scholarly journals Prediction of Real-World Long-Term Outcomes of People with CF Homozygous for the F508del Mutation Treated with CFTR Modulators

2021 ◽  
Vol 11 (12) ◽  
pp. 1376
Author(s):  
Danya Muilwijk ◽  
Marlou Bierlaagh ◽  
Peter van Mourik ◽  
Jasmijn Kraaijkamp ◽  
Renske van der Meer ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Real World ◽  
Target Therapy ◽  
Chloride Concentration ◽  
Sweat Chloride ◽  
Limited Effectiveness ◽  
Pulmonary Exacerbations ◽  
Cftr Modulators

The clinical response to cystic fibrosis transmembrane conductance regulator (CFTR) modulators is variable within people with cystic fibrosis (pwCF) homozygous for the F508del mutation. The prediction of clinical effect in individual patients would be useful to target therapy to those who would benefit from it. A multicenter observational cohort study was conducted including 97 pwCF (F508del/F508del), who started lumacaftor/ivacaftor (LUM/IVA) treatment before June 2018. In order to assess the associations of individual in vivo and in vitro biomarkers with clinical outcomes, we collected clinical data regarding sex, age, and sweat chloride concentration (SwCl) at baseline and after six months of LUM/IVA; the percent predicted forced expiratory volume in 1 s (ppFEV1) and the number of pulmonary exacerbations (PEx) during the three years before up to three years after modulator initiation; and the forskolin-induced swelling (FIS) responses to LUM/IVA, quantified in intestinal organoids. On a group level, the results showed an acute change in ppFEV1 after LUM/IVA initiation (2.34%, 95% CI 0.85–3.82, p = 0.003), but no significant change in annual ppFEV1 decline in the three years after LUM/IVA compared to the three years before (change: 0.11% per year, 95%CI: −1.94–2.19, p = 0.913). Neither of these two outcomes was associated with any of the candidate predictors on an individual level. The median number of pulmonary exacerbations (PEx) per patient year did not significantly change in the three years after LUM/IVA compared to the years before (median: 0.33/patient year, IQR: 0–0.67 before vs. median: 0/patient year, IQR: 0–0.67 after p = 0. 268). The PEx rate after modulator initiation was associated with the PEx rate before (IRR: 2.26, 95%CI: 1.67–3.08, p < 0.001), with sex (males vs. females IRR: 0.36, 95%CI: 0.21–0.63, p = 0.001) and with sweat chloride concentration (SwCl) at baseline (IRR: 0.96, 95%CI: 0.94–0.98, p = 0.001). The change in SwCl was also significant (−22.9 mmol/L (95%CI: −27.1–−18.8, p < 0.001) and was associated with SwCl at baseline (−0.64, 95%CI: −0.90–−0.37, p < 0.001) and with sex (males vs. females 8.32, 95%CI: 1.82–14.82, p = 0.013). In conclusion, ppFEV1 decline after CFTR modulator initiation remains difficult to predict in individual patients in a real-world setting, with limited effectiveness for double CFTR modulator therapies. The PEx rate prior to CFTR modulator treatment initiation, sex and SwCl at baseline could be potential predictors of long-term PEx rate and of changes in SwCl after modulator initiation.

scholarly journals Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis

2020 ◽  
Vol 57 (1) ◽  
pp. 1902426 ◽  
Author(s):  
Anabela S. Ramalho ◽  
Eva Fürstová ◽  
Annelotte M. Vonk ◽  
Marc Ferrante ◽  
Catherine Verfaillie ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Data ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Vast Number ◽  
Sweat Chloride ◽  
Intestinal Organoids ◽  
Rectal Biopsies ◽  
Cftr Modulators

RationaleGiven the vast number of cystic fibrosis transmembrane conductance regulator (CFTR) mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF).ObjectivesTo study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data.MethodsIntestinal organoids were grown from rectal biopsies in a cohort of 97 subjects with CF. Residual CFTR function was measured by quantifying organoid swelling induced by forskolin and response to modulators by quantifying organoid swelling induced by CFTR correctors, potentiator and their combination. Organoid data were correlated with clinical data from the literature.ResultsAcross 28 genotypes, residual CFTR function correlated (r2=0.87) with sweat chloride values. When studying the same genotypes, CFTR function rescue by CFTR modulators in organoids correlated tightly with mean improvement in lung function (r2=0.90) and sweat chloride (r2=0.95) reported in clinical trials. We identified candidate genotypes for modulator therapy, such as E92K, Q237E, R334W and L159S. Based on organoid results, two subjects started modulator treatment: one homozygous for complex allele Q359K_T360K, and the second with mutation E60K. Both subjects had major clinical benefit.ConclusionsMeasurements of residual CFTR function and rescue of function by CFTR modulators in intestinal organoids correlate closely with clinical data. Our results for reference genotypes concur with previous results. CFTR function measured in organoids can be used to guide precision medicine in patients with CF, positioning organoids as a potential in vitro model to bring treatment to patients carrying rare CFTR mutations.

scholarly journals Long-Term Outcomes in Real Life of Lumacaftor–Ivacaftor Treatment in Adolescents With Cystic Fibrosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Stéphanie Bui ◽  
Alexandra Masson ◽  
Raphaël Enaud ◽  
Léa Roditis ◽  
Gaël Dournes ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Real Life ◽  
Chloride Concentration ◽  
Electronic System ◽  
Antibiotic Use ◽  
Response To Treatment ◽  
Life Study ◽  
Sweat Chloride

Background: The combination of the CFTR corrector lumacaftor (LUM) and potentiator ivacaftor (IVA) has been labeled in France since 2015 for F508del homozygote cystic fibrosis (CF) patients over 12 years. In this real-life study, we aimed (i) to compare the changes in lung function, clinical (e.g., body mass index and pulmonary exacerbations) and radiological parameters, and in sweat chloride concentration before and after initiation of LUM/IVA treatment; (ii) to identify factors associated with response to treatment; and (iii) to assess the tolerance to treatment.Materials and Methods: In this tri-center, non-interventional, and observational cohort study, children (12–18 years old) were assessed prospectively during the 2 years of therapy, and retrospectively during the 2 years preceding treatment. Data collected and analyzed for the study were exclusively extracted from the medical electronic system records of the patients.Results: Forty adolescents aged 12.0–17.4 years at LUM/IVA initiation were included. The lung function decreased significantly during and prior to treatment and increased after LUM/IVA initiation, becoming significant after 2 years of treatment. LUM/IVA significantly improved the BMI Z-score and sweat chloride concentration. By contrast, there was no significant change in exacerbation rates, antibiotic use, or CT scan scores. Age at LUM/IVA initiation was lower in good responders and associated with greater ppFEV1 change during the 2 years of treatment. LUM/IVA was well-tolerated.Conclusion: In F508del homozygote adolescents, real-life long-term LUM/IVA improved the ppFEV1 trajectory, particularly in the youngest patients, nutritional status, and sweat chloride concentration but not exacerbation rates or radiological scores. LUM/IVA was generally well-tolerated and safe.

scholarly journals Forskolin-induced swelling of intestinal organoids predicts long-term cystic fibrosis disease progression

2021 ◽  
Author(s):  
D. Muilwijk ◽  
E. de Poel ◽  
P. van Mourik ◽  
S.W.F. Suen ◽  
A.M. Vonk ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Disease Progression ◽  
Pancreatic Insufficiency ◽  
Chloride Concentration ◽  
Predictive Biomarker ◽  
Sweat Chloride ◽  
Intestinal Organoids ◽  
Clinical Consequences ◽  
Related Liver Disease

ABSTRACTPatient-derived organoids hold great potential as predictive biomarker for disease expression or therapeutic response. Here, we used intestinal organoids to estimate individual cystic fibrosis transmembrane conductance regulator (CFTR) function of people with cystic fibrosis, a monogenic life-shortening disease associated with more than 2000 CFTR mutations and highly variable disease progression. In vitro CFTR function in CF intestinal organoids of 176 individuals with diverse CFTR mutations was quantified by forskolin induced swelling and was strongly associated with longitudinal changes of lung function and development of pancreatic insufficiency, CF-related liver disease and diabetes. This association was not observed when the commonly used biomarker of CFTR function sweat chloride concentration was used. The data strongly exemplifies the value of an organoid-based biomarker in a clinical disease setting and supports the prognostic value of forskolin induced swelling of intestinal organoids, especially for people with CF who have rare CFTR genotypes with unclear clinical consequences.

scholarly journals Poor recovery from cystic fibrosis pulmonary exacerbations is associated with poor long-term outcomes

2017 ◽  
Vol 52 (10) ◽  
pp. 1268-1275 ◽  
Author(s):  
Don B. Sanders ◽  
Qianqian Zhao ◽  
Zhanhai Li ◽  
Philip M. Farrell
Keyword(s):  
Cystic Fibrosis ◽  
Long Term Outcomes ◽  
Poor Recovery ◽  
Pulmonary Exacerbations

scholarly journals Impact of Airway Inflammation on the Efficacy of CFTR Modulators

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3260
Author(s):  
Carla M. P. Ribeiro ◽  
Martina Gentzsch
Keyword(s):  
Cystic Fibrosis ◽  
Airway Inflammation ◽  
Primary Cultures ◽  
Lavage Fluid ◽  
Improved Outcomes ◽  
Inflammatory Stimuli ◽  
Infection And Inflammation ◽  
The Impact ◽  
Cftr Modulators

Defective CFTR biogenesis and activity in cystic fibrosis airways leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection and inflammation. Most cystic fibrosis patients have at least one copy of the F508del CFTR mutation, which results in a protein retained in the endoplasmic reticulum and degraded by the proteosomal pathway. CFTR modulators, e.g., correctors, promote the transfer of F508del to the apical membrane, while potentiators increase CFTR activity. Corrector and potentiator double therapies modestly improve lung function, whereas triple therapies with two correctors and one potentiator indicate improved outcomes. Enhanced F508del rescue by CFTR modulators is achieved by exposing F508del/F508del primary cultures of human bronchial epithelia to relevant inflammatory stimuli, i.e., supernatant from mucopurulent material or bronchoalveolar lavage fluid from human cystic fibrosis airways. Inflammation enhances the biochemical and functional rescue of F508del by double or triple CFTR modulator therapy and overcomes abrogation of CFTR correction by chronic VX-770 treatment in vitro. Furthermore, the impact of inflammation on clinical outcomes linked to CFTR rescue has been recently suggested. This review discusses these data and possible mechanisms for airway inflammation-enhanced F508del rescue. Expanding the understanding of how airway inflammation improves CFTR rescue may benefit CF patients.

scholarly journals Elexacaftor-Tezacaftor-Ivacaftor: The First Triple-Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy

2020 ◽  
Vol 25 (3) ◽  
pp. 192-197 ◽  
Author(s):  
Kaden Ridley ◽  
Michelle Condren
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Trials ◽  
Genetic Mutations ◽  
Transmembrane Conductance Regulator ◽  
Triple Combination ◽  
Transmembrane Conductance ◽  
Sweat Chloride ◽  
Cystic Fibrosis Transmembrane

Elexacaftor-tezacaftor-ivacaftor is a newly approved triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapy that contains 2 correctors and a potentiator of the CFTR channel. Its labeled indication for use is for persons 12 years of age and older with at least 1 F508del mutation for the CFTR gene. This drug combination provides potential therapy to many patients who had previously been excluded from CFTR modulation therapy due to the nature of their genetic mutations. The efficacy demonstrated in clinical trials surpasses the currently available therapies related to lung function, quality of life, sweat chloride reduction, and reducing exacerbations. The most common adverse events seen in clinical trials included rash and headache, and laboratory monitoring is recommended to evaluate liver function. Continued evaluation of patient data is needed to confirm its long-term safety and efficacy. Elexacaftor-tezacaftor-ivacaftor is a monumental and encouraging therapy for cystic fibrosis; however, approximately 10% of the CF population are not candidates for this or any other CFTR modulation therapy.

scholarly journals Progress in precision medicine in cystic fibrosis: a focus on CFTR modulator therapy

Breathe ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. 210112
Author(s):  
Daniel H. Tewkesbury ◽  
Rebecca C. Robey ◽  
Peter J. Barry
Keyword(s):  
Cystic Fibrosis ◽  
Precision Medicine ◽  
Real World ◽  
Chloride Ion ◽  
Transmembrane Conductance Regulator ◽  
Therapeutic Approaches ◽  
Transmembrane Conductance ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane ◽  
Cftr Modulators

The genetic multisystem condition cystic fibrosis (CF) has seen a paradigm shift in therapeutic approaches within the past decade. Since the first clinical descriptions in the 1930s, treatment advances had focused on the downstream consequences of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel. The discovery of the gene that codes for CFTR and an understanding of the way in which different genetic mutations lead to disruption of normal CFTR function have led to the creation and subsequent licensing of drugs that target this process. This marks an important move towards precision medicine in CF and results from clinical trials and real-world clinical practice have been impressive. In this review we outline how CFTR modulator drugs restore function to the CFTR protein and the progress that is being made in this field. We also describe the real-world impact of CFTR modulators on both pulmonary and multisystem complications of CF and what this will mean for the future of CF care.

scholarly journals A European regulatory perspective on cystic fibrosis: current treatments, trends in drug development and translational challenges for CFTR modulators

2018 ◽  
Vol 27 (148) ◽  
pp. 170124 ◽  
Author(s):  
Stefano Ponzano ◽  
Giulia Nigrelli ◽  
Laura Fregonese ◽  
Irmgard Eichler ◽  
Fabio Bertozzi ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Drug Development ◽  
Forced Expiratory Volume ◽  
The European Union ◽  
End Points ◽  
Sweat Chloride ◽  
European Regulatory ◽  
Clinical Models ◽  
Cf Transmembrane Conductance Regulator ◽  
Cftr Modulators

In this article we analyse the current authorised treatments and trends in early drug development for cystic fibrosis (CF) in the European Union for the time period 2000–2016. The analysis indicates a significant improvement in the innovation and development of new potential medicines for CF, shifting from products that act on the symptoms of the disease towards new therapies targeting the cause of CF. However, within these new innovative medicines, results for CF transmembrane conductance regulator (CFTR) modulators indicate that one major challenge for turning a CF concept product into an actual medicine for the benefit of patients resides in the fact that, although pre-clinical models have shown good predictability for certain mutations, a good correlation to clinical end-points or biomarkers (e.g. forced expiratory volume in 1 s and sweat chloride) for all mutations has not yet been achieved. In this respect, the use of alternative end-points and innovative nonclinical models could be helpful for the understanding of those translational discrepancies. Collaborative endeavours to promote further research and development in these areas as well as early dialogue with the regulatory bodies available at the European competent authorities are recommended.

Test for the Concentration of Electrolytes in Cystic Fibrosis of the Pancreas Utilizing Pilocarpine by Iontophoresis, by Lewis E. Gibson and Robert E. Cooke,Pediatrics; 1959;24:545–549

PEDIATRICS ◽  
1998 ◽  
Vol 102 (Supplement_1) ◽  
pp. 230-231
Author(s):  
Victor Chernick
Keyword(s):  
Cystic Fibrosis ◽  
Filter Paper ◽  
Direct Injection ◽  
Heat Stroke ◽  
Chloride Concentration ◽  
Hot Water ◽  
Sweat Test ◽  
High Concentration ◽  
Sweat Chloride ◽  
Plastic Bag

Aim. To develop a method for stimulating sweating that is rapid, painless, and avoids the risk of heat stress. Background. Since the discovery that there is a high concentration of sodium and chloride in the sweat of patients with cystic fibrosis of the pancreas in 1953, the sweat test has been performed by placing the patient's body in a plastic bag with or without hot water bottles to stimulate sweating. This method is unsatisfactory because of complications such as hyperpyrexia and heat stroke. Direct injection of a cholinergic agent intradermally is painful and therefore not practical. Methods. A rheostat with a milliampere meter was constructed at a cost of ∼$7 that allowed the iontophoresis of pilocarpine into the skin using negative and positive (2-cm diameter) electrocardiography electrodes. The positive electrode was placed on the flexor surface of the arm over a filter paper soaked in 0.2 mL of 0.2% pilocarpine nitrate. Current (0.2 mA) was applied for 5 minutes and then sweat was collected onto a preweighed filter paper for 30 minutes. Sweat chloride was determined by a polarographic method. Sweat tests were performed on 25 patients with cystic fibrosis (CF), 17 asymptomatic relatives and 27 control patients. Patients with CF had sweat chloride concentration &gt;80 mEq/L; relatives, 32.5 mEq/L (highest 57 mEq/L); and control subjects, 21.1 mEq/L (highest 60 mEq/L). Conclusions. The iontophoresis of pilocarpine into the skin is a rapid, painless, safe, and reliable method for stimulating sweating and facilitating the determination of sweat chloride concentration.

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