF who received IV ABX only in the post-ETI period (p=0.0021) resulting in a discordance of 27.2%. PO ABX were prescribed for 119 pwCF in both periods whereas 35 pwCF did not have PO ABX prescribed in either period. There were 52 pwCF who received PO ABXs in the pre-ETI period only compared to 18 pwCF who received PO ABX in the post-ETI period only (p=0.0001) resulting in a discordance of 31.3%. The number of patients receiving ABX directed against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus significantly decreased between periods. The median duration of ABX did not significantly change for IV (9.2 days vs. 8.9 days, p=0.958) or PO (14 days vs. 14 days, p=0.384) ABX during both periods. Conclusion CMKC pwCF experienced a dramatic decline in prescribing both PO and IV ABX following approval of ETI. Future investigations are necessary to determine this trend nationwide and ascertain the overall impact from decreased ABX exposure in pwCF. Disclosures All Authors: No reported disclosures

A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes.

Background People with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF. Methods We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers. Results We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA &gt;360minutes [225,&gt;360] vs. placebo 330minutes [285,&gt;360], p=0.8) or secondary outcomes. There were no adverse events. Conclusions Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators. ClinicalTrials.gov registration NCT04006873 (02/07/2019)

Aetiology of Significant Liver Test Abnormalities in a Single-Centre Cohort of People with Cystic Fibrosis Exposed to Elexacaftor/Tezacaftor/Ivacaftor, Utilizing the Updated RUCAM.

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) has been associated with substantial multisystem benefits for people with CF eligible for therapy. In a minority, tolerance has been limited by hepatic toxicity. It is unknown whether there may be particular risk factors for significant drug-induced elevation in transaminases. We aimed to determine the cause of raised transaminases following the introduction of E/T/I, and whether E/T/I can safely be continued in some individuals with elevated transaminases. At a large, single, adult CF centre, individuals with transaminases >3×the upper limit of normal (ULN) since commencing E/T/I underwent clinical assessment to exclude known causes of raised transaminases. Where an alternative cause could not be identified, individuals were discussed with hepatology to advise on further investigations to establish aetiology in addition to calculation of the updated Roussel Uclaf Causality Assessment Method (RUCAM) score to assess causality grading of drug-induced liver injury (DILI) due to E/T/I, and to guide management of ongoing CFTR modulator therapy. Of 337 adults taking E/T/I for a median of 27 months, 19 (5.6%) had transaminases >3×ULN. In 12 individuals, there was clear evidence of an aetiology unrelated to E/T/I (RUCAM scores -2 to 1 [excluded-unlikely]). Of the remaining cases, two had RUCAM scores in the 'possible' range and one had a RUCAM score in the 'probable' range. Liver biopsy was performed in four individuals, showing hepatic steatosis in one individual, normal histology in one individual, and hepatocyte necrosis suggestive of DILI in two individuals. E/T/I was suspended in those with hepatocyte necrosis, with one permanent discontinuation due to synthetic dysfunction. One individual with hepatocyte necrosis on histology was successfully re-established on E/T/I therapy. Alternative causes were identified in the majority of patients with clinically significant increases in transaminases following E/T/I, highlighting the importance of thorough investigation. Multidisciplinary assessment involving an experienced hepatologist is crucial in cases of diagnostic uncertainty or suggestion of significant DILI, as discontinuation of therapy can have significant consequences for individuals.

Medication use in people with cystic fibrosis before and after modulator therapy

BackgroundLong-term changes in medication dispensings post cystic fibrosis transmembrane conductance regulator (CFTR) modulator initiation have not been described. Our study aimed to investigate changes in medication use following the initiation of modulator therapy in people with cystic fibrosis (PwCF) in Australia. MethodsUsing a 10% sample of the Australian Pharmaceutical Benefits Scheme (PBS) data between 2013 and 2022, linear regression was used to analyse dispensings in PwCF who initiated any modulator (cases) and matched PwCF controls not dispensed a modulator. The difference in mean number of total monthly dispensings pre- and post-modulator initiation was analysed, with separate analyses by medication class. ResultsA total of 247 cases were matched 1:1 to controls (case and control median age 21 years (IQR: 13–32), 55.1% male). Immediately after modulator initiation, the mean number of dispensings was 0.9 higher in the modulator group, but then decreased to the level of controls after approximately 5 years. After 7.5 years, cases had decreased opioids compared to the pre-modulator period (β-coefficient: −0.00131, 95% CI: −0.00164, −0.00097) whilst controls did not (β: −0.00014, 95% CI: −0.00042, 0.00014). Over the same time period controls had an increase in psychotropics (β: 0.00389, 95% CI:0.00295, 0.00484) whilst cases remained stable (β: −0.00014, 95% CI: −0.0006, 0.00031). Women's health medications increased in cases (β:0.00026, 95% CI:0.0001, 0.00042) but decreased in controls (β: 0.00044, 95% CI: 0.00063, −0.00025). ConclusionsModulator initiation in PwCF was associated with decreased dispensings of opioids and psychotropics, and increased dispensings of women's health medications, suggesting improved patient outcomes across multiple clinical domains.

Socio-economic burden of cystic fibrosis in Europe: a systematic review of cost of illness evidence

Abstract Background Cystic Fibrosis (CF) is one of the most prevalent severe genetic diseases, with a high economic impact on healthcare systems due to its complexity. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in therapeutic regimens with Cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Therefore, strategies to ensure equitable access to these treatments should be optimized. Our study aimed to summarize existing literature regarding the costs of CF in Europe. Methods A systematic literature review was performed querying three online database (PubMed, Scopus, Web of Science) from January 2013 to March 2023. Studies carried out in European countries, written in English language, and focused on the socio-economic burden of CF were selected. Results Overall, 11 studies were considered. Across countries, the average total annual cost for a CF patient amounted to €14.174,00-53.256,00, higher for children (€15.771-60.412,00) compared to adults (€15.714-€47.217,00). The largest expenditures were recorded for annual direct healthcare costs, which amounted, per patient, to €9861,00-28.827,00, followed by direct non-healthcare costs (€4512,00-18.329,00). For adults, drugs, tests, and hospitalizations represented the primary cost drivers of direct healthcare costs, while for children, direct non-healthcare costs, especially for caregivers, were predominant. Moreover, indirect costs, whose main expenses were related to productivity loss and early retirement, ranged between €1,094-12,443 per patient per year. Conclusions The CF management is associated with relevant costs. CFTR modulators represent an important therapeutic opportunity of reducing the clinical and economic burden of CF. Therefore, new evidence and value-based economic evaluations, that also take into account a social perspective, are needed to support the decision-making process. Key messages • The use of new health economic models is needed to guide the policy-makers in a value-based evaluation of Cystic Fibrosis treatments that take into account their whole value. • The assessment of the socio-economic burden of Cystic Fibrosis could guide the identification of the main actions to be implemented to respond adequately to the real health needs of patients.