Kalydeco (ivacaftor) / Vertex - LARVOL DELTA

Pre-clinical Evidence for Ivacaftor as a Potential Repurposed Therapy for High-Grade Serous Ovarian Cancer and Endometrial Cancer (EACR 2025) - "Cells were treated with 15uM ivacaftor and 30uM carboplatin for 24, 48, and 72 hrs for flow cytometry analysis using Apoptosis, DNA Damage and Cell Proliferation Kit (BD Biosciences) which stained for fluorophores against cleaved PARP, H2Ax, and BrdU. In conclusion, Ivacaftor demonstrated significant single agent anti-tumour potential in preclinical HGSOC and endometrial cancer models, supporting its further investigation as a repurposed therapy for ROR1-expressing ovarian and endometrial cancers."

Preclinical • Cystic Fibrosis • Endometrial Cancer • Genetic Disorders • High Grade Serous Ovarian Cancer • Immunology • Oncology • Ovarian Cancer • Respiratory Diseases • Solid Tumor • ANXA5 • AURKA • ROR1

CFTR modulator drugs can reduce the invasive properties of colorectal cancer cells (EACR 2025) - "Given recent advances in small-molecule modulators that restore CFTR function in CF patients, this study explored the potential of repositioning these modulators to address CFTR downregulation in sporadic CRC.Material and Using a panel of CRC cell lines, we investigated whether CFTR modulators can increase CFTR functional expression in cells with various genetic backgrounds and whether such improvements could reduce their oncogenic properties.Result and Our data show that treatment with the CFTR folding correctors VX-661 and VX-445 led to a significant, approximately three-fold increase in CFTR abundance in CRC cells expressing reduced but detectable levels of the channel. Our findings suggest that CFTR modulators may hinder the oncogenic properties of CRC cells. Further in vivo studies are necessary to fully assess their potential benefits for repositioning as a CRC treatment."

Colorectal Cancer • Cystic Fibrosis • Genetic Disorders • Immunology • Oncology • Respiratory Diseases • Solid Tumor • CFTR

Ivacaftor Impact in an Adolescent Without a Cystic Fibrosis-Associated CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) Mutation for Chronic Pancreatitis: Single-Patient Study Tracking Flare Frequency and Health Data Compared to Historical Records. (clinicaltrials.gov) - P=N/A | N=1 | Active, not recruiting | Sponsor: Mission: Cure

New trial • Cystic Fibrosis • Genetic Disorders • Immunology • Pancreatitis • Pulmonary Disease • Respiratory Diseases

Repurposing FDA-approved allosteric drugs as non-competitive inhibitors of human UGTs: An integrated computational study and biochemical validation. (PubMed, Toxicol Appl Pharmacol) - "Pharmacokinetic modelling suggests that clinically relevant concentrations of ivacaftor and cinacalcet may modulate UGT1A9- and UGT1A1-mediated clearance, revealing a previously unrecognized drug-drug-interaction risk. Altogether, the work delivers the small-molecule allosteric probes for UGTs, establishes a general workflow for mining existing drugs as phase-II enzyme modulators, and provides a structural framework for developing isoform-selective UGT therapeutics."

FDA event • Journal • CNS Disorders • Depression • Psychiatry • UGT1A1 • UGT1A9

Preliminary proposals for the follow-up of infants born to mothers with cystic fibrosis treated with CFTR modulators during the first two years of life. (PubMed, Arch Pediatr) - "The number of pregnancies in women with cystic fibrosis (CF) has significantly increased in recent years, leading to a corresponding rise in the number of healthy infants exposed to cystic fibrosis transmembrane conductance regulator modulator (CFTRm) such as elexacaftor-tezacaftor-ivacaftor (ETI) or Kaftrio/Kalydeco® (K/K) triple therapy. A working group from the Société Française de la Mucoviscidose has developed recommendations for monitoring these children during the first two years and beyond. Given the increasing number of infants born to mothers taking CFTR modulators, as well as questions regarding their immediate care during the maternity stay and the feasibility of breastfeeding, it is crucial for pediatricians to be aware of these recommendations, which are based on a comprehensive review of the literature."

Journal • Cataract • Cystic Fibrosis • Genetic Disorders • Immunology • Ophthalmology • Pediatrics • Pulmonary Disease • Respiratory Diseases • CFTR

Differential Expression and Microsystem Physiology Reveal Predominant and Drug Reversible CFTR-Related Defects in Idiopathic Pancreatitis. (PubMed, bioRxiv) - "Additionally, the test methods and model systems discovered in this study will significantly expedite the discovery of diagnostic and therapeutic tools for treating idiopathic pancreatitis. For the first time, we provided molecular and physiologic evidence supporting the benefit of CFTR modulator drug ivacaftor in human CFTR-related pancreatitis."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Oncology • Pancreatic Cancer • Pancreatitis • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CCL20 • CFTR • CXCL8

In vitro restoration of colistin susceptibility by ivacaftor with non-replication in a murine pneumonia model (ECFS 2025) - "Under in vitro conditions, ivacaftor restore colistin sensitivity in previously resistant isolates. This effect was not maintained in vivo in a mouse pneumonia model. The synthesis of a variety of phosphoethanolamine seems to be the reaction of the bacteria after exposure to ivacaftor."

Preclinical • Infectious Disease • Pneumonia • Respiratory Diseases

Health outcomes for PwCF switching from a CFTR modulator therapy (CFTRm) to elexaftor/tezacaftor/ivacaftor (ETI) compared with those starting on ETI naively. A study using Irish registry data (ECFS 2025) - "This preliminary analysis suggests that despite C2's higher baseline BMI, PwCF who switched from Ivacaftor displayed similar patterns to modulator-nave patients and those who switched from a less effective CFTRm. Further analysis will include 2024 data, and stratification by genotype and disease severity."

HEOR • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Scoping review protocol: Diet composition and quality in children with cystic fibrosis in the modulator era (ECFS 2025) - "Dates were limited 2012-present, from when ivacaftor was first licensed for US CwCF... This review is currently underway and full results will be available by June 2025. It will outline future research opportunities and determine the need for and scope of a systematic review."

Clinical • Review • Cystic Fibrosis • Genetic Disorders • Immunology • Novel Coronavirus Disease • Respiratory Diseases

Mental health issues in children aged 6 to 12 on triple modulator therapy in Bulgaria (ECFS 2025) - "The boy due to very conserved lung health is currently on a reduced dose in the morning and stopped the ivacaftor in the evening, and mood changes disappeared however the observed benefits on lung and weight were not maintained...Paracelsus is credited for the saying "The dose makes the poison" so maybe dosing according the age should not be the best solution for CF patients. We still are waiting for the miracle drug without side effects, because sometimes mental health issues override the positive benefits for the organism of the drug itself."

Clinical • CNS Disorders • Cystic Fibrosis • Depression • Genetic Disorders • Immunology • Mood Disorders • Psychiatry • Pulmonary Disease • Respiratory Diseases

Silent' lung disease progression in people receiving elexacaftor/tezcaftor/ivacaftor (ETI) therapy revealed by Oxygen Enhanced-MRI (OE-MRI) and Multiple breath washout with Short extension (MBWShX­) (ECFS 2025) - "Reliance on conventional OMs may lead to false reassurance about disease stability over time; particularly in relation to assessing safe withdrawal of standard treatments. In contrast, OE-MRI and MBWShX appear to have the additional sensitivity required to demonstrate subtle disease progression that may predominate in the post-modulator era. This could allow earlier intervention, tailored care and provide a more reliable future trial outcome.Funded by the CF Foundation"

Pulmonary Disease • Respiratory Diseases

Analyzing the impact of elexacaftor/tezacaftor/ivacaftor treatment and Pseudomonas infection on gene expression in cystic fibrosis primary bronchial epithelial cultures (ECFS 2025) - "Our study underscores the importance of incorporating live bacteria to faithfully replicate the CF lung for investigating how bacterial infections and CFTR modulators impact gene expression in airway epithelia."

Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Respiratory Diseases • CFTR

​​​​​Elexacaftor/tezacafor/ivacaftor improves bronchial dilatation in a real-world cohort of adolescents with cystic fibrosis (ECFS 2025) - "Objective: Elexacaftor/ tezacaftor/ivacaftor (ETI) improves clinical status of adolescents with cystic fibrosis (aCF). ETI improves significantly bronchial dilatation and bronchial wall thickness in aCF. Our data suggest a decrease in the number of bronchiectasis at 1 year ETI in correlation with improvement in bronchial inflammation, lung distension and mucus distal bronchial obstruction."

Clinical • Real-world • Real-world evidence • Bronchiectasis • Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Pediatrics • Pneumonia • Pulmonary Disease • Respiratory Diseases

CFTR mRNA delivery with a revolutionary non-LNP nanoemulsion formulation to differentiated primary human airway epithelium and airway organoid (ECFS 2025) - "Our results demonstrate the capability of the NEEDTM platform to deliver optimised CFTR mRNA in ALI hAE and hBE cultures, as well as CF organoid. These preclinical data warrant further investigation of CFTR delivery and functional rescue in cells derived from CF patients."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

First report of continuous administration of elexacaftor/tezacaftor/ivacaftor from in utero to 1 year of age (ECFS 2025) - "Continuous administration of ETI from pregnancy to 14 months was well tolerated, seems to hinder CF pulmonary and pancreatic disease, and to preserve vas deferens."

Cystic Fibrosis • Developmental Disorders • Gastrointestinal Disorder • Genetic Disorders • Immunology • Infectious Disease • Pancreatitis • Pediatrics • Pulmonary Disease • Respiratory Diseases

Highly-effective CFTR modulation and lung development by age, gender, and height among children with cystic fibrosis (ECFS 2025) - "Highly effective modulator therapy (HEMT), such as ivacaftor (IVA) has lead to profound improvements for people with cystic fibrosis... This study shows that while all age groups benefit from IVA, girls age 11-13 and boys age 13-15 have an additional annual increase in FVC that would be lost without IVA. Additionally, those who are shorter or grew the slowest are at the greatest risk for impaired lung development, but this is offset by IVA.Impact of IVA on FVC for males age 13-15Age131415No IVAslow3.021163.3255943.630028No IVAaverage3.1716633.6096564.047649No IVAfast3.021163.5209374.020714IVAslow3.021163.4232663.825371IVAaverage3.1716633.6477124.123761IVAfast3.1716633.6857684.199873"

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Challenges in evaluating the Long-term effectiveness of cystic fibrosis modulator therapies after rapid and widespread adoption: a dual-approach study (ECFS 2025) - "Ivacaftor was associated with improved ppFEV1 across all age groups, with the magnitude of improvement approximately 50% of that observed in clinical trials. The results support the use of within-subject analysis in future modulator effectiveness studies, but caution is advised in younger individuals due to developmental changes that may affect pre- and post-treatment comparability."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Real world study of effect of elexacaftor/tezacafor/ivacaftor in school age children with cystic fibrosis (ECFS 2025) - "Elexacaftor/tezacaftor/ivacaftor (ETI) improves sweat chloride, pulmonary function, nutrition, and quality of life in people with cystic fibrosis (CF)...This abstract focuses on the school age cohort. Participants aged 6 to 12 years homozygous for the F508del mutation who switched from Orkambi or heterozygous for F508del nave from modulators were recruited at ETI initiation and were followed up over 12 months... ETI improves respiratory disease of school age children with cystic Fibrosis."

Clinical • Real-world • Real-world evidence • Cystic Fibrosis • Genetic Disorders • Immunology • Pediatrics • Respiratory Diseases • CXCL8 • ELANE • IL6

CFTR Modulator VX770 Inhibits Cell Senescence and Mitigates Bleomycin Induced Pulmonary Fibrosis in Mouse Lung (ATS 2025) - "To date, only Pirfenidone and Nintedanib have been approved by the FDA for the treatment for IPF patients. Our results demonstrate that VX770 mitigates the BLM-induced pulmonary fibrosis in mice in part by inhibiting inflammation and AT2 cell senescence. There are controversies about whether VX770 potentiates murine CFTR, thus the mechanism of action in these studies remains to be determined. This study thus provides evidence of the anti-fibrotic role of VX770 and warrants for further investigations of its therapeutic potential in treatment of IPF."

Preclinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CCL2 • CDKN1A • COL1A1 • CTHRC1 • IL6 • KRT7 • RUNX1 • TGFB1 • VIM

Ivacaftor Restrains Th2 Cell Development Through a CFTR/IL-4/GATA3 Axis and Reduces Alternaria-induced Allergic Airway Inflammation (ATS 2025) - "Collectively, these findings demonstrate that CFTR plays a direct role in modulating T cell sensitivity to IL-4, reducing the IL-4/GATA3 signaling axis and restraining Th2 development. The CFTR potentiator ivacaftor represents a new class of therapies to be repurposed for allergic disease."

Allergic Bronchopulmonary Aspergillosis • Asthma • Cystic Fibrosis • Genetic Disorders • Inflammation • Otorhinolaryngology • Respiratory Diseases • Sinusitis • CD4 • GATA3 • IL13 • IL4 • IL5

Complex Neonatal Presentation of Cystic Fibrosis (CF) with Concurrent Diaphragmatic Hernia and Multiorgan System Failure (ATS 2025) - "Initial days of his neonatal course were complicated with multiorgan failure including echo revealing pericardial effusions with an ejection fraction of 39% upon admission , AST and ALT of 4,177 U/L and 1,182 U/L, respectively, and grade 2 intraventricular hemorrhages.The baby required a multidisciplinary approach, including a cooling protocol that was discontinued after 2 hours due to abnormal coagulation parameters, and hydrocortisone for cardiac support...He was started on ivacaftor therapy for CF on day 39...It also emphasizes the need for further research to explore the interplay between CF and associated congenital conditions, as well as the uncommon neonatal presentations of CF. Additionally, rigorous studies are needed to assess the risk/benefit ratio of prenatal ETI use to improve management and outcomes."

Cardiovascular • Cystic Fibrosis • Gastroenterology • Genetic Disorders • Hematological Disorders • Immunology • Respiratory Diseases • CFTR

Nasal Transcriptomics Associate With Sinonasal Disease Response to Trikafta (ATS 2025) - "This abstract is funded by: NHLBI R01-HL149693 RATIONALE: Highly effective modulators like elexa/teza/ivacaftor (ETI) have made a significant impact in people living with CF (pwCF), yet variability in clinical responses remains unexplained. We identified transcriptomic profiles in nasal respiratory epithelium from pwCF that were significantly associated with change in sinonasal disease symptoms after ETI treatment initiation. Models including the TS showed high accuracy in predicting sinonasal response to ETI."

Inflammation • Otorhinolaryngology • CD163 • CXCL10 • FCGR1A • IL17C • IRF8

Cyclodextrin-Based Inclusion Complexes Improve the In Vitro Solubility and Pharmacokinetics of Ivacaftor Following Oral Administration in Mice. (PubMed, AAPS PharmSciTech) - "In addition, HP-β-CD extended the release of IVA from the IVA/HP-β-CD complexes with a longer Tmax of 7.05 h compared to 2.96 h with Kalydeco® tablets. These results demonstrate that CD inclusion complexes of IVA using HP-β-CD can be a successful alternative approach to improving the solubility of IVA while extending its release."

Journal • PK/PD data • Preclinical • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

LONGITUDE: An observational study of the long-term effectiveness of elexacaftor/tezacaftor/ivacaftor in people aged ≥12 years with cystic fibrosis using data from the United Kingdom Cystic Fibrosis Registry - 2-year analysis. (PubMed, J Cyst Fibros) - "People with CF aged ≥12 years in the UK who initiated ELX/TEZ/IVA had sustained improvements in multiple CF-related health outcomes, consistent with results from clinical trials. These results support the positive impact of ELX/TEZ/IVA on the lives of people with CF."

Journal • Observational data • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Transplantation

Ivacaftor affects the susceptibility of standard-of-care drugs used to treat Mycobacterium abscessus lung disease. (PubMed, Antimicrob Agents Chemother) - "We found that one of the CFTR modulators, ivacaftor, kills MAB in a concentration-dependent manner, with killing efficacy comparable to amikacin and imipenem, drugs in guideline-based regimens. Using clinical isolates of MAB, amikacin 1/4× MIC concentration combined with ivacaftor killed 2.67 log10 CFU/mL MAB."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases • CFTR