tezacaftor (VX-661) / Vertex - LARVOL DELTA

Pharmacogenomic analyses of corrector-resistant cystic fibrosis (NACFC 2026) - "To validate that our platform can identify hits that influence PM expression of disease variants, we conducted a genome-wide CRISPR knockout screen to identify hits that modulate the surface display of the correctorresponsive F508del variant in the presence of vanzacaftor-tezacaftor (VT). Our preliminary data demonstrate that we have developed a powerful methodology that will be extended to conduct genome-wide CRISPR screens with VT-resistant variants. This methodology enables us to screen thousands of guide RNAs against cellular machinery to identify drug targets for enhancing CFTR stability and PM expression. Consequently, we aim to identify strategies for restoring CFTR function for pwCF who are underserved by existing therapies."

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

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

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

Investigating the effects of in-vivo inhibition of sphingolipid delta- 4 desaturase (DEGS) by tezacaftor (NACFC 2026) - "Since DEGS is also a retinol isomerase [7], we will now investigate potential issues related to retina and vision. Further tests are also ongoing to better assess the consequences of DEGS inhibition from a mechanistic perspective, particularly in the brain. Nevertheless, all the results acquired so far are overall encouraging, from a drug-safety standpoint."

Preclinical

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

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

VX25-828-101: Safety and Efficacy of VX-828/Deutivacaftor Combination Therapy With and Without Tezacaftor in Subjects With Cystic Fibrosis (clinicaltrialsregister.eu) - P1/2 | N=55 | Not yet recruiting | Sponsor: Vertex Pharmaceuticals Inc.

New P1/2 trial • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Vanzacaftor-Tezacaftor as an alternative therapeutic resource for the ETI-Resistant L467F-F508del Allele: Ex vivo prediction and exploratory clinical assessment. (PubMed, J Cyst Fibros) - "Our findings demonstrate that the Vanzacaftor/Tezacaftor combination possesses superior corrective potency capable of rescuing the severe trafficking defect of the L467F-F508del complex allele. This study identifies a promising therapeutic solution for patients currently orphaned by standard-of-care modulators and highlights the utility of integrating ex vivo screening with clinical monitoring in defining precision medicine strategies."

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

Acne in Cystic Fibrosis: Tips for Prescribing Isotretinoin in the Genomodulatory Era. (PubMed, Case Rep Dermatol Med) - "The package insert says that vitamin A supplementation should be stopped, presenting a therapeutic dilemma. We review the literature and previous reports of isotretinoin use in patients with CF to provide guidance on how to successfully treat acne while minimizing adverse effects, including in patients on genomodulatory therapy."

Journal • Acne Vulgaris • Cystic Fibrosis • Genetic Disorders • Immunology • 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

Elexacaftor/Tezacaftor/Ivacaftor for Cystic Fibrosis and Rare CFTR Variants: In Vitro Translation to a Phase 3, Double-Blind, Randomized, Placebo-controlled Trial and Real-World Study. (PubMed, Am J Respir Crit Care Med) - "In vitro, clinical, and real-world data support elexacaftor/tezacaftor/ivacaftor treatment in people carrying a range of CFTR variants and no F508del. The response of 84% of rare CFTR variants that produce protein to protein-stabilizing therapy suggests variants in many regions of the protein causes disease via protein destabilization."

Journal • P3 data • Preclinical • Real-world evidence • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Current drug hypersensitivity challenges facing patients with cystic fibrosis. (PubMed, J Cyst Fibros) - "The CFTR correctors (vanzacaftor, elexacaftor, tezacaftor, lumacaftor) and potentiators (ivacaftor, deuterated ivacaftor) target the underlying CFTR defect to improve protein function...Piperacillin has been defined as a leading drug culprit within non-immediate drug allergy in patients with CF, with a growing body of evidence alluding to the central role of T-lymphocytes...This phenomenon has led us to hypothesise that increased levels of inflammation and dysregulation of regulatory T-cells in CF patients could propagate adverse reactions to CFTR modulators that resolve alongside underlying infection. The introduction of CFTR modulator therapies has been highly transformative for patients with CF, therefore, adverse reactions to these compounds that lead to cessation of treatment are serious and important to understand."

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

Systemic and airway T cell dynamics with influenza-specific immune recovery by cystic fibrosis elexacaftor/tezacaftor/ivacaftor therapy. (PubMed, Respir Res) - No abstract available

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

Inflammatory response in CF airway epithelial cells: a comparative study of modulators and wild-type CFTR rescue. (PubMed, Front Pharmacol) - "The combination of pharmacological modulators such as lumacaftor, tezacaftor, and elexacaftor restore CFTR activity at the plasma membrane and improve lung function in patients carrying CFTR mutations such as F508del, their effects on inflammation are less clear. These findings suggest that beyond ion transport, the proper folding and structural integrity of CFTR are important for regulating inflammation, potentially through interactions with other cellular proteins involved in inflammatory pathways. This work highlights the need to develop therapeutic strategies that not only restore chloride channel function but also fully correct CFTR misfolding to better control inflammation in CF."

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

Delayed Bullous Drug Eruption Induced by Elexacaftor/Tezacaftor/Ivacaftor. (PubMed, Pediatr Dermatol) - "Herein we present a novel case of delayed bullous drug eruption, arising 2 years after elexacaftor/tezacaftor/ivacaftor initiation, with subsequent successful drug re-introduction. Documentation of the possible serious cutaneous adverse effects of elexacaftor/tezacaftor/ivacaftor will importantly aid understanding of the potential for drug re-challenge in these cases."

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

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