elexacaftor (VX-445) / Vertex - LARVOL DELTA

Next-Generation CFTR Modulators Control Multiple Mechanisms in Improving the Pathophysiology in ADPKD (KIDNEY WEEK 2026) - "Methods The aim of this study was to examine the therapeutic effect of the CFTR modulators VX809, VX661, and VX445 in Pkd1 R3277C mouse model treated every other day for 3 months. Conclusion These findings support the idea that correction of CFTR post translational modification and trafficking can improve the cystic phenotype in RC mice. Next generation of CFTR modulators show potential as therapeutic agents in ADPKD."

Autosomal Dominant Polycystic Kidney Disease • Nephrology • Polycystic Kidney Disease • Renal Disease • PKD1 • PRKD1 • SLC9A3R2

Activation of CFTR Suppresses Calcium-cAMP Signaling and Cyst Growth in ARPKD (KIDNEY WEEK 2026) - "Methods In the present study WT (C57Bl/6) and ARPKD ( Pkhd1 del3-4/del3-4 ) mice models were used and treated with CFTR modulators (VX809 and VX445). Conclusion Overall, results showed that CFTR may act as a key player in intracellular Calcium & cAMP signaling which contributes to ARPKD cyst growth. Activating CFTR, rather than inhibiting it, may be a promising therapeutic way to limit ARPKD disease progression"

Hepatology • Polycystic Kidney Disease • PKHD1 • STIM1

The New Landscape of Cystic Fibrosis in the Era of Highly Effective Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy. (PubMed, J Mother Child) - "As patient life expectancy continues to increase, comorbidities such as arterial hypertension, hypercholesterolaemia, cardiovascular disease, and malignancies will assume greater clinical importance. Selecting optimal therapeutic strategies remains a significant clinical challenge due to the numerous potential interactions between modulators and other medications."

Journal • Review • Cardiovascular • Cystic Fibrosis • Dyslipidemia • Genetic Disorders • Hypertension • Immunology • Oncology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CFTR

CFTR correctors suppress Ca²⁺-cAMP signaling and cyst growth in primary cultures of ARPKD cholangiocytes. (PubMed, Cell Calcium) - "These changes were accompanied by profound remodeling of intracellular signaling, including elevated resting cytosolic Ca²⁺, an increased thapsigargin-releasable endoplasmic reticulum Ca²⁺ pool, increased STIM1 expression, reduced IP₃ receptor expression, a marked increase in intracellular cAMP, and a switch in adenylyl cyclase isoform expression characterized by increased AC3 and reduced AC6...Treatment with either VX-809 or VX-445 improved many of these abnormalities by increasing CFTR expression, partially restoring PC1 and PC2 expression, attenuating abnormal Ca²⁺ and cAMP signaling, reducing cholangiocyte proliferation and cyst growth, and shifting CFTR membrane distribution toward the WT pattern...These findings identify coordinated remodeling of Ca²⁺- and cAMP-dependent signaling as a central feature of ARPKD cholangiocytes and show that CFTR correctors are associated with improvement of multiple disease-associated pathways. Our results support..."

Journal • Cystic Fibrosis • Genetic Disorders • Hepatology • Immunology • Nephrology • Polycystic Kidney Disease • Pulmonary Disease • Renal Disease • Respiratory Diseases • CFTR • PKD1 • PKHD1 • STIM1

Validation of a Method for Quantifying Elexacaftor, Elexacaftor-M23, Tezacaftor, Tezacaftor-M1, and Ivacaftor by HPLC-PDA. (PubMed, Drug Metab Bioanal) - "The method is fast, reproducible, and suitable for the simultaneous quantification of CFTR modulators and their main metabolites in plasma. It is applicable in clinical laboratories for the therapeutic monitoring and optimization of cystic fibrosis pharmacotherapy."

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

Elexacaftor/tezacaftor/ivacaftor (ETI) for rare mutations 1506T, 1525-42G > A, and 2622 + 1G > A: Case report of theratyping for a pediatric cystic fibrosis patient (NACFC 2026) - "ETI is an effective treatment for our pediatric patient with the 1506T, 1525-42G > A, and 2622 + 1G > A variants. Sustained improvement was seen in sweat chloride, ppFEV1, BMI, and admission rates after three years of ETI. With theratyping, our patient was able to gain access to ETI before the label extension over three years later."

Case report • Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Pediatrics • Respiratory Diseases • CFTR

CFTR nonsense mutations that escape nonsense mediated decay exhibit CFTR function by readthrough inducing compounds (NACFC 2026) - "Robust swelling by correcting CFTR function in the organoids is measured after ELX-02 250uM (readthrough agent) is treated with VX-445 3uM and VX-661 3uM (CFTR modulators) for 24 hrs resulting in 643 ± 60 % swelling x time. CFTRQ1411X mice escape NMD retaining WT levels of Cftr mRNA. CFTR function is restored with limited toxicity in intestinal organoids, meaning that some nonsense mutations may be corrected by CFTR modulators when cotreated with a readthrough agent. Next, we will administer ELX-02 and the CFTR modulators to CFTRQ1411X mice to determine if CFTR function can be restored and CF manifestations reduced in vivo."

Gastrointestinal Disorder • CFTR

Implications of a basolateral-to-apical Cl− gradient on CFTR Cl− ion transport in two primary human airway cell models (NACFC 2026) - " In both PALI- and VALI-differentiated hBE cultures treated with tezacaftor (TEZ), lumacaftor (LUM), or elexacaftor/tezacaftor (ELX/TEZ), Cl− gradient conditions enhanced CFTR function. Use of a Cl− gradient expanded the CFTR Cl− transport assay window in both PALI- and VALI-differentiated hBE cultures, with a more pronounced effect in PALI cultures. CFTR function was similarly enhanced in PALI-S–differentiated non-CF small airway cultures, supporting applicability to distal airway models. While PALI differentiation yields more in vivo–like epithelial morphology, incorporation of a Cl− gradient may improve assay sensitivity for CFTR functional studies."

Gene Therapies • Pulmonary Disease • Respiratory Diseases

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

Targeted ribosomal subunit depletion sensitizes elexacaftorresistant P67L CFTR to correction (NACFC 2026) - "However, P67L-CFTR is responsive to drugs that bind early to the nascent peptide (Tezacaftor/Lumacaftor), which synergistically improve folding and trafficking when used alongside VX-445. This study distinguishes the pro-folding benefits of targeted ribosomal stress from global ribosome velocity deceleration. By utilizing the fast-misfolding P67L-CFTR variant as a translational biosensor, we uncouple generalized biogenesis surveillance from specific, protective chaperone recruitment. This work aims to provide a novel biological framework for how altered translation environments can temporarily stabilize nascent peptides, revealing how endogenous cellular networks can naturally mimic the structural stabilization provided by early-binding pharmacological therapies."

AP-MS interactomics reveals cellular pathways altered by novel macrocyclic corrector IDOR-4 in CFTR class II variants (NACFC 2026) - "Pharmacological correctors such as elexacaftor (VX-445) and tezacaftor (VX-661) partially rescue these mutation-induced defects by stabilizing CFTR during folding. Our research provides a framework for discerning the underlying protein quality control of CFTR variants not reached with clinically approved drugs. Our results provide a better understanding of IDOR-4 biological mechanism of action. Future studies using siRNA-mediated perturbation will functionally validate key interactors and define their roles in mutationand drug-specific correction pathways."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CALR • CANX • CDC37 • HSP90AA1

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

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

Functional Proteomics and Biological Screening of Protein Misfolding Under ER Stress Conditions in a Neuroblastoma Cell Model. (PubMed, Curr Issues Mol Biol) - "This study investigates the cytoprotective efficacy and molecular targets of Vx-445 in Thapsigargin-induced ER stress in a neuronal cell model. These phenotypic modifications correlated with changes in proteomic expression and were validated by Drug Affinity Responsive Target Stability (DARTS) analysis to map restored cellular pathways and identify potential protein interaction partners. Together, these findings uncover alternative molecular targets for Vx-445, providing a mechanistic basis for drug repurposing strategies in endoplasmic reticulum stress-related diseases."

Journal • CNS Disorders • Neuroblastoma • Oncology • Proteinopathy • Solid Tumor

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

Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases. (PubMed, Isr J Chem) - "VX-770, a CFTR potentiator, and CFTR correctors like VX-809, VX-661, and VX-445, have gained FDA approval and widespread clinical use, greatly enhancing the health and survival of many CF patients. This review explores current and future CFTR modulator therapies, and applications of established paradigms to membrane protein misfolding diseases. Ongoing research and innovation hold the potential for further improvements in CF management and the treatment of protein misfolding diseases."

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

Incorporation and properties of the tris-fluoromethylated motif into heterocycles, amino acids and analogues of elexacaftor and tezacaftor. (PubMed, Chem Sci) - "log P comparisons again indicated an increase in polarity (lower log P) when switching (Me)2(CF3)C- to (FCH2)3C-. In the case of tezacaftor replacing the (Me)2(CH2OH)C- substituent with (FCH2)3C- made the molecule more lipophilic indicating that the polarity induced by three fluorines is not sufficient to outcompete an OH group."

Journal

Risk of drug-related aggression in pediatric populations: a pharmacovigilance analysis using the FAERS database. (PubMed, Front Pediatr) - "Signals for tezacaftor, elexacaftor, macrogol, desloratadine, and ebastine were identified despite absent FDA label warnings. The strongest signals were for ebastine (ROR: 23.40) and perampanel (17.41), while montelukast had the highest case volume (N = 1,392). Most drugs showed the highest aRORs in early childhood, except levetiracetam, which peaked in adolescence...This study identifies robust signals linking multiple drugs to pediatric aggression, with elevated risks observed particularly in younger children and females. These findings underscore the need for heightened clinical vigilance, consideration of demographic-specific risks, and updated regulatory labeling to improve pediatric drug safety."

Adverse events • Journal • Pediatrics

Safety and efficacy of elexacaftor/tezacaftor/ivacaftor in children ≥2 years with cystic fibrosis: 96-week interim results from a phase 3 open-label extension study. (PubMed, J Cyst Fibros) - "ELX/TEZ/IVA remained generally safe and well-tolerated in this extension trial. SwCl and lung function improvements reported in parent trial were maintained through additional 96 w of treatment. These results demonstrate long-term safety and efficacy, and CF disease-modifying potential of ELX/TEZ/IVA in children ≥2y."

Journal • P3 data • P3 data: top line • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Functional Rescue of CFTR-Dependent Transport in a Pancreatic Ductal Epithelial Cell Model: The Impact of Pharmacological Modulation and Inflammation. (PubMed, Int J Mol Sci) - "CFTR activity was stimulated with forskolin and further modulated using the potentiator ivacaftor (VX770) and the correctors tezacaftor (VX661) and elexacaftor (VX445), while specificity was confirmed with the CFTR inhibitor PPQ102. Notably, inflammatory stimulation did not abolish CFTR modulator responses, although it modified some downstream epithelial outputs. These findings identify CAPAN-1 cells as a physiologically relevant model for investigating CFTR function in the pancreatic duct environment and show that CFTR modulator responses are maintained, although functionally reshaped, under inflammatory conditions."

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

Profiling the CFTR Variant Selectivity and Off-Target Interactions of VX-121. (PubMed, bioRxiv) - "The approval of VX-121, a VX-445 analog that serves as a key component of Alyftrek, potentially provides a new therapeutic option for those with rare CF variants. Finally, using photo-crosslinking, we show that VX-121 avoids a key off-target interaction of VX-445. Together, our findings provide new insights into the similarities and differences between current approved CF therapeutics."

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

Impact of elexacaftor/tezacaftor/ivacaftor on the presence of bacterial and fungal pathogens in the lower respiratory tract of children with cystic fibrosis. (PubMed, Respir Med) - "In this exploratory study of young, modulator-naïve children with CF, ETI initiation was associated with changes in the lower airway microbiology composition assessed by IS. These findings highlight potential shifts in lower airway microbiology and the importance of age-appropriate lower airway sampling in future paediatric studies."

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

Keeping up with CFTR modulator eligibility. (PubMed, Paediatr Respir Rev) - "Since ivacaftor's approval for a single gating variant in 2012, eligibility has broadened to over 180 variants with the highly effective therapies elexacaftor/tezacaftor/ivacaftor and recently launched vanzacaftor/tezacaftor/deutivacaftor...However, clinical response remains variable, influenced in part by baseline characteristics, pharmacokinetics, pharmacogenetics, and environmental exposures. We outline evolving approaches to determining eligibility and strategies to improve methods to predict, verify, and monitor clinical response in an era of personalised medicine."

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

Altered functional interactions between CFTR disease mutants ΔF508 and G551D and the protein kinase A catalytic subunit. (PubMed, J Physiol) - "For both mutants, the clinically used potentiator drug combination elexacaftor + ivacaftor boosts catalytic channel activation by PKA more efficiently than non-catalytic activation. For ΔF508 CFTR, but not for G551D CFTR, a combination of clinically used potentiator drugs evokes substantial PKA-independent channel activity but suppresses non-catalytic activation by PKA. These findings help us to understand the activation defects caused by two common CF mutations and suggest room for further improvement of potentiator drugs currently used in CF therapy."

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

Safety and efficacy of elexacaftor/tezacaftor/ivacaftor in adolescents and adults with cystic fibrosis and F508del-gating and F508del-residual function genotypes: Results from an open-label extension study. (PubMed, Ann Am Thorac Soc) - "ELX/TEZ/IVA remained generally safe and well-tolerated with no new safety findings. Improvements in lung function, CFTR function, respiratory symptoms, and nutritional status after starting ELX/TEZ/IVA were maintained through 96 weeks of follow-up. These results demonstrate the safety and durable efficacy of ELX/TEZ/IVA in adolescents and adults with F/G or F/RF genotypes."

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