elexacaftor (VX-445) / Vertex - LARVOL DELTA

Barriers to the Pharmacologic Rescue of W1282X CFTR. (PubMed, Biochemistry) - "Additionally, acute in vitro treatments with approved modulators VX-809 or VX-661 result in immediate potentiation of W1282X-dependent ion transport, showing that F508del CFTR correctors also augment W1282X CFTR channel activity...Clinically approved CFTR correctors VX-445, VX-121, and VX-809 elicited potentiation of G551D CFTR...Moreover, unlike other CFTR mutations such as F508del, proteasome blockade using ALLN partially rescues W1282X at the plasma membrane. These results highlight ways in which detailed mechanistic analysis and modulator profiling are needed to characterize CFTR mutations such as W1282X and that modulator function in rare variants can be quite distinct from classical findings based strictly upon F508del CFTR."

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

Treatment outcomes of nontuberculous mycobacterial infection in the Danish Cystic Fibrosis Cohort 2012-23. (PubMed, J Cyst Fibros) - "While causality cannot be demonstrated, declining incidence and prevalence rates of NTM were observed during the study period in which HEMT was introduced. Improved respiratory outcomes were observed in those with NTM-PD. These findings support reconsideration of current treatment thresholds for NTM-PD in CF in the context of the HEMT era."

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

General trends in the calnexin-dependent expression and pharmacological rescue of clinical CFTR variants. (PubMed, Elife) - "Though corrector selectivity is generally dictated by the properties of mutations, we find that CANX enhances the sensitivity of CF variants within a domain-swapped region of membranes spanning domain 2 to the type III corrector VX-445...Interestingly, we find that the loss of CANX results in widespread perturbations of CF variant interactomes and that the proteostatic effects of CANX are generally decoupled from changes in CFTR activity. Together, our findings reveal how the proteostasis machinery may shape the variant-specific effects of corrector molecules."

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

Cystic fibrosis-related diabetes in the era of modern treatment using CFTR modulators in pediatric patients-a systematic review. (PubMed, Front Pediatr) - "While early findings suggest CFTR modulators may offer metabolic benefits and potentially delay or reduce the need for insulin therapy in children CFRD, current evidence is limited. Larger, pediatric-focused clinical trials with standardized glycemic outcomes are essential to determine the long-term efficacy and safety of CFTRm in managing or preventing CFRD."

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

New Role of Protein Misfolding Corrector in the ER Stress-Inflammation Axis: Possible Therapeutic Indication in Neuronal and Epithelial Tumor Cells. (PubMed, Int J Mol Sci) - "In this study, the efficacy of the drug Vx-445 (Elexacaftor), used in the pharmacological treatment of cystic fibrosis, was assessed in human adenocarcinomic basal alveolar epithelial (A549) and neuronal (SH-SY5Y) cell lines, where ER stress was induced by Thapsigargin. The results obtained suggest a significant effect of Vx-445 in restoring cellular homeostasis, leading to reduced expression of inflammation-related proteins, such as IL-6, tested by ELISA. Although preliminary, these results encourage further studies to explore the potential repurpose of Vx-445 as a therapeutic candidate for conditions involving ER stress and chronic inflammatory diseases associated with protein misfolding, beyond its current use in cystic fibrosis."

Journal • Alzheimer's Disease • CNS Disorders • Cystic Fibrosis • Genetic Disorders • Huntington's Disease • Immunology • Inflammation • Movement Disorders • Oncology • Parkinson's Disease • Proteinopathy • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CASP4 • IL6 • STAT3

CFTR correctors potentiate gating mutants causing cystic fibrosis. (PubMed, J Cyst Fibros) - "In conclusion, CFTR modulator VX-445 can promote channel activity of gating mutants, an effect which is dependent on the integrity of its binding site. Potentiation could also be observed with correctors VX-809 and VX-121, indicating that more generally, CFTR correctors can promote channel activity."

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

CFTR Modulators Are Not Associated With Reduction in Cancer Incidence: A Propensity Matched Analysis of 15,280 Cystic Fibrosis Patients (ACG 2025) - "We aimed to assess the long-term cancer risk and/or benefit with CFTR modulators. We conducted a retrospective cohort study in the United States using the TriNetX Research Network to identify patients with CF, then stratified into two groups: CF patients treated with CFTR modulators (Deutivacaftor, Elexacaftor, Ivafactor, Lumacaftor, Tezacaftor and Vanzacaftor) within 3 years after CF diagnosis and those who were not (controls). A total of 7640 patients with CF treated with CFTR modulators were propensity matched with 7640 controls. Among unmatched samples, patients in the treatment group were younger, more males, White, with higher rates of malnutrition, and lower rates of smoking and family history of malignancy (all p < 0.0001). Furthermore, CF patients who recieved CFTR modulators were more likely to be treated with antibiotics and less likely to be on IS agents (p < 0.0001)."

Clinical • Biliary Cancer • Cystic Fibrosis • Gastric Cancer • Gastrointestinal Cancer • Genetic Disorders • Immunology • Oncology • Respiratory Diseases • Solid Tumor

CFTR mutation abrogates Prevotella mediated regulation of epithelial cell defense against Staphylococcus aureus (NACFC 2025) - "Together, these findings highlight a protective role for Prevotella in epithelial defense against S. aureus infection. Prevotella mediated protection was associated with the recruitment and activation of neutrophils and reduced S. aureus adherence to the epithelium, which is a critical first step for infection and persistence. This natural defense mechanism may be impaired in the lungs of people with CF due to the altered response to Prevotella in CFTR mutant epithelial cells."

Infectious Disease • CFTR • CXCL8 • IL6

Olfactory function and sinonasal opacification improve in young children with CF treated with elexacaftor/tezacaftor/ivacator (ETI) (NACFC 2025) - "While elexacaftor/tezacaftor/ ivacaftor (ETI) has been shown to improve pulmonary function and CRS symptoms across age groups, ETI treatment does not lead to improvement in OD in adults. YCwCF have sinonasal opacification on imaging and have OD at baseline. After one year of ETI, improvements occurred in olfactory odor identification, OBV, and sinonasal opacification. Caregiver-reported QoL was near normal at baseline and showed no significant change after ETI."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Otorhinolaryngology • Pediatrics • Respiratory Diseases • Sinusitis

Discovery of non-aminoglycoside small molecules that enhance eRF3 degrader-induced translational readthrough of CFTR nonsense mutations (NACFC 2025) - "To address this issue, following a high-throughput screen (HTS) in the presence of the eRF3 degrader CC-90009, we applied medicinal chemistry optimization to identify small molecules (non-aminoglycosides, eRF3 degrader enhancers) that exhibit an additive or synergistic effect with SRI-47749, thereby effectively improving translational RT and restoring CFTR function...Addition of CFTR correctors elexacaftor and tezacaftor (ET) to SRI-50308 and SRI-47749 further improved CFTR protein expression and function... SRI-50308 is a novel non-aminoglycoside that enhances the translational readthrough induced by eRF3 degraders such as SRI-47749, thereby restoring substantial CFTR function from PTC alleles in primary cells. Further evaluation of these novel "eRF3 degrader enhancers" on the readthrough CFTR nonsense variants is a promising approach to multi-drug readthrough therapy for nonsense suppression."

CFTR

A CFTR mouse model to study nonsense mutations independent of nonsense-mediated decay (NACFC 2025) - "Intestinal organoids produced robust swelling when treated with either G418 or ELX-02 (readthrough agents) with VX-445 and VX-661 (CFTR modulators) for 24 hrs, and CFTR function was not increased when SMG1i (NMD inhibitor) was added. The RNA produced from CFTRQ1411X mice does not undergo NMD. Effective CFTR restoration was achieved in the intestinal organoids with limited toxicity, indicating that nonsense mutations which do not undergo NMD may be therapeutically targetable with currently discovered readthrough agents in combination with approved CFTR modulators. We plan to treat CFTRQ1411X mice with ELX-02 and CFTR modulators to determine if this combination treatment can restore CFTR function in vivo and reduce CF manifestations in these mice."

Preclinical • Cystic Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Evaluating Elexacaftor/Tezacaftor (ETI) for the treatment of patients with non-cystic fibrosis bronchiectasis (NCFB) U.S. (WBC 2024) - "Aim Our study is an open-label, single center trial of orally administered elexacaftor, tezacaftor and ivacaftor (ETI) in 30 individuals with NCFB who have one known CFTR mutation and/or mildly elevated sweat chloride measurements (i.e., 30-59 mEq/L). Figure 1. Summary of trial design."

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

Targeted eRF3a degradation amplifies nonsense mutation readthrough in a CF murine model (NACFC 2025) - "Organoids treated with G418 (readthrough agent) and VX-445 and VX-661 (CFTR modulators) for 24 hrs with either SMG1i (NMD inhibitor), CC-90009 (0.01 μM), or SJ6986 (0.05 μM) produced the following FIS area under the curve (AUC) results respectively: 1970 ± 33, 2730 ± 36, and 2810 ± 77 (% swelling x time). The intestinal organoids effectively responded to the CRBN modulators producing robust CFTR function as measured by FIS. The lack of NMD inhibition needed in combination with these modulators is exciting as NMD inhibition by SMG1i is toxic and difficult to overcome in therapy development. We plan to treat primary airway cells from the same mice to verify that restoration of CFTR function can be achieved in the airway as well when using CRBN modulators."

Preclinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • Targeted Protein Degradation • CRBN • GSPT1

Restoration of anion transport to W1282X-CFTR expressing human bronchial epithelial cells by synthetic anion transporters (NACFC 2025) - "As controls, cells were chronically treated with the nonsense-mediated mRNA decay (NMD) inhibitor SMG1i (1 μM), elexacaftor (2 μM), tezacaftor (3 μM) and ivacaftor (1 μM) (S/E/T/I) for 24 h at 37 °C. diF-OPBU anionophores restored anion transport to human bronchial epithelial cells expressing W1282X-CFTR and their action was synergistic with NMD inhibition and CFTR modulation. Future studies will evaluate whether MSNs achieve efficient, controlled delivery of anionophores to airway epithelial cells."

CFTR

Quality-by-Design-Driven RP-HPLC Method Development and Validation for Impurity Analysis of Elexacaftor, a Cystic Fibrosis Drug, with LC-MS/MS-Based Degradant Identification. (PubMed, ACS Omega) - "The method robustness was established by utilizing the DoEs in the part of the QbD concept. The method's stability was evaluated under diverse conditions including acid and base hydrolysis, oxidative and water hydrolysis, and thermal and photolytic degradation and was helpful for process development as well as quality checks in bulk drug manufacturing."

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

Intervention mapping for the development of a new model of care for people with cystic fibrosis in the era of highly effective modulator therapy. (PubMed, Arch Pediatr) - "It will combine quantitative and qualitative research approaches and rely on an 'action research' method. Anticipating and supporting the reorganization of CF care in France requires a robust research program to find the best model that meets the expectations of all key stakeholders."

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

Identification of early changes in multiple biomarkers following CFTR modulator initiation in patients with cystic fibrosis. (PubMed, Ther Adv Respir Dis) - "This study identified clinical, biologic, and functional parameters showing treatment effect early after initiation of CFTR modulator therapy. These parameters may serve as potential predictors of long-term responses to CFTR modulator treatment."

Biomarker • Journal • Observational data • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR • CRP

Implications for cystic fibrosis therapy: Potentiator icenticaftor is superior to ivacaftor in improving function and maintaining stability of F508del CFTR. (PubMed, Sci Prog) - "CFTR-expressing BHK-21 cells and non-cystic fibrosis (CF) and CF primary human bronchial epithelial cultures were treated for 48 hours with elexacaftor/tezacaftor (ELX/TEZ) plus IVA or icenticaftor and then western blot analyses were performed to assess CFTR protein maturation. Primary N1303K CFTR cultures did not exhibit enhanced rescue with icenticaftor when compared to IVA, indicating that different CFTR mutations respond differently to potentiators.ConclusionIcenticaftor is superior to IVA as a potentiator for ELX/TEZ-rescued F508del CFTR, as 48-hour treatment with icenticaftor enhanced F508del function but did not destabilize F508del. Understanding the mechanisms underlying CFTR potentiator activities may offer further benefits for people with CF who have F508del or other CFTR mutations."

Journal • Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Genetic Disorders • Immunology • Non‐Cystic Fibrosis Bronchiectasis • Pulmonary Disease • Respiratory Diseases • CFTR

A systematic review and meta-analysis of the treatment modalities available for children afflicted from cystic fibrosis. (PubMed, BMC Pediatr) - "The study underscores the effectiveness of certain treatments, such as triple therapy and physiotherapy exercises, for CF while highlighting the considerable variability in treatment outcomes. Notably, nutritional interventions need to be carefully reassessed. The findings emphasize integrating physiotherapy and targeted pharmacological interventions into standard CF management tailored to individual needs."

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

Dual potentiator and corrector activity of CFTR modulators when treating W1282X CFTR in cell-based systems (NACFC 2025) - " Fisher rat thyroid and primary human airway epithelial cell systems were used to examine W1282X CFTR and assess activity of clinically approved CFTR modulators, including ivacaftor (VX-770), lumacaftor (VX-809), tezacaftor (VX-661), elexacaftor (VX-445), and vanzacaftor (VX-121). These findings demonstrate that binary classification of CFTR modulators into "correctors" and "potentiators" is dependent on the particular variant being examined. Many modulators may possess dual functionality depending on the underlying mutation. For W1282X CFTR, corrector agents exhibit acute potentiation through a mechanism that appears to involve improved folding and increased sensitivity to endogenous (constitutive) levels of cellular cAMP and PKA."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

The CF airway cytokine IL-1β enhances CFTR modulator efficacy (NACFC 2025) - "CFTR modulators consisting of the CFTR correctors elexacaftor and tezacaftor plus the CFTR potentiator ivacaftor (ETI) have led to substantial clinical benefits, including reduction of some airway inflammatory markers...To confirm the inhibitory effect of Anakinra on IL-1b-induced inflammation, IL-1b-increased IL-8, IL-6 and IL-1b mRNA levels (n = 2) were evaluated by qPCR... SMM and IL-1b enhance F508del CFTR rescue via IL-1R activation coupled to increased ER protein folding capacity. We are currently addressing additional mechanisms of inflammation-enhanced CFTR rescue. Pre-clinical testing of CFTR modulators, including their effect on rare CFTR mutations, must be performed under conditions relevant to the inflamed environment of CF airways."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Respiratory Diseases • CFTR • CXCL8 • IL1B • IL6

Airway clearance remains an important part of treatment in adults on ETI (NACFC 2025) - "Background: Elexacaftor/tezecaftor/ivacaftor (ETI) is a highly effective CFTR modulator used for the treatment of cystic fibrosis (CF)in patients with specific genetic mutations... Our data indicates there is a rise in FEV1 post ETI therapy but over time there is a decline in FEV1 with an overall concave trajectory. In individuals who self-reported minimal airway clearance measures, the decline in lung function was greater. ETI therapy has also led to an increase in BMI and the data indicates this may have a negative impact on lung function."

Clinical • Cystic Fibrosis • Diabetes • Genetic Disorders • Immunology • Infectious Disease • Metabolic Disorders • Respiratory Diseases

Functional restoration of yeast Yor1 models of CF-causing alleles: mutation-specific assessment of genetic and pharmacologic strategies (NACFC 2025) - "Elexacaftor and putative PTC readthrough compounds are being analyzed in this experimental context for functional restoration of Class II mutations and PTC alleles...(Tezacaftor (VX-661) and ivacaftor (VX-770) showed only weak effects)... PTC and missense mutations in yeast Yor1 serve to identify novel genetic targets and inform mechanisms that underlie pharmacologic correction of CF-causing disease mutations. Rescue of the N1303K and F508del models by genetic modifiers discovered using the yeast gene-deletion strain library has provided testable hypotheses being pursued in CF cell models. Pharmacophenomic analysis may be predictive of conserved gene networks that modulate protein biogenesis mechanisms and operate on functionally distinct CF alleles, and can be used to elucidate allele-specific pharmacologic rescue of CFTR disease mutations."

Understanding modulator responses for two rare CFTR variants reported among the Sri Lankan cystic fibrosis population (NACFC 2025) - "The effect of corrector compounds (elexacaftor:E, tezacaftor:T and/or vanzacaftor:V) on processing was tested after 24 hours incubation with the vehicle, DMSO added as control. Our studies suggest that individuals harboring variants V456A and Y913C have the potential to respond to the triple combinations ETI and VTD while individuals harboring the variant Y913C additionally have the potential to respond to Ivacaftor too. Future studies are required to understand this differential rescue effect."

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

Evaluation of CFTR function in airway epithelial cells from CF-SPID individuals (NACFC 2025) - "HNECs were untreated or pretreated with 3 μM elexacaftor (E) and 3 μM tezacaftor (T) 48 hours before the Ussing experiments. Short-circuit current (ISC) was measured after sequential addition of 100 μM amiloride, 10 μM forskolin (Fsk) and 100 μM 3-isobutyl-1-methylxanthine (IBMX), 10 μM ivacaftor, 10 μM CFTRinhibitor-172 and 100 μM ATP... CF-SPID airway epithelial cells have heterogeneous levels of CFTR function. Low levels of spontaneous CFTR activity may serve as a marker for reassessment of a CF-SPID individual and consideration of a diagnosis of CF. Pretreatment with ET increases spontaneous CFTR activity in a subset of CF-SPID subjects."

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