Kalydeco (ivacaftor) / Vertex - LARVOL DELTA

Targeting Cystic Fibrosis Transmembrane Conductance Regulator (CFTR): a therapeutic interest in pulmonary arterial hypertension? (ERS 2026) - "In human PAH-PASMC and PAH-PAEC, we studied the pharmacological activation of CFTR by Ivacaftor and the re-expression of CFTR using a lentivirus (LV-CFTR)...Conclusion : In-vitro and in-vivo CFTR knockdown promotes the development of PAH. Pharmacological activation or re-expression of CFTR represents a promising therapeutic strategy in PAH."

Cardiovascular • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Arterial Hypertension • Respiratory Diseases • CFTR

Effect of selective furin inhibition on matrix metalloproteinases in COPD (ERS 2026) - "The CFTR potentiator ivacaftor (VX‑770) was also included to assess potential additive effects...Selective inhibition of furin with BOS‑857 reduces MMPs implicated in COPD pathophysiology. These findings support furin inhibition as a promising strategy to correct COPD protease imbalance."

Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Respiratory Diseases • MMP1 • MMP10 • MMP2 • MMP28 • MMP9

Natural history study of exocrine pancreatic function in infants with cystic fibrosis less than 12 months of age (NACFC 2026) - " This hybrid, decentralized study enrolled infants with CF age 90%) were pancreatic insufficient and 97% were taking PERT. There was little to no change in mean FE-1 concentration seen from age 6 months to 12 months. Despite most infants being pancreatic insufficient throughout the measurement period, growth parameters remained in normal ranges."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Cigarette smoke exposure limits efficacy of CFTR modulator therapy in preclinical models (NACFC 2026) - "CS exposure limits modulator stimulated CFTR functional efficacy in both in vitro and in vivo models. Our biochemical data suggest that CS alters the biochemical expression of CFTR at least partially through enhanced TGF- ?signaling. Our data indicate a direct relationship between CS exposure and ivacaftor efficacy, emphasizing the importance of reducing smoke exposure in patients on CFTR-directed therapy."

Preclinical • CFTR

Assessment of H1N1-induced viral exacerbation in G551D cystic fibrosis ferrets (NACFC 2026) - " Age and sex-matched wild-type (non-CF) and daily ivacaftoradministered G551D-CFTR (G551D CF) ferrets were challenged with a sublethal intranasal inoculation of H1N1 (106 FFU, A/California/07/2009)... We establish H1N1-induced viral exacerbation as a clinically relevant phenotype in G551D CF ferrets, characterized by a heightened antiviral response with skewed Th17 activity, increased mucus accumulation, and marked mucociliary dysfunction. Baseline mucus accumulation did not alter viral burden in CF ferrets. Despite comparable viral load, CF ferrets exhibited more severe histopathologic viral pneumonia, indicating that host response predominantly drives severity."

Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Influenza • Pneumonia • Pulmonary Disease • Respiratory Diseases • CXCL8 • IL17A • IL2 • IL4 • IL6

Increasing documentation of eye exams for children with cystic fibrosis treated with modulators (NACFC 2026) - "Background: Non-congenital lens opacities have been described in pediatric patients taking Ivacaftor containing Cystic Fibrosis Transmembrane Conductance Regulator modulators... Having a systematic process allows for improvement in our documentation of eye exams. We were also able to identify barriers in completing the exam which allowed for further interventions to improve care."

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

Membrane cholesterol modulates CFTR function and structural dynamics (NACFC 2026) - "TEVC experiments show that treatment with M ?CD, leading to acute cholesterol depletion, has a greater impact on CFTR potentiators, Ivacaftor (VX-770) and P1 as compared to pore blocker, GlyH-101... These studies reveal a relationship between cholesterol abundance and CFTR's sensitivity to potentiation along with potential lipidprotein interaction sites that may explain changes in CFTR behavior. Importantly, these results suggest that CFTR can be tuned post-translationally via its surrounding lipid environment. Future studies aim to use site-directed mutagenesis to investigate the functional importance of these interaction sites."

ETI therapy rescues dysmotility in the gut of humanized F508del male mice (NACFC 2026) - "To assess the effect of CFTR modulators, mice received in vivo ETI (i.p., 4 days; 20 mg/kg elexacaftor, 10 mg/kg tezacaftor, 30 mg/kg ivacaftor [6]). We report that CFTR dysfunction in hCF mice alters ileal contractile dynamics and sensitivity to cholinergic input, neurite innervation, and ETI effectively modulates these abnormalities. Overall, these results support the use of humanized F508del mice as a suitable model to study GI dysmotility in CF. The increase in peristaltic wave parameters observed may result from abnormal neuro-muscle function in the hCF mice or as a compensatory response to abnormal traffic in the gut lumen."

Preclinical • Cystic Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Ferret alveolar type 2 cell models identify CFTR as a key regulator of distal lung fluid homeostasis and a target for pharmacologic rescue (NACFC 2026) - "The effects of pharmacologic potentiation were examined using the CFTR potentiator VX-770... Our findings identify CFTR as a key regulator of alveolar fluid homeostasis in AT2 epithelia, primarily promoting fluid secretion but also influencing absorption dynamics. CFTR dysfunction disrupts both processes, resulting in impaired ASL regulation. These primary ferret AT2-derived organoid and ALI models provide a translational platform for investigating distal lung CF pathophysiology and for evaluating CFTR-targeted therapies."

Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • EPCAM • KRT5 • TP63

A novel LC-MS/MS method for simultaneous quantification of vanzacaftor, tezacaftor, deutivacaftor, elexacaftor, ivacaftor, and metabolites in plasma matrix (NACFC 2026) - " Internal standard (temazepam, 0.01 ng/mL) was added to 0.2 mL plasma samples, which were extracted with methyl tert-butyl ether. A rapid, sensitive, and robust UHPLC-MS/MS method was successfully developed and validated for the simultaneous quantification of CFTR modulators and their active metabolites in human plasma. The method offers advantages, including low sample volume, short analytical run time, and improved sensitivity compared to previously published methods. This assay is well-suited for therapeutic drug monitoring in clinical settings as well as pharmacokinetic and research applications."

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

Activation of ΔR CFTR and relevance to nucleotide-based genetic intervention (NACFC 2026) - "Both WT and ΔR1 exhibited similar transepithelial currents following stimulation with low dose forskolin or 5 ?M ivacaftor... Our findings indicate ΔR1 CFTR can be stimulated by CFTR modulators or compounds that enhance cAMP/PKA in airway epithelia. Increased pharmacologic activation of ΔR CFTR may be valuable in the context of nucleotide-based strategies to improve airway epithelial ion transport and mucociliary clearance."

Cystic Fibrosis • Gene Therapies • Genetic Disorders • Immunology • Respiratory Diseases

CFTR functions as a negative regulator of calcium flux in human CD4+ T cells (NACFC 2026) - "After washing in calcium-containing HBSS, cells were loaded with the ratiometric calcium indicator Fura Red-AM (1 ?M, 30 minutes) and treated with the CFTR potentiator ivacaftor (5 ?M) or vehicle control for 15 minutes... These data show that CFTR functions as a negative regulator of calcium influx in human CD4+ T cells, constraining a proximal signaling event governing activation, differentiation, and effector function. Given the central role of calcium signaling in T cell polarization, loss of CFTRmediated restraint provides a mechanistic basis for exaggerated Th2 and Th17 responses in cystic fibrosis. Increased heterogeneity following CFTR potentiation suggests differential regulation of signaling thresholds across T cell subsets, with implications for variable immune phenotypes in CF."

Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Respiratory Diseases • CD4 • CFTR

Concerning Secular Trends in Antibiotic Treatment of Acute Drops in FEV1 in Patients Who Are Not Taking CFTR Modulators (NACFC 2026) - " We identified HEMT-naïve patients who had not had ETI or Ivacaftor during the study period (2017-2024)... In HEMT-naïve CF patients, antibiotic treatment and follow-up of acute lung function drops declined after 2020, despite similar magnitudes of FEV1 decline across periods. This suggests a true shift toward less aggressive management of pulmonary exacerbations in the post-ETI era, even among HEMT-ineligible patients susceptible to classical CF respiratory decline."

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

Targeted Insertion of Corrective cDNA Restores CFTR Function in Cystic Fibrosis Pancreatic Ductal Epithelium (NACFC 2026) - "Ussing assay with chloride ion gradient in the bulk edited culture showed short circuit current difference ( ΔIsc) of 26.6 ± 4.0 ?A/cm2, while unedited G551D cells showed 6.6 ± 3.5 and 2.9 ± 1.5 ?A/cm2 with and without potentiation via VX-770, respectively... We have demonstrated that our mutation-agnostic gene correction approach, namely targeting integration of corrective CFTR cDNA, is also effective to restore CFTR function in CF pancreatic ductal epithelium. Future studies will focus on demonstrating the rescue of more relevant CF-associated pancreatic duct dysfunctions, such as altered bicarbonate transport and pH regulation. Our results confirm the targeted insertion of corrective cDNA as an approach to achieve a therapeutic for CF-associated pancreatic disease via direct in vivo correction or gene and cell therapy."

Cystic Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Immunology • Pancreatitis • Respiratory Diseases

Increased Risk of Hepatic Tumors in Aged CFTR-G551D Ferrets Is Partially Mitigated by CFTR Modulator Therapy (NACFC 2026) - "CF animals included ivacaftor (VX-770)–treated (ON VX-770) and untreated (OFF VX-770) ferrets... Aged CF ferrets show an increased risk of hepatic tumors and gallbladder neoplasia in association with liver injury and inflammation. Treatment with CFTR modulators was linked to a lower incidence of these lesions, suggesting a partial protective effect of CFTR restoration. These findings emphasize the importance of long-term hepatic surveillance in CF and support further investigation of CFTR modulation as a factor influencing liver cancer risk."

Angiosarcoma • Cystic Fibrosis • Gallbladder Cancer • Genetic Disorders • Hepatitis C • Hepatocellular Cancer • Hepatology • Immunology • Liver Cancer • Liver Failure • Metabolic Dysfunction-Associated Steatotic Liver Disease • Mucinous carcinoma • Oncology • Respiratory Diseases • Sarcoma

Characterizing CFTR-Related Disorder Bronchiectasis and Response to Modulator Therapy: A Prospective Multicenter Registry Cohort (NACFC 2026) - "The majority were prescribed combination HEMT and 3 prescribed ivacaftor alone (Table)... CFTR dysfunction is an emerging endotype of bronchiectasis. In a cohort with access to HEMT, treatment was well-tolerated and associated with improved respiratory symptoms and significant reduction in exacerbations. Ongoing enrollment and longitudinal follow-up will build on these preliminary findings."

Clinical • Bronchiectasis • Cough • Cystic Fibrosis • Genetic Disorders • Immunology • Non‐Cystic Fibrosis Bronchiectasis • Pulmonary Disease • Respiratory Diseases • CFTR

Assessment of Altered CFTR Modulator Metabolism from Prescribed Concurrent Medication and Pharmacogenetic Variation in People with Cystic Fibrosis (NACFC 2026) - " Biorepository samples and data from the CF Foundation were collected from the GOAL (ivacaftor-only) and GOAL-E2 studies... A significant proportion of GOAL and GOAL-E2 participants were concurrently taking CYP3A4/5-altering medication and have pharmacogenetic variants that, together, may modify CFTR modulator metabolism. These factors may increase the risk of altered exposure, including subtherapeutic concentration. Next, we will evaluate the association of the pharmacogenetic- and drug interactions with primary clinical outcomes."

Biomarker • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CYP3A4 • CYP3A5

Determinants of Staphylococcus aureus Persistence in the CF Rat Lung Following Highly Effective Modulator Therapy (NACFC 2026) - " Our lab developed the humanized G551D (hG551D) rat model of CF that responds to CFTR modulation via ivacaftor... Our data demonstrate that Sa undergoes mutations following HEMT in the CF lung, driving Sa to the SCV phenotype and altering purine metabolism. Further investigation into the mechanism behind the role of purine metabolism in Sa persistence in the CF lung following CFTR correction is ongoing."

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

Microbial modulation of CFTR modulator exposure: In vitro interactions between elexacaftor-tezacaftor-ivacaftor and pulmonary and gut bacteria from people with cystic fibrosis. (PubMed, Biomed Pharmacother) - "CFTR modulators and CF-associated microbiota interact bidirectionally in vitro. Elexacaftor and ivacaftor exert compound-, species- and strain-dependent effects on bacterial growth independent of their canonical role in restoring CFTR function, while multiple bacterial species decrease detectable parent-drug concentrations in culture supernatants."

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

Identification of Der p1 inhibitors: Combining AI-based QSAR, molecular docking, molecular dynamics simulations and quantum physics. (PubMed, Comput Biol Chem) - "Molecular docking results revealed that the top three docking scores were -25.5456, -20.6206 and -19.9821 kcal/mol for betrixaban, ceritinib and ivacaftor, respectively. The integrated computational workflow identified Betrixaban as the most promising FDA-approved candidate for Der p1 inhibition based on its favorable overall binding affinity and stable protein complex, while Ceritinib demonstrated superior electronic interactions and hydrogen-bond stability that may support future lead optimization. These findings provide a rational framework for drug repurposing against Der p1 and warrant further experimental validation through biochemical and cellular assays."

Journal • Allergy • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

A Phase 2 Study Evaluating Safety and Tolerability of RCT2100 (CFTR mRNA) in Healthy Participants and in Participants With CF (clinicaltrials.gov) - P2 | N=128 | Active, not recruiting | Sponsor: ReCode Therapeutics | Recruiting ➔ Active, not recruiting | N=192 ➔ 128

Enrollment change • Enrollment closed • First-in-human • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Functional and biochemical characterization of Alyftrek® components reveals high-potency rescue of F508del-CFTR. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "Alyftrek® (vanzacaftor/tezacaftor/deutivacaftor, VTD) is a triple CFTR modulator therapy for patients with cystic fibrosis (CF). Collectively, these findings demonstrate the high potency of S-vanzacaftor at nanomolar concentrations, both alone and in combination with tezacaftor. The potentiator deutivacaftor exhibited efficacy comparable to that of ivacaftor."

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

Contrasting Impacts of Two ABCB11 Variants Affecting the Same Residue in Progressive Familial Intrahepatic Cholestasis Type 2. (PubMed, Am J Physiol Gastrointest Liver Physiol) - "In vitro, ursodeoxycholic acid combined with glycerol phenylbutyrate increased ABCB11T463P canalicular expression (40.2 ± 7.7% of the wild-type, p <0.0001) and improved transport activity (32.4 ± 10.3% of the wild-type, p <0.0001). VX-770 and SBC040 increased ABCB11T463I function from 37.9 ± 2.5% (DMSO) to 73.2 ± 12.3% and 76.1 ± 17.5%, respectively, of the wild-type activity (p <0.0001). ABCB11 missense variations, even affecting the same residue, can cause various molecular defects, resulting in mild to severe phenotypes. 3D structure and in vitro analyses could be used to predict the severity of missense variants and guide the treatment of PFIC2 patients with pharmacological modulators."

Journal • Cholestasis • Hepatology • Transplantation • ABCB1

Revision Endoscopic Sinus Surgery in Cystic Fibrosis With Chronic Rhinosinusitis: Before and After Cystic Fibrosis Transmembrane Conductance Regulator Triple Modulator Therapy. (PubMed, Am J Rhinol Allergy) - "There were 32 patients treated with triple modulator therapy, or elexacaftor/tezacaftor/ivacaftor (ETI). In the years prior to ETI, 18 of these same patients (56.25%) underwent revision FESS. Patients on other modulator therapy had a hazard ratio of 0.85 for revision FESS (not significant).ConclusionThe current study shows a low rate of revision FESS in patients taking ETI, consistent with prior reports on improved quality of life and radiographic measures in these patients."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Nasal Polyps • Otorhinolaryngology • Pulmonary Disease • Respiratory Diseases • Sinusitis • Transplantation • CFTR

Sustainable Synthesis of Quinolones and the Main Based-Drug Ivacaftor by Aquoline. (PubMed, ACS Omega) - "These compounds represent key pharmacophores and essential intermediates in the development of various drugs. Notably, the same reaction system is crucial to obtain Ivacaftor, a commercially available drug for managing cystic fibrosis (CF)."

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