Triple Therapy for Cystic Fibrosis <i>Phe508del</i>–Gating and –Residual Function Genotypes

Barry, Peter J.; Mall, Marcus; Álvarez, Antonio; Colombo, Carla; Groot, K.M. de Winter-de; Fajac, Isabelle; McBennett, Kimberly; McKone, Edward F.; Ramsey, Bonnie W.; Sutharsan, Sivagurunathan; Taylor‐Cousar, Jennifer L.; Tullis, Elizabeth; Ahluwalia, Neil; Jun, Lucy S.; Moskowitz, Samuel M.; Prieto-Centurion, Valentin; Tian, Simon; Waltz, David A.; Xuan, Fengjuan; Zhang, Yaohua; Rowe, Steven M.; Polineni, Deepika

doi:10.1056/nejmoa2100665

Cited by 156 publications

(115 citation statements)

References 18 publications

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“…The group ( n = 34) had a baseline mean sweat chloride on ivacaftor indicative of substantial drug response (52.6 mmol/L), but this value fell to 23.9 mmol/L at the 6-month visit after transitioning to ETI. This is below even the indeterminate range as a diagnostic test for CFTR dysfunction ( 34 ) and recapitulates recent clinical trial data in this population ( 35 ). Those entering the study on ivacaftor also experienced clinically meaningful and statistically significant improvements in ppFEV 1 , BMI, and respiratory symptoms when transitioning to ETI, supporting the benefit of drug-induced CFTR modulation even when CFTR function is already in the intermediate range.…”

Section: Discussionsupporting

confidence: 84%

Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial

Nichols

Paynter

Heltshe

et al. 2022

Am J Respir Crit Care Med

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169

126

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Rationale:The cystic fibrosis (CF) modulator drug elexacaftor/tezacaftor/ivacaftor (ETI) proved highly effective in controlled clinical trials for individuals with ≥1 F508del allele, which occurs in at least 85% of people with CF (PwCF). Objective: PROMISE is a post-approval study to understand the broad effects of ETI through 30 months clinical use in a more diverse US patient population with planned analyses after 6 months. Methods: Prospective, observational study in 487 PwCF age ≥12 years with ≥1 F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in ppFEV 1 , sweat chloride concentration, body mass index, and selfreported respiratory symptoms. Results: average age was 25.1 years. 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor while 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV 1 improved 9.76 percentage points (95% CI 8.76, 10.76) from baseline, CFQ-R Respiratory Domain score improved 20.4 points (95% CI 18.3, 22.5), and sweat chloride decreased -41.7 mmol/L (95% ). BMI also significantly increased.Changes were larger in those naïve to modulators but substantial in all groups, including those treated with ivacaftor at baseline. Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naïve to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV 1 in the overall study population.

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Section: Discussionsupporting

confidence: 84%

Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial

Nichols

Paynter

Heltshe

et al. 2022

Am J Respir Crit Care Med

Self Cite

169

126

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“…L/I decreased the total bacterial load and increased the diversity of the airway microbiome in F508del homozygous patients [30]. ETI treatment has showed to confer additional benefits relative to previous CFTR modulators in patients with F508del homozygosity [8], F508del-gating or F508del-residual function genotypes [31]. To evaluate the microbiological effect of more effective CFTR rescue, longer observation times are needed.…”

Section: Discussionmentioning

confidence: 99%

Elexacaftor/Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation and Advanced Lung Disease: A 48-Week Observational Study

Carnovale

Iacotucci

Terlizzi

et al. 2022

JCM

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Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is the newest cystic fibrosis transmembrane conductance regulator (CFTR) modulator drug approved for the treatment of patients with cystic fibrosis (pwCF) aged ≥6 years with at least one copy of the F508del mutation (F) in the CFTR gene or another mutation that is responsive to treatment with ETI. This study determined the effectiveness and safety of ETI in a cohort of severely affected pwCF with an F/F genotype. Methods: Retrospective observational study in F/F pwCF treated for 48 weeks, enrolled in an ETI managed access program available to subjects with advanced lung disease (ppFEV1 < 40). Twenty-six patients from three centres were included. The main outcomes included lung function, sweat chloride concentration (SCC), nutrition, frequency of pulmonary exacerbations (PEx), CFQ-R, and safety. Results: ppFEV1 improved by 12.06 (95%CI 8.54, 15.57) from baseline after 4 weeks of treatment with ETI, 15.32 (11.3, 19.34) after 24 weeks, and 14.48 (10.64, 18.32) after 48 weeks. The increase in FEV1 was accompanied by a decrease in SCC, improvement of BMI, and noticeable reduction in PEx. An overall good safety profile was observed. Conclusions: In F/F pwCF with advanced lung disease with an F/F genotype, ETI was safe and associated with clinical improvement.

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“…The newly developed CFTR corrector elexacaftor (VX445) in the combination named trikafta, where it is combined with the corrector VX661 and the potentiator ivacaftor (VX770), administered to F508del-homozygous and F508del-heterozygous with minimal function mutation patients, has been shown to be effective and safe, and results in a clinical response that is appreciably better than that of previous CFTR modulators. In fact, in these patient cohorts, the triple-combination regimens significantly reduced sweat chloride concentration, decreased the incidence of pulmonary exacerbations, and ameliorated FEV 1 [32]. The use of the triple combination (VX445 + VX661 + VX770) gave also positive outcomes in rescuing some other CFTR rare mutations [33,34].…”

Section: Introductionmentioning

confidence: 91%

NBD2 Is Required for the Rescue of Mutant F508del CFTR by a Thiazole-Based Molecule: A Class II Corrector for the Multi-Drug Therapy of Cystic Fibrosis

et al. 2021

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Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, an anion channel that regulates epithelial surface fluid secretion. The deletion of phenylalanine at position 508 (F508del) is the most common CFTR mutation. F508del CFTR is characterized by folding and trafficking defects, resulting in decreased functional expression of the protein on the plasma membrane. Several classes of small molecules, named correctors, have been developed to rescue defective F508del CFTR. Although individual correctors failed to improve the clinical status of CF patients carrying the F508del mutation, better results were obtained using correctors combinations. These results were obtained according to the premise that the administration of correctors having different sites of action should enhance F508del CFTR rescue. We investigated the putative site of action of an aminoarylthiazole 4-(3-chlorophenyl)-N-(3-(methylthio)phenyl)thiazol-2-amine, named FCG, with proven CFTR corrector activity, and its synergistic effect with the corrector VX809. We found that neither the total expression nor the maturation of WT CFTR transiently expressed in human embryonic kidney 293 cells was influenced by FCG, administrated alone or in combination with VX809. On the contrary, FCG was able to enhance F508del CFTR total expression, and its combination with VX809 provided a further effect, being able to increase not only the total expression but also the maturation of the mutant protein. Analyses on different CFTR domains and groups of domains, heterologously expressed in HEK293 cells, show that NBD2 is necessary for FCG corrector activity. Molecular modelling analyses suggest that FCG interacts with a putative region located into the NBD2, ascribing this molecule to class II correctors. Our study indicates that the continuous development and testing of combinations of correctors targeting different structural and functional defects of mutant CFTR is the best strategy to ensure a valuable therapeutic perspective to a larger cohort of CF patients.

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Triple Therapy for Cystic Fibrosis Phe508del–Gating and –Residual Function Genotypes

Cited by 156 publications

References 18 publications

Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial

Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial

Elexacaftor/Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation and Advanced Lung Disease: A 48-Week Observational Study

NBD2 Is Required for the Rescue of Mutant F508del CFTR by a Thiazole-Based Molecule: A Class II Corrector for the Multi-Drug Therapy of Cystic Fibrosis

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