vanzacaftor (VX-121) / Vertex - LARVOL DELTA

Differentiating between BK activation and potentiation by vanzacaftor enantiomers. (PubMed, Am J Physiol Cell Physiol) - No abstract available

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

Rethinking CFTR variant responsiveness: Differential responses to vanzacaftor and elexacaftor. (PubMed, J Cyst Fibros) - "Cystic fibrosis (CF) care has been revolutionized by CFTR modulators, particularly the triple combination elexacaftor/tezacaftor/ivacaftor (ETI)...A nextgeneration modulator combination, vanzacaftor/tezacaftor/deutivacaftor (VTD), shows promise in addressing this gap...Broader access to raw data and individualized in vitro-clinical correlations are essential for informed therapeutic decisions. VTD offers new hope for pwCF with rare or previously unresponsive variants, reinforcing the importance of a personalized, datadriven approach to CF care."

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

Evaluating Vanzacaftor-Based Triple Therapy in F508del/MF Cystic Fibrosis: Insights from the SKYLINE 102 and SKYLINE 103 Trials (ASHP 2025) - No abstract available

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

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

Improvements in health-related quality of life in people with cystic fibrosis ≥6 years of age treated with vanzacaftor/tezacaftor/deutivacaftor. (PubMed, J Cyst Fibros) - "VNZ/TEZ/D-IVA was associated with higher HRQoL in adolescents and adults aged ≥14 years compared to ELX/TEZ/IVA, with largest changes in participants with F/MF genotypes, and in children aged 6-11 years compared to ELX/TEZ/IVA baseline. These results highlight potential HRQoL benefits from greater CFTR function restoration with VNZ/TEZ/D-IVA."

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

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

Investigating the differentiation and function of pulmonary ionocytes from human induced pluripotent stem cells (NACFC 2025) - "HNEs from Bridge47 were treated with a combination of Elexacaftor, Ivacaftor, Tezacaftor(ETI), Vanzacaftor, Ivacaftor, Tezacaftor (VTI) or DMSO vehicle control for 48 hours prior to mounting on Ussing chambers for CFTR functional testing. In summary, we show in a human system is FOXI1 is crucial for ionocyte differentiation and that its targeted deletion led to impaired chloride transport, which is restored by FOXI1-overexpression. Notably, a small proportion of wildtype ionocyte can mitigate the CF defect in airway chloride transport, highlighting potential therapeutic implications for CF. Future research will focus on elucidating the ionocyte's role in regulating fluid transport, mucociliary clearance, airway rheology, and communication with surrounding cell-types."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR • MUC5B • SCGB1A1 • TP63

Continuous glucose monitoring in young children with cystic fibrosis: a BEGIN sub-study (NACFC 2025) - P | "Background: The approval of elexacaftor/tezacaftor/ivacaftor (ETI) for people with cystic fibrosis (CF) with one or more copies of the F508del mutation provides an opportunity to understand non-pulmonary effects of highly effective modulator therapy (HEMT: ivacaftor, ETI, deutivacaftor/ tezacaftor/vanzacaftor). The BEGIN study offers an unprecedented opportunity to understand early complications of CF and the effects of HEMT initiation. This sub-study confirms the presence of hyperglycemia (glucose values >200 mg/dL) and hypoglycemia (glucose < 55 mg/dL) in young children with CF as measured by CGM. Unfortunately, we found no apparent difference in hyperglycemia or hypoglycemia between baseline and 12 months after initiation of ETI."

Clinical • Cystic Fibrosis • Diabetes • Genetic Disorders • Hypoglycemia • Immunology • 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

Theratyping of 400 CF-associated variants in FRT cells to assess variant responsiveness to triple combination CFTR modulator vanzacaftor/ tezacaftor/ivacaftor (VNZ/TEZ/IVA) (NACFC 2025) - "We recently published findings from a large-scale theratyping study, evaluating 655 CFTR variants, including 478 variants without FDA approval at the time, for their responsiveness to elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), the active ingredients of Trikafta® [1]...A clinical investigation of the new Vertex triple combination (ALYFTREK®)i... We demonstrated significant rescue efficacy of VNZ/TEZ/IVA for a high percentage of CFTR variants currently not on the label for approved HEMT, indicating that confirmatory studies by Vertex would be valuable for future label expansions. VNZ/TEZ/IVA treatment may provide a therapeutically meaningful approach for several variants that did not positively respond to ELX/TEZ/IVA."

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

Functional recovery of I507del: From single-channel to primary airway epithelial cells (NACFC 2025) - "However, unlike F508del, I507del is marginally responsive to the combination of Elexacaftor/Tezacaftor/Ivacaftor (ETI). To address this therapeutic gap, we evaluated I507delCFTR responsiveness to a variety of correctors including the newly approved Vanzacaftor in combination with Tezacaftor and Ivacaftor (VTI) in both primary and immortalized cell models, while directly comparing its rescue efficacy to that of ETI and to other experimental corrective maneuvers...Mature CFTR (band C) was absent in Western blots of HEK293 cell lysates transiently and stably expressing I507del-CFTR and after 24 h treatment with correctors at 37°C and 27°C (C4a, C18, FDL169, Gallicaftor and Elexacaftor/Tezacaftor)... I507del CFTR is responsive to VTI at level below the commonly accepted 10% therapeutic threshold. However, natural history studies indicate that increasing CFTR function from < 1% ∼5% WT could produce therapeutic benefit [1]. Furthermore, strategies that increase..."

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

Differential BK channel potentiation by vanzacaftor enantiomers enables therapy for modulator-ineligible people with cystic fibrosis (NACFC 2025) - "Acute experiments used increasing concentrations of R- and S-vanzacaftor; chronic experiments used elexacaftor at 5 μM and vanzacaftor enantiomers at 3 μM as these concentrations are reached at steady state in pwCF taking elexacaftor in Trikafta™ and S-vanzacaftor in Alyftrek™. Enhancing apical loop currents between ANO1 and BK by potentiating BK in pwCF with minimal function CFTR mutations can meaningfully and thus therapeutically enhance mucociliary function even in the absence of functional CFTR."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • ANO1 • BMI1 • 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

YOGA-CF: a randomised controlled clinical trial – recruitment progress and participant demographics (NACFC 2025) - "An Vanzacaftor 619.2 546.1 2025 eV Vanzacaftor 619.2 440.1 3035 eV Tezacaftor 521.1 440 2530 eV Deutivacaftor 411.2 172.2 2530 eV M1-Tezacaftor 493.2 388.2 2530 eV M1-Ivacaftor 408.5 353 2025 eV Vanzacaftor-d3 578.2 331.1 22 Tezacaftor-d9 530.2 327.1 22 Vanzacaftor-d3 578.2 331.1 22 Figure 1 (abstract 117): Linear Regression Curve of Alyftrek. YOGA-CF is currently recruiting to time and target highlighting the desire of the CF community (patients and CF teams) to engage with real world remote clinical trials and the importance of identifying non-pharmacological strategies to improve outcomes. Final recruitment data available for NACFC 2025."

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

(R)-vanzacaftor potentiates BKCa channels in the absence of CFTR correction or potentiation. (PubMed, Am J Physiol Cell Physiol) - "We previously demonstrated the CFTR correctors VX-445 (elexacaftor) and S-VX-121 (vanzacaftor) potentiate heterologously-expressed BKCa channels, as well as in primary human bronchial epithelial cells (HBEs). In contrast, the CFTR inhibitor, CFTRinh172 did not alter the effects of S- and R-VX-121 on vasoreactivity, confirming CFTR is not involved in this response. These data demonstrate R-VX-121 represents a novel BKCa potentiator that does not modulate CFTR function, suggesting R-VX-121 may be clinically useful as a BKCa agonist."

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

Differential BK channel potentiation by vanzacaftor enantiomers enables therapy for modulator-ineligible people with cystic fibrosis. (PubMed, J Clin Invest) - No abstract available

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

VX-445 (elexacaftor) inhibits chloride secretion across human bronchial epithelial cells by directly blocking KCa3.1 channels. (PubMed, PNAS Nexus) - "We demonstrate that VX-445 directly inhibits KCa3.1, as do similar molecules VX-659 and VX-121; however, only VX-659 inhibited KCa2.3 and KCa2.2 with a similar affinity to KCa3.1. To summarize, acute addition of CFTR correctors to HBEs reduces transepithelial Cl- secretion due to inhibition of KCa3.1."

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

Evolving nutrition therapy in cystic fibrosis: Adapting to the CFTR modulator era. (PubMed, Nutr Clin Pract) - "Approximately 95% of people with CF qualify for treatment with a CFTR modulator. This review discusses the basics of CFTR gene mutations and changes in nutrition status related to treatment with CFTR modulators."

Journal • Review • Cardiovascular • Cystic Fibrosis • Diabetes • Dyslipidemia • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Hypertension • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • CFTR

Evaluation of rectal organoid responses to vanzacaftor/tezacaftor/ivacaftor in people with CF poorly responsive to elexacaftor/tezacaftor/ivacaftor modulator therapy (ECFS 2025) - "We showed promising in vitro reponses to VTI in 2 pwCF with rare genotypes poorly responsive to ETI, suggesting that VTI may benefit a broader population compared to ETI."

Effect of vanzacaftor/tezacaftor/ivacaftor on cystic fibrosis airway epithelial cells (ECFS 2025) - "Objectives: The latest triple-component CFTR modulator drug, consisting of vanzacaftor (V), tezacaftor (T) and deutivacaftor (D), is becoming a new treatment alternative to the established combination of elexacaftor (E), tezacaftor (T) and ivacaftor (I) in people with cystic fibrosis (pwCF)...ISC was measured after sequential addition of 100 M amiloride, 10 M forskolin (Fsk) and 100 M 3-isobutyl-1-methylxanthine (IBMX), 10 M I, 10 M CFTRinhibitor-172 (CFTRinh172) and 100 M ATP... Our results show significantly greater restoration of CFTR function in F508del/F508del HNEC treated with VTI compared to ETI. These results are in line with the improved sweat chloride values seen in the clinical trial.Supported by Ministry of Health of the Czech Republic, grant no NU23-07-00079."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Comparing elexacaftor and vanzacaftor: impact on CFTR functional rescue and protein maturation (ECFS 2025) - "Objectives: Many individuals with Cystic Fibrosis (CF) benefit from Trikafta, a combination of CFTR modulators: Elexacaftor/Tezacaftor/Ivacaftor (ETI)...It is uncertain whether the newly FDA-approved combination: Alyftrek (Vanzacaftor/Tezacaftor/Deutivacaftor; VTD) will mediate an improved clinical outcome for this segment of the population. We were prompted to compare the two Class III correctors: Elexacaftor versus Vanzacaftor... Vanzacaftor shows similar improvements to Elexacaftor in F508del-CFTR channel activity despite greater potency and efficacy in enhancing F508del-CFTR maturation, with ongoing studies exploring the mechanisms behind different molecular consequences of these modulators. Support provided by Cystic Fibrosis Canada and the Cystic Fibrosis Foundation."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

​​​​Elexacaftor/tezacaftor/ivacaftor: eligibility, tolerability and indications (ECFS 2025) - "Overall, 13 (3.6%) pwCF with classic CF have mutations not amenable to ETI; three have mutations responsive to vanzacaftor; one has participated in a trial of mRNA. most pwCF tolerate ETI with few adverse effects. most pwCF tolerate ETI with few adverse effects. A few ppwCF with only mild disease opt not start ETI. Many are concerned about weight gain."

CNS Disorders • Cystic Fibrosis • Gastroenterology • Gastroesophageal Reflux Disease • Gene Therapies • Genetic Disorders • Immunology • Insomnia • Mood Disorders • Otorhinolaryngology • Psychiatry • Pulmonary Disease • Respiratory Diseases • Sinusitis • Sleep Disorder