Kalydeco (ivacaftor) / Vertex - LARVOL DELTA

VX21-522-001: A Phase 1/2 Study of VX-522 in Participants With Cystic Fibrosis (CF) (clinicaltrials.gov) - P1/2 | N=39 | Suspended | Sponsor: Vertex Pharmaceuticals Incorporated | Trial primary completion date: May 2027 ➔ Dec 2026

Trial primary completion date • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

CFTR Modulators Counteract F508del CFTR Functional Defects in a Pancreatic Epithelial Model of Cystic Fibrosis. (PubMed, Life (Basel)) - "This study evaluated the effects of the CFTR modulators, VX770 (ivacaftor), VX661 (tezacaftor), and VX445 (elexacaftor), administered either individually or in combination, on CFPAC-1 cells, a pancreatic ductal epithelial cell line derived from a cystic fibrosis patient harboring the F508del CFTR mutation. However, they did not reduce cytokine expression under pro-inflammatory conditions. Collectively, these findings show that CFTR modulators can restore critical aspects of cystic fibrosis pancreatic epithelial physiology in vitro, even under pro-inflammatory stress, supporting their potential relevance beyond the airway disease."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • CFTR • CXCL8 • IL1B • IL6

Long term causal effects of ivacaftor on airway microbiology and lung function outcomes in people with cystic fibrosis: An emulation of target trials with the U.S. CF Foundation Patient Registry data (NACFC 2025) - No abstract available

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

Understanding the action of bamocaftor as a potential drug candidate against Cystic Fibrosis Transmembrane Regulator protein: A computational approach. (PubMed, PLoS One) - "The simulation revealed that the CFTR protein remained more stable and compact when complexed with Bamocaftor, when compared to Ivacaftor and Galicaftor. Our findings reveal the action of bamocaftor on CFTR protein with p.Phe508del variation. However, the absence of in-vivo or in-vitro studies is a limitation, and further experimental validation is necessary to confirm its efficacy and safety."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Primary Suspect Drugs of Cataracts in Pediatric Patients: An FDA Adverse Events Reporting Database Analysis. (PubMed, J Cataract Refract Surg) - "Three potential drug-adverse event pairs were identified for pediatric cataracts, including a previously infrequently described association with ivacaftor and topotecan. Prednisolone, consistent with known corticosteroid-induced cataractogenesis, also demonstrated a positive signal. These findings raise drug safety concerns and warrant further investigation."

Adverse events • Journal • Cataract • Ophthalmology • Pediatrics

AIFA Board of Directors approves the reimbursability... [Google translation] (Italian Medicines Agency) - "...two medicines for cystic fibrosis, Kaftrio (ivacaftor/tezacaftor/elexacaftor) in combination with ivacaftor and Kalydeco (ivacaftor) as monotherapy or in combination with ivacaftor/tezacaftor/elexacaftor....The reimbursement-eligible generic is Dalbavancin Teva (dalbavancin), an antibiotic indicated in acute bacterial skin and soft tissue infections (ABSSSI) in adults and paediatric patients aged 3 months and older."

Reimbursement • Cystic Fibrosis • Infectious Disease

Divergent Neurobehavioral Effects of CFTR Modulators Elexacaftor and Ivacaftor in Mice. (PubMed, bioRxiv) - "Among these, the elexacaftor-tezacaftor-ivacaftor combination (Trikafta) and its updated formulation, vanzacaftor-tezacaftor-deutivacaftor (Alyftrek), represent major therapeutic milestones. Additionally, we confirmed the presence of Cftr mRNA in the amygdala and hippocampus, brain regions implicated in anxiety and depression. These findings provide preclinical support for the reported mental health side effects experienced by some people with CF and offer new insights into CFTR function within the central nervous system, potentially guiding the development of future CF therapies with improved neuropsychiatric profiles."

Journal • Preclinical • CNS Disorders • Cystic Fibrosis • Depression • Genetic Disorders • Immunology • Mood Disorders • Psychiatry • Pulmonary Disease • Respiratory Diseases • CFTR

Elexacaftor/tezacaftor/ivacaftor prescription in lung transplant recipients with cystic fibrosis in the US. (PubMed, J Cyst Fibros) - "ETI was newly prescribed to almost 30 % of eligible LTx recipients in the U.S. Even when including patient clinical characteristics in the model, CF center prescribing pattern was one of the strongest factors associated with ETI prescription after LTx."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Otorhinolaryngology • Pulmonary Disease • Respiratory Diseases • Transplantation

VX21-522-001: A Phase 1/2 Study of VX-522 in Participants With Cystic Fibrosis (CF) (clinicaltrials.gov) - P1/2 | N=33 | Suspended | Sponsor: Vertex Pharmaceuticals Incorporated | Trial completion date: Mar 2025 ➔ May 2027 | Recruiting ➔ Suspended | Trial primary completion date: Mar 2025 ➔ May 2027

Trial completion date • Trial primary completion date • Trial suspension • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

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