Fibrosis Transmembrane Conductance Regulator Modulators Research Articles

Preservation of β-cell Function in Pancreatic Insufficient Cystic Fibrosis With Highly Effective CFTR Modulator Therapy.

Elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta) enhances aberrant cystic fibrosis transmembrane conductance regulator function and may improve the insulin secretory defects associated with a deterioration in clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). This longitudinal case-control study assessed changes in β-cell function and secretory capacity measures over 2 visits in individuals with PI-CF who were initiated on ETI after the baseline visit (2012-2018) and (1) restudied between 2019 and 2021 (ETI group) vs (2) those restudied between 2015 and 2018 and not yet treated with cystic fibrosis transmembrane conductance regulator modulator therapy (controls). Nine ETI participants (mean ± SD age, 25 ± 5 years) and 8 matched controls were followed up after a median (interquartile range) 5 (4-7) and 3 (2-3) years, respectively (P < .01), with ETI initiation a median of 1 year before follow-up. Clinical outcomes, glucose-potentiated arginine, and mixed-meal tolerance test measures were assessed with comparisons of within- and between-group change by nonparametric testing. Glucose-potentiated insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls but not in the ETI group, with C-peptide changes different between groups (P < .05). Deterioration in basal proinsulin secretory ratio was observed in controls but improved, as did the maximal arginine-induced proinsulin secretory ratio, in the ETI group (P < .05 for all comparisons). During mixed-meal tolerance testing, early insulin secretion improved as evidenced by more rapid insulin secretory rate kinetics. ETI preserves β-cell function in CF through effects on glucose-dependent insulin secretion, proinsulin processing, and meal-related insulin secretion. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF.

Lung Transplantation in a New Era in the Field of Cystic Fibrosis.

Lung transplantation for people with cystic fibrosis (PwCF) is a critical therapeutic option, in a disease without a cure to this day, and its overall success in this population is evident. The medical advancements in knowledge, treatment, and clinical care in the field of cystic fibrosis (CF) rapidly expanded and improved over the last several decades, starting from early pathology reports of CF organ involvement in 1938, to the identification of the CF gene in 1989. Lung transplantation for CF has been performed since 1983, and CF now accounts for about 17% of pre-transplantation diagnoses in lung transplantation recipients. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been the latest new therapeutic modality addressing the underlying CF protein defect with the first modulator, ivacaftor, approved in 2012. Fast forward to today, and we now have a growing CF population. More than half of PwCF are now adults, and younger patients face a better life expectancy than they ever did before. Unfortunately, CFTR modulator therapy is not effective in all patients, and efficacy varies among patients; it is not a cure, and CF remains a progressive disease that leads predominantly to respiratory failure. Lung transplantation remains a lifesaving treatment for this disease. Here, we reviewed the current knowledge of lung transplantation in PwCF, the challenges associated with its implementation, and the ongoing changes to the field as we enter a new era in the care of PwCF. Improved life expectancy in PwCF will surely influence the role of transplantation in patient care and may even lead to a change in the demographics of which people benefit most from transplantation.

Impact of lumacaftor/ivacaftor and tezacaftor/ivacaftor on treatment response in pulmonary exacerbations of F508del/F508del cystic fibrosis

BackgroundPulmonary exacerbations (PEx) remain a major cause of morbidity and mortality in people with cystic fibrosis (PWCF). Although the combination cystic fibrosis transmembrane conductance regulator (CFTR) modulators lumacaftor/ivacaftor and tezacaftor/ivacaftor have been shown to reduce PEx frequency, their influence on clinical and biochemical responses to acute PEx treatment is unknown. MethodsWe performed a secondary analysis of STOP2, a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx. Propensity score matching was used to compare outcomes in antibiotic-treated F508del/F508del PWCF receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor with those observed in antibiotic-treated F508del/F508del controls not receiving CFTR modulator therapy. The primary outcome measure was the change in percent predicted FEV1 (ppFEV1) following completion of intravenous (IV) antibiotics, with post-antibiotic changes in symptoms, serum C-reactive protein (CRP) concentrations and weight included as secondary endpoints. ResultsAmong 982 PEx events in randomized PWCF, 480 were homozygous for F508del, of whom 289 were receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor at initiation of antibiotic therapy. Modulator-treated F508del/F508del PWCF did not demonstrate greater improvements in ppFEV1, symptoms, serum CRP or weight following antibiotic treatment compared to modulator-naïve controls matched for age, sex, baseline ppFEV1, genotype, body mass index, initial CRP, initial symptoms, exacerbation history, diabetic status, randomization arm and concomitant medical therapy. ConclusionIn the acute setting, CFTR modulator therapy with lumacaftor/ivacaftor or tezacaftor/ivacaftor does not convey additional clinical or biochemical advantage above standardized PEx treatment in F508del/F508del PWCF.

Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on sputum viscoelastic properties, airway infection and inflammation in patients with cystic fibrosis.

Recent studies demonstrated that the triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and reduces pulmonary exacerbations in cystic fibrosis (CF) patients with at least one F508del allele. However, effects of ETI on downstream consequences of CFTR dysfunction, i.e. abnormal viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. The aim of this study was to determine the longitudinal effects of ETI on airway mucus rheology, microbiome and inflammation in CF patients with one or two F508del alleles aged ≥12 years throughout the first 12 months of therapy. In this prospective observational study, we assessed sputum rheology, the microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ETI. In total, 79 patients with CF and at least one F508del allele and 10 healthy controls were enrolled in this study. ETI improved the elastic modulus and viscous modulus of CF sputum at 3 and 12 months after initiation (all p<0.01). Furthermore, ETI decreased the relative abundance of Pseudomonas aeruginosa in CF sputum at 3 months and increased the microbiome α-diversity at all time points. In addition, ETI reduced interleukin-8 at 3 months (p<0.05) and free neutrophil elastase activity at all time points (all p<0.001), and shifted the CF sputum proteome towards healthy. Our data demonstrate that restoration of CFTR function by ETI improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele over the first 12 months of therapy; however, levels close to healthy were not reached.

Spirometric and anthropometric improvements in response to elexacaftor/tezacaftor/ivacaftor depending on age and lung disease severity.

Introduction: Triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) was introduced in August 2020 in Germany for people with CF (pwCF) ≥12years (yrs.) of age and in June 2021 for pwCF ≥6yrs of age. In this single-center study, we analyzed longitudinal data on the percent-predicted forced expiratory volume (ppFEV1) and body-mass-index (BMI) for 12months (mo.) after initiation of ETI by linear mixed models and regression analyses to identify age- and severity-dependent determinants of response to ETI. Methods: We obtained data on 42 children ≥6-11yrs, 41 adolescents ≥12-17yrs, and 143 adults by spirometry and anthropometry prior to ETI, and 3 and 12mo. after ETI initiation. Data were stratified by the age group and further sub-divided into age-specific ppFEV1 impairment. To achieve this, the age strata were divided into three groups, each according to their baseline ppFEV1: lowest 25%, middle 50%, and top 25% of ppFEV1. Results: Adolescents and children with more severe lung disease prior to ETI (within the lowest 25% of age-specific ppFEV1) showed higher improvements in lung function than adults in this severity group (+18.5 vs. +7.5; p = 0.002 after 3mo. and +13.8 vs. +7.2; p = 0.012 after 12mo. of ETI therapy for ≥12-17years and +19.8 vs. +7.5; p = 0.007 after 3mo. for children ≥6-11yrs). In all age groups, participants with more severe lung disease showed higher BMI gains than those with medium or good lung function (within the middle 50% or top 25% of age-specific ppFEV1). Regression analyses identified age as a predictive factor for FEV1 increase at 3mo. after ETI initiation, and age and ppFEV1 at ETI initiation as predictive factors for FEV1 increase 12mo. after ETI initiation. Discussion: We report initial data, which suggest that clinical response toward ETI depends on age and lung disease severity prior to ETI initiation, which argue for early initiation of ETI.

827-P: Effects of Elexacaftor/Tezacaftor/Ivacaftor Triple Combination Therapy on Glycaemic Control and Body Composition in Patients with Cystic Fibrosis–Related Diabetes

Introduction: Cystic fibrosis related diabetes (CFRD) is the most common extra pulmonary complication of cystic fibrosis (CF). Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are a group of new drugs for the treatment of CF and elexacaftor+tezacaftor+ivacaftor (ETI) triple combination therapy has been approved as first choice therapy in the treatment of patients with at least 1 copy of F508del mutation. Data on the effects of CFTR modulators on glucose metabolism in patients with or without CFRD are limited to small studies with conflicting results. Aim of the study: to evaluate the effectiveness of ETI on glucose metabolism, glucose variability and body composition in patients with CFRD. Methods: We conducted a prospective observational study on 24 CF patients with CFRD requiring insulin therapy. We performed an evaluation of glycometabolic control, glucose variability (assessed with 14 days-flash glucose monitoring) and body composition (with bio-impedance analysis) before and six months after the beginning of ETI. Data are expressed as median and interquartile ranges. Results: We demonstrated an improvement in both HbA1c [from 7.0% (6.5, 7.4) to 6.6 (6.0, 7.1), p&amp;lt;0,05] and coefficient of variation [CV - from 35.0 (29.0, 44.5) to 28.2 (25.2, 33.1), p&amp;lt; 0.01], despite unchanged insulin requirements. Over the treatment period, percent of fat mass (FM) significantly increased [from 12.1% (7.2, 16.2) to 15.4% (11.8, 18.6), p&amp;lt;0.05]. Conclusions: ETI improves glycometabolic regulation in patients with CFRD on insulin therapy. A longer follow-up is needed to better characterize the body composition changes induced by ETI and their metabolic consequences. Disclosure V.Grancini: None. A.Gramegna: None. L.Zazzeron: None. G.Alicandro: None. L.L.Porcaro: None. F.V.Piedepalumbo: None. C.Lanfranchi: None. V.Daccò: None. E.Orsi: None.

THU-298 - Beneficial effect of cystic fibrosis transmembrane conductance regulator modulators on adults with cystic fibrosis liver disease

THU-298 - Beneficial effect of cystic fibrosis transmembrane conductance regulator modulators on adults with cystic fibrosis liver disease

P161 Desensitization to highly effective modulator therapy – international approach and call for collaboration

Cutaneous adverse reactions have been documented in patients initiated on available cystic fibrosis transmembrane conductance regulator modulators (CFTRm), ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor, with a reported incidence of less than 5%. It is increased, up to 10.9%, in patients initiated on elexacaftor/tezacaftor/ivacaftor (E/T/I). Reports have been published regarding various approaches to management of highly effective modulator therapy (HEMT) rash, including graded challenges and a standardized desensitization.

P020 Therapy with elexacaftor/tezacaftor/ivacaftor in a patient with compound heterozygous CFTR mutation and the complex CFTR-allele Phe508del; Leu467Phe

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) was shown to be highly efficacious in patients who have at least one copy of the F508del variant. Cis variants in F508del mutations might influence the response to CFTR modulator therapy. We report the response to ETI in a patient with CF who is heterozygous for the complex Phe508del;Leu467Phe allele.

P321 Impact of short-term CFTR modulators treatment on changes in nutritional and glucose status in cystic fibrosis paediatric patients with different glucose tolerance

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are drugs that could change the course of the disease in cystic fibrosis (CF) patients and also nutrition status and glucose metabolism. Our study aimed to assess the impact of CFTR modulators treatment on nutritional and glucose status in CF pediatric patients with different glucose tolerance.

P342 Serum sodium, chloride and potassium levels after start CFTR modulators treatment in CF pediatric patients

Cystic fibrosis can lead to electrolyte imbalance. Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF) and also could change the ions’ status. However, there is a lack of evidence on whether the electrolyte level in the blood differs after CFTR modulator treatment.

P064 Bilateral cataracts in an adolescent following the use of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies

P064 Bilateral cataracts in an adolescent following the use of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies

P079 Personalized CFTR modulator therapy for G85E and N1303K homozygous patients with cystic fibrosis

Objectives: The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators elexacaftor/tezacaftor/ivacaftor (ETI) are approved for people with CF (pwCF) and at least one F508del-allele in Europe. In the US, ETI label was expanded by >100 rare CFTR mutations responsive in fisher rat thyroid cells, including G85E, but not N1303K. However, the effect of ETI on G85E or N1303K CFTR proteins is unknown.

EPS1.08 Immunogenic adverse events to CFTR modulators – an international survey

Objective: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has been rolled out across Europe for the treatment of Cystic Fibrosis (CF). These new therapies have a predominately positive effect on people with CF (pwCF), improving lung function, weight and reducing pulmonary exacerbations. However, immunogenic reactions to CFTR modulators can occur and may lead to drug discontinuation. We aimed to assess the frequency and severity of these reactions.

WS10.01 The French Compassionate Programme of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with advanced lung disease and no F508del CFTR variant

Objective: The European Medicines Agency has approved the cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) for people with cystic fibrosis (pwCF) carrying at least one F508del variant. The United States Food and Drug Administration (FDA) also approved ETI for pwCF carrying one of 177 rare variants. Our objective was to evaluate ETI in pwCF with advance lung disease and no F508del variant.

P306 Changes in glucose tolerance in people with cystic fibrosis after initiation of first-generation CFTR modulator treatment

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been shown to have a beneficial effect on pulmonary function and nutritional status, but their effect on glucose tolerance is not yet fully understood. In the current study, we evaluated the change in glucose tolerance and insulin secretion after first-generation CFTR modulator treatment in adults with cystic fibrosis (CF).

WS05.02 A Phase-1 multiple ascending dose healthy volunteer study to evaluate the safety, tolerability, and pharmacokinetics of GDC-6988, a dry powder formulation of a selective inhaled potentiator of TMEM16A

Objectives: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are not indicated for ~10% of people with CF and may not fully restore CFTR function. GDC-6988 is a potent and selective potentiator of TMEM16A and is expected to enhance calcium-induced anion transport, increase airway fluid secretion, and promote mucus hydration and clearance. We previously reported outcomes in healthy volunteers with a nebulized formulation of GDC-6988. Here we present blinded outcomes from an ongoing Phase 1 study of a dry powder (DP) formulation of GDC-6988.

P284 Assessing the potential of the FIB-4 index as a screening tool for advanced liver fibrosis in an adult cystic fibrosis population

Cystic fibrosis related liver disease (CFLD) affects a small proportion of people with CF (PWCF) but is associated with a significant increase in morbidity and mortality. The development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators has led to dramatic improvements in life expectancy for PWCF. Consequently, there has been a significant emergence of liver dysfunction complicating the clinical course of the disease. The FIB-4 index has been shown to be an accurate, non invasive method for assessing liver fibrosis in non CF liver disease. We aimed to assess whether the FIB-4 index could reliably exclude significant fibrosis in an adult population of PWCF.

Impact of Elexacaftor-Tezacaftor-Ivacaftor on lung disease in cystic fibrosis.

In people with cystic fibrosis (pwCF), the impact of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, such as Elexacaftor-Tezacaftor-Ivacaftor (ETI), on structural changes in the lungs is unclear. To determine the impact of ETI on clinical parameters and on structural lung disease as measured by the changes in the chest computed tomography (CT) scans in pwCF. Percent predicted forced expiratory volume in one second(ppFEV1), body mass index (BMI), and microbiologic data were collected at initiation and 3-month intervals for 1 year. Chest CT scans before starting ETI therapy (baseline) and at 1-year on ETI therapy were compared by two pulmonologists independently. The sample size was 67 pwCF, 30 (44.8%) males, median age of 25 (16, 33.5) years. Significant increases in ppFEV1 and BMI observed by 3 months of ETI therapy persisted throughout 1 year of ETI therapy (p < 0.001 at all-time points for both). After 1 year on ETI, pwCF had significant reductions in Pseudomonas aeruginosa (-42%) and MRSA (-42%) positivity. None of the pwCF had worsening of chest CT parameters during 1 year of ETI therapy. Comparing chest CT findings at baseline and at 1-year follow-up, bronchiectasis was present in 65 (97%) pwCF and at 1-year follow-up decreased in 7 (11%). Bronchial wall thickening 64 (97%), decreased in 53 (79%). Mucous plugging in 63 (96%), absent in 11 (17%), and decreased in 50 (77%). Hyperinflation/air trapping in 44 (67%), decreased in 11 (18%), absent in 27 (44%) CONCLUSIONS: ETI significantly improved clinical outcomes and lung disease as documented by improvement in chest CT scans.

Individualized approach to elexacaftor/tezacaftor/ivacaftor dosing in cystic fibrosis, in response to self-reported anxiety and neurocognitive adverse events: A case series.

The prevalence of mental health disorders is high among people with Cystic Fibrosis. The psychological symptoms in CF are associated with poor adherence, worse treatment outcomes, and greater health utilization/cost. Mental health and neurocognitive Adverse Events (AEs) have been reported with all available Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators in small groups of patients. We report our experience with a dose reduction strategy in 10 of our patients on elexacaftor/tezacaftor/ivacaftor (7.9% of total number of patients) who self-reported developing intense anxiety, irritability, sleep disturbance and/or mental slowness after initiation of full dose treatment. Standard dose elexacaftor/tezacaftor/ivacaftor resulted in 14.3 points improvement in mean Percent Predicted Forced Expiratory Volume in 1s (ppFEV1), and a mean difference in sweat chloride of -39.3mmol/L. We initially discontinued and/or reduced therapy according to the AEs severity, with a subsequent planned dose escalation every 4-6weeks guided by sustainability of clinical effectiveness, absence of AEs recurrence, and patients' preferences. Clinical parameters including lung function and sweat chloride were monitored for up to 12weeks to assess ongoing clinical response to the reduced dose regimen. Dose reduction resulted in resolution of self-reported mental/psychological AEs, without loss of clinical effectiveness (ppFEV1 was 80.7% on standard dose, and 83.4% at 12weeks on reduced dose; sweat chloride was 33.4 and 34mmol/L on standard and reduced dose, respectively). Furthermore, in a subgroup of patients who completed 24weeks of the reduced dose regimen, repeat low dose Computed Tomography imaging showed a significant response when compared to pre-initiation of elexacaftor/tezacaftor/ivacaftor.