The triple CFTR modulation therapy demonstrated good tolerability with only mild or moderate adverse effects and very low rate of discontinuation [20, 21]. Epub 2016 Feb 22. Lee SE, Farzal Z, Daniels MLA, Thorp BD, Zanation AM, Senior BA, Ebert CS Jr, Kimple AJ. The results of these phase 3 clinical studies were similar for the F508del–minimal function and F508 homozygous patients, showing an improvement of FEV1 % pred (in the range of 10.4–13.8%) compared to the control [20] or actively-controlled patients [21], reduction of the sweat chloride concentration (−39.1 to −43.4) and higher patient-reported quality of life. CFTR modulators are a class of drugs which directly target the defective CFTR protein in cystic fibrosis (CF), improving its function with resultant clinical improvements. 2018 Jun 1;197(11):1433-1442. doi: 10.1164/rccm.201710-1983OC. While this discovery constituted an improvement for numerous CF patients F508del homozygous, it is a life changing treatment for those patients with F508del–minimal function genotypes, in whom previous CFTR modulators were ineffective. Despite heterogeneity in patient response, the majority of CF patients will be greatly impacted by using a CFTR modulator therapy, thus changing the trajectory of their life. In addition, even with these novel drug therapies, managing infections will continue to be a challenge, thus the CF community will need to adapt the standards for an improving, but ageing CF population. … Thank you for your interest in spreading the word on European Respiratory Society . The triple-combination or Trikafta has recently received FDA approval for patients aged 12 years or older who have at least one copy of the F508del CFTR mutation [22, 23]. Effects of Lumacaftor-Ivacaftor Therapy on Cystic Fibrosis Transmembrane Conductance Regulator Function in Phe508del Homozygous Patients with Cystic Fibrosis. Pharmacological modulators of F508del-CFTR, aimed at correcting the cellular processing defect (correctors) and the gating defect (potentiators) in CFTR protein, are regarded as promising therapeutic agents for CF disease. This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. 2020 Jul;34(4):573-580. doi: 10.1177/1945892420912368. Over the past decade, CFTR protein modulators have been developed, which improve CFTR function either through potentiation of the abnormal protein channel at the cell surface (eg, ivacaftor) or through correction of protein transport to the cell surface (eg, lumacaftor and tezacaftor); these treatments have now been approved by the European Medicines Agency and US Food and Drug Administration for use in people with cystic fibrosis … Driving causes proposed for this variability [28] as well as disease severity [29] have been the genetic variants within and outside the CFTR locus [30]. These CFTR modulators are each approved for specific mutations and age groups. In this review, we discuss issues regarding drug interactions, organ transplantation and CFTR modulation. Enter multiple addresses on separate lines or separate them with commas. Authors: On behalf of the European CF Society (ECFS) Strategic Planning Task Force on ‘Speeding up access to new drugs for CF’: Margarida Amaral6, Kris de Boeck7, Jane C Davies1, […] Read more. Pediatr Clin North Am. While patients homozygous for F508del are usually prescribed either lumacaftor plus ivacaftor or tezacaftor plus ivacaftor, patients with only one copy of F508del are rarely prescribed these treatments given their reported inefficacy. It has been demonstrated that lumacaftor acts to stabilise the mutant CFTR in the early stages of biogenesis by interacting directly with the CFTR protein [14, 15]. Recent evidence suggests respiratory viral infection may trigger the muco-inflammatory phenotype observed in the CF airways. The Cystic Fibrosis Foundation has put forth efforts through the Infection Research Initiative to tackle these issues, including the development of new anti-infective therapies. A defective CFTR protein produces an impaired ion and fluid secretion in the epithelial cells affecting several organs and leading to severe lung disease. Airway Inflammation and Host Responses in the Era of CFTR Modulators. Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators represent a paradigm shift in the treatment landscape of CF ().The effects of CFTR modulators on respiratory function, pulmonary exacerbations, and quality of life have been well documented, as these important clinical endpoints form the basis for regulatory agency approval (). HHS Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene [1]. Overall the triple-combination, elexacaftor, tezacaftor, and ivacaftor (marketed as Trikafta, Vertex Pharmaceuticals), demonstrated statistically significant and/or clinically meaningful improvements in lung function (10–14% of FEV1 % pred) and respiratory-related quality of life for patients with one copy of the F508del mutation and a minimal-function mutation and patients with two F508del copies [20, 21]. Nash EF(1), Middleton PG(2), Taylor-Cousar JL(3). Clin Case Rep. 2019 Feb 17;7(4):616-618. doi: 10.1002/ccr3.2053. Identification of 99% of CFTR gene mutations in Bulgarian-, Bulgarian Turk-, and Roma cystic fibrosis patients. Cystic fibrosis transmembrane conductance regulator-modifying medications: the future of cystic fibrosis treatment. Recent studies are evaluating the impact that CFTR modulators such as lumacaftor/ivacaftor have on infections, including patients with severe lung disease [55]. • S 19 : Dilemmas in CFTR modulators • S 25 : Novel clinical outcome measures in pre-school children with cystic fibrosis • S 29 : What’s influencing adherence ? Treating Specific Variants Causing Cystic Fibrosis. NIH Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators - an international survey. Online ISSN: 2073-4735, Copyright © 2020 by the European Respiratory Society. It is reasonable to speculate that these drugs will alter the natural history of the disease. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. However, accumulating evidence from previous CFTR modulators prescriptions suggest that not all the patients who are predicted to respond to these treatments might experience the expected benefit. THERANOSTICS BY TESTING CFTR MODULATORS … Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Mutations that result in CFTR being expressed on the cell surface but incorrectly regulated, such as G551D, were the most straightforward targets. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. It is an oral medication approved by the U.S. Food and Drug Administration (FDA), the EU, and Health Canada for CF patients as young as 1 with at least one mutation (such as G551D) that impairs chloride ion flow. Research efforts to evaluate the clinical effectiveness and impact on infections is ongoing in future triple-combination CFTR modulator therapy studies [51]. CFTR modulators increase the phagocytic capacity in CF macrophages, alter CF macrophage cytokine production, and alter CF monocyte activation 27, 50, 51. This excludes many patients who may benefit from the multisystem effects of CFTR modulator treatment. The three main types of modulators are potentiators, correctors, and amplifiers. The aims of my research were to investigate the mechanisms Of action of small-molecule CFTR modulators that regulate CFTR function. Instead, tezacaftor/ivacaftor (Symdeko, Vertex Pharmaceuticals) appeared to have a more favourable adverse event and drug-drug interaction profile [7, 18, 19] than lumacaftor/ivacaftor. Although the triple-combination therapy achieved an improvement in patients homozygous for F508del much higher than previous CFTR modulators, reaching levels comparable to the benefit of ivacaftor for G551D patients, the benefit observed for patients with only one F508del copy involved more profound significance for the CF treatment paradigm of these patients. In this study, although treatment with lumacaftor/ivacaftor reduced exacerbations, the unacceptably frequent adverse events resulted in a very high discontinuation rate [55]. CFTR modulators have dramatically changed the clinical course of CF in those fortunate enough to receive them. Furthermore, it remains to be determined whether the next generation of modulators will be effective for individuals bearing rare mutations that are Orkambi resistant. Experts in the CF field still maintain that “structural biology and functional studies are a powerful combination to elucidate fundamental knowledge about CFTR and are key for the development of better drugs to enable people with CF to live full and active lives” [44, 45]. In addition to the lung disease symptoms, CF usually affects pancreas, liver and digestive system, often leading to pancreatic insufficiency, CF-related diabetes, CF liver disease, severe malabsorption and meconium ileus [56–58]. The first U.S. Food and Drug Administration (FDA) approved drug was ivacaftor (VX-770; Kalydeco, Vertex Pharmaceuticals) [9], a “potentiator” that affected the gating properties of mutant CFTR channel activity (e.g. Potentiators and correctors. The most common mutation, the deletion of phenylalanine at position 508 (F508del), induces misfolding of the protein that is retained in the endoplasmic reticulum and degraded by proteasomal pathways [6]. This was followed by phase 2 clinical studies where a triple combination of CFTR modulators was tested in patients who were heterozygous for the F508del CFTR mutation and a minimal-function mutation (F508del–minimal function genotype), demonstrating improvements in CFTR function and clinical outcomes. CFTR modulators are an exciting new class of drugs that treat the underlying defect with small molecules that either improve intracellular trafficking or activates the defective CFTR channel. Even in the era of CFTR modulation therapies, the detection, diagnosis, and treatment of some CF micro-organisms remains challenging, especially for patients with more advanced stages of lung disease [51]. This last decade has created historical moments for CF, primarily driven by the development of CFTR modulators. It has been demonstrated that Orkambi showed a modest response to some of these rare mutations (A455E, M1101K, N1303K) in heterologous expression systems [38, 39]. Thus, differences in the type of microbial infections across patients and even within a single patient over time could explain the low efficacy in some cases and the high patient-to-patient variability in Orkambi response. Ivacaftor is a CFTR potentiator that improves channel opening and is commissioned in the UK for patients with gating mutations, most commonly G551D. CFTR modulators are currently considered contraindicated in patients with a solid organ transplant. 2016 Aug;63(4):751-64. doi: 10.1016/j.pcl.2016.04.006. There are more than 1900 different variants of the CFTR gene, but most people with CF (over 90% in the UK) have at least one copy of the faulty F508del gene. SPEEDING UP ACCESS TO NEW DRUGS FOR CYSTIC FIBROSIS: CONSIDERATIONS FOR CLINICAL TRIAL DESIGN AND DELIVERY. Electronic address: edward.nash@heartofengland.nhs.uk. These encouraging results led to the first phase 3, multicentre, randomised, double-blind, placebo-controlled clinical trial where the triple-combination, elexacaftor, tezacaftor, and ivacaftor, was randomised versus placebo for 403 patients with F508del–minimal function genotypes for 24 weeks [20]. However, long-term treatment (24–48 h) of lumacaftor in combination with ivacaftor in vitro diminishes the pharmacological correction of F508del-CFTR [16, 17]. However, treatment with antibiotic tobramycin and antimicrobial peptide, has been shown to restore Orkambi-mediated rescue of F508del-CFTR function in human bronchial epithelial cells infected with clinical strains of P. aeruginosa [54]. Lumacaftor/ivacaftor initiation in two liver transplantation patients under tacrolimus and antifungal azoles. It may be foreseeable that additional therapies or changes to standard of care are needed for these patients, in hopes of changing the scenario from a life-shortening disease to a treatable chronic condition. In addition to CFTR-directed modulators, CFTR dysfunction might be compensated by targeting alternative ion channels, such as ENaC (Moore and Tarran, 2018), the calcium-activated chloride channel transmembrane protein membrane 16A (TMEM16A) (Sondo et al., 2014), and the solute carrier 26A9 (SLC26A9) (Balázs and Mall, 2018). These drugs demonstrate disease modulation by decreasing pulmonary exacerbations as well as lung function decline, a correlate of survival [ 1 eCollection 2019 Apr. We do not capture any email address. Moreover, a reduction of exacerbations was observed for patients with F508del–minimal function genotypes compared to placebo [20], as well as improvements of BMI [20, 21], which in CF, usually correlates with better survival. First for patients with gating mutations who benefited from Kalydeco, then for those patients with one F508del copy who could benefit from Orkambi, and most recently, patients with at least one F508del copy who can benefit from Trikafta. Epub 2019 Jun 27. This site needs JavaScript to work properly. JAMA.  |  COVID-19 is an emerging, rapidly evolving situation. Why this difference? This patient-to-patient variability has been represented in vitro using patient samples, where it was observed that patient responses to lumacaftor or Orkambi can largely vary even among people carrying the same CFTR mutation [25–27]. In addition, scientists are comparing and trying to elucidate the robustness of current methods and markers used to evaluate the benefit of these new modulation therapies [27, 46, 47]. Copyright © 2018 Elsevier Ltd. All rights reserved.  |  4 September 2019. Currently these drugs are confined to people with a limited selection of genetic mutations. Among the approved CFTR modulators, Trikafta can be applicable to the largest number of CF patients [20, 22], as it aims to target those with at least one copy of the F508del CFTR mutation, accounting for up to 90% of people with CF [24]. Symdeko was approved, alongside F508del, for a large number of “residual function” CFTR mutations based on in vitro culture responses, paving the way for the triple CFTR modulation [7]. Subsequently, a CFTR “corrector” drug, lumacaftor (VX-809), in combination with ivacaftor (lumacaftor/ivacaftor or Orkambi, Vertex Pharmaceuticals) [12] also showed a modest clinical improvement for patients bearing F508del mutation [13]. Breathe articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. Petrova G, Yaneva N, Hrbková J, Libik M, Savov A, Macek M Jr. Mol Genet Genomic Med. Because different mutations cause different defects in the protein, the medications that have been developed so far are effective only in people with specific mutations. Patients with CFhave mutations in the CFTR gene, which is supposed to create a protein thatregulates the flow of water and chloride in and out of the cells that line thelungs, pancreas, and other organs. Epub 2012 Jun 26. Cystic fibrosis is caused by a faulty gene that affects the production of a protein called CFTR. Ann Pharmacother. CFTR modulators currently in the clinic The clinical introduction of CFTR modulators, which are able to restore some CFTR function, has significantly improved … However, CFTR mutations can lead to theproduction of defective proteins or to producing no protein at all. However, it should not be forgotten that there still remains 10% of the CF population who do not have a targeted CFTR modulator treatment. Conflict of interest: O. Laselva has nothing to disclose. Am J Respir Crit Care Med. 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