tezacaftor (VX-661) / Vertex - LARVOL DELTA

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

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

Exposure of dams to Elexacaftor/ Tezacaftor/Ivacaftor during pregnancy and breastfeeding induces reversible alterations in newborn wild type CD-1 mice. (PubMed, J Cyst Fibros) - "We here demonstrate that exposure to ETI during pregnancy is associated with observable molecular changes in the brain lipidome, which are not likely limited to the inhibition of DEGS. These changes are reverted when exposure to ETI ceases."

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

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

Restoration of ezrin via calpain inhibition reinstates immune function in CF alveolar macrophages (NACFC 2025) - "PBMCs from pwCF (n = 6) were differentiated into MΦs (PBD-hMs) in the presence of hMCSF and treated with Trikafta (VX-445: 5 μM; VX-661 + VX-770: 5 μM) or vehicle ± LPS. Reduced ezrin activation in CF AMs impairs immune signaling, survival and phagocytosis in response to LPS. Calpain inhibition restores ezrin activation, improving AM survival and phagocytosis in mouse CF AMs. Trikafta therapy does not restore ezrin levels localization and signaling in LPS-treated CF PBD-hMs, suggesting that a combined therapy will be necessary to fully restore the immune dysregulations in pwCF."

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

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

Novel readthrough compounds for the treatment of CF patients with nonsense mutations (NACFC 2025) - "16HBEge cells, primary human nasal epithelial (HNE) cells, and intestinal organoids, carrying G542X or Y122X mutations, were treated with URN-1 and URN-2 molecules and compared to the reference compound ELX-02 at 100 or 200 μM for 48 h before experiments, alone or in combination with a NMD inhibitor (SMG1, 0.5 μM, 24 h) and ETI (VX-661 3 μM/VX-445 3 μM/VX-770 100 nM). A structure-based drug design approach yielded compounds that efficiently readthrough CFTR UGA and UAA PTCs. URN molecules are more efficient than ELX-02 to rescue G542X- and Y122X-CFTR activity in heterologous and primary in vitro models."

Clinical

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

Bridging the CFTR gap: investigating the role of CFTR in individuals with cystic fibrosis (CF)-like pulmonary symptoms and borderline to elevated sweat chloride to elucidate mechanism and therapeutics (NACFC 2025) - "HNEs were tested for baseline function in addition to being treated with CFTR modulators (Elexacaftor (E), Ivacaftor (I), Tezacaftor (T) and Vanzacaftor (V)). Based on our studies, we have delineated three categories: Category 1 (Bridge3): Wild-type CFTR function (74% WT), borderline sweat-chloride (33 mmol/L) – indicating a non–CFTR-mediated environmental or immune-related phenotype. Category 2 (Bridge8): Wild-type CFTR function (106% WT), elevated sweat-chloride (62 mmol/L) – implicating alternative CFTR-related pathways (e.g., carbonic anhydrase XII). Category 3 (Bridge4–7): Reduced CFTR function (24%–31%WT), sweat-chloride (>30 mmol/L) – an instructive example of CFTR dysfunction-driven phenotype."

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

Additive effect of combinational treatment with Splisense ASO Spl84 and Trikafta (NACFC 2025) - " The effect of SPL84, ETI (VX-661, VX-445, VX-770) and the combinational treatment of SPL84+ETI were assessed in HBE cells derived from heterozygous patients carrying the 3849 and F508del mutations. Studies in HBE cells support the potential benefit of combinational treatment with SPL84 and modulator drugs over each drug alone in heterozygote people with CF carrying the 3849 mutation and a modulator responsive mutation. SPL84 is currently in a global phase 2 study assessing both safety and efficacy in people with CF carrying the 3849 mutation."

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

Impact of routine pulmonary medications on modulator-rescued CFTR in cystic fibrosis cells (NACFC 2025) - "Co-treatment of ET with azithromycin, tobramycin, pulmozyme, or hypertonic saline did not significantly alter modulator-rescued CFTR function (Table 1)...F508del CFBEs were treated with vehicle or elexacaftor/tezacaftor (ET) followed by co-treatment with common pulmonary medications... As anticipated, cells expressing F508del CFTR have a significant increase in CFTR function after treatment with CFTR modulators (ET). This rescued CFTR function was not significantly altered by the addition of other common pulmonary medications in vitro. These findings suggest that these medications are unlikely to interfere with CFTR modulator therapy."

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

Beyond ivacaftor: potentiator icenticaftor enhances function and maintains stability of corrected F508del CFTR (NACFC 2025) - "Rescue of F508del and other mutant CFTR proteins is feasible with the triple therapy, Trikafta/Kaftrio, composed of two corrector compounds, elexacaftor (ELX) and tezacaftor (TEZ), plus potentiator ivacaftor (IVA). Icenticaftor is superior to IVA as a potentiator for ELX/TEZ-rescued F508del CFTR as chronic treatment with icenticaftor enhanced F508del function but did not destabilize F508del. Understanding the mechanisms underlying CFTR potentiator activities may offer further benefits for pwCF harboring F508del or other CFTR mutations, thereby improving therapeutics aimed at increasing CFTR maturation and function."

Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Restore the function of CFTR mutants using gain-of-function of CFTR variants (NACFC 2025) - "To test the function of the GOF CFTR variants in vivo, transgenic mice expressing either wild-type or D173R-CFTR under the control of a tetracycline-responsive promoter were generated and their function were evaluated in CFTR-deficient mice...Treatment with CFTR correctors (ET, Elexacaftor and Tezacaftor) increased expression and function of N1303 K CFTR, which was further increased when K978C and N1303 K was combined... We show here that the CFTR GOF variants improve the function of W1282X and N1303 K CFTR. Our previous results showed the GOF mutations such as D173R and D1341R restored the function of G551D CFTR. In combination, our results demonstrated that the GOF CFTR variants improve the function of multiple CFTR mutants that are not responsive to CFTR modulators."

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

Pharmacogenomic analysis of corrector-resistant cystic fibrosis (NACFC 2025) - "To date, we have generated reporter cell lines carrying variants with modest to no response to vanzacaftor/ tezacaftor including W57G, L227R, L467P, I507del, R560K, Y569D, L558S, W1098R, and N1303K and will benchmark them against a reporter cell line carrying the corrector-responsive F508del variant. To validate our system, we performed four genome-wide CRISPR knockout screens with F508del reporter cells – we measured CFTR stability with and without elexacaftor/tezacaftor (ET), surface display after ET, and ratio of surface display to total CFTR after ET... Our preliminary data demonstrate that we have developed a powerful screening methodology that will be extended to conduct genome-wide CRISPR knockout, inhibition, and activation screens with different CFTR variants in the presence or absence of correctors. This methodology enables us to screen thousands of guide RNAs against cellular machinery to identify drug targets for enhancing CFTR stability and plasma membrane..."

Biomarker • Genomic analysis • Omic analysis • Cystic Fibrosis • Genetic Disorders • Hematological Malignancies • Immunology • Leukemia • Respiratory Diseases • Targeted Protein Degradation