lumacaftor (VX-809) / 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

Rescue of the CFTR chloride channel with nonsense mutations is markedly improved under inflammatory conditions. (PubMed, Eur Respir J) - "We tested the efficacy of a triple combination of small molecules including the readthrough agent ELX-02, the CFTR corrector VX-809, and the eRF3A degrader CC-90009, on cultured airway epithelia from patients carrying the G542X mutation. The effect of inflammatory stimuli could be mediated by enhanced translational readthrough and/or reduced NMD. Our results suggest that rescue of CFTR with nonsense mutations could be more effective than expected in vivo Our findings may also lead to the identification of novel targets to correct the effect of nonsense mutations in CF and other genetic diseases."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • GSPT1 • IL17A • IL4 • TNFA

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

Characterization of SPTLC2 as a key driver promoting microglial activation and energy metabolism reprogramming after ischemic stroke through bulk and single-cell analyses combined with experimental validation. (PubMed, Cell Biol Toxicol) - "Our study highlights SPTLC2 as a critical mediator of microglial activation and metabolic reprogramming in ischemic stroke, providing a foundation for developing novel therapeutic strategies targeting SPTLC2 to improve stroke outcomes."

Journal • Cardiovascular • Ischemic stroke • Metabolic Disorders • FLI1

Lipid-peptide nanoparticle mediated delivery of CFTR mRNA in a combination therapy with CFTR correctors (NACFC 2025) - "CFTR IVT mRNA delivered by novel LPNP formulations is a promising novel therapeutic for CF. Co-delivery of CFTR mRNA with VX-809 appears to stabilise the mRNA encoded wild type CFTR protein, enhancing the potential efficacy and durability of CFTR mRNA as a therapy."

Combination therapy • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Rare Diseases • Respiratory Diseases • BMI1

Evidence against synonymous polymorphism neutrality with rare CFTR variants that display altered modulator responsiveness and clinical phenotype (NACFC 2025) - " Here, we investigated the impact of c.2562T >G sSNP on CFTR processing, function and sensitivity to CFTR modulators (VX-809 and/or VX-770)... Our findings argue against sSNP neutrality during CFTR protein biogenesis and modulator responsiveness, emphasizing ways in which silent codons can alter local kinetics of mRNA translation and epistatically modulate outcomes of rare CF-causing variants. Such effects likely influence the spectrum of CF clinical features, thus representing a mechanistic contributor to genotype-phenotype relationships and response to precision therapeutics."

Clinical • CFTR

Computational Drug Repositioning for Targeting PfEMP1: Potential Therapeutics for Cerebral Malaria in Plasmodium falciparum. (PubMed, Biotechnol Appl Biochem) - "Among the top candidate molecules are Lumacaftor, Vilazodone, Tucatinib, Lenvatinib, and Hydrocortisone Cypionate, which exhibit favorable docking energies (-9.1 to -8.3 kcal/mol) and potential oral bioavailability, as determined by receptor-based screening and absorbed, distributed, metabolized, and eliminated (ADME) analysis. Gibbs's free energy landscape analysis further reinforces the stability of these drug-protein complexes, underscoring their potential as therapeutic agents. These findings highlight the significant role of computational approaches in drug discovery and offer valuable insights into repurposing FDA-approved drugs for cerebral malaria treatment."

Journal • Infectious Disease • Malaria

Developing Type II F508del-CFTR correctors with a protective effect against respiratory viruses. (PubMed, Eur J Med Chem) - "Among the most active candidates, the bithiazole 3b showed broad-spectrum antiviral activity in the sub- or low-micromolar range against selected viruses from the Picornaviridae, Flaviviridae, and Coronaviridae families, and a notable F508del-CFTR correction-both alone and in combination with VX809-in FRT cells. Further confirmation of CFTR correction was obtained in the CFBE41o- cell line and in primary cultures of human airway epithelial cells homozygous for F508del, the gold standard for evaluating CFTR rescue strategies, particularly in combination with VX445. In addition to its biological activity, compound 3b exhibited a favorable preclinical pharmacokinetic profile in vitro. These findings collectively highlight compound 3b as a promising multitarget candidate for cystic fibrosis, providing a solid foundation for the development of a simplified CF therapy to mitigate PE."

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

Thermodynamic Coupling between Folding Correctors and the First of Dimerized Nucleotide Binding Domains in CFTR. (PubMed, ACS Bio Med Chem Au) - "Although folding correctors elexacaftor/VX-445 and lumacaftor/VX-809 have been combined to correct the NBD1 misfolding, the exact correction pathway is still unknown. However, the binding of folding correctors allosterically protected the α-subdomain from misfolding until subsequent core formation. This thermodynamic protective mechanism, unlike the chaperone-based one in cotranslational NBD1 folding, may restore posttranslational NBD1 folding for tight Mg/ATP-mediated NBD dimerization in the F508del mutation and also potentially apply to treating other cystic fibrosis patients with rare mutations."

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

Thermodynamic basis for CFTR activity potentiation. (PubMed, Res Sq) - "While folding correctors VX-445 and VX-809 are sufficient to restore the Mg/ATP-dependent dimerization between the two nucleotide binding domains (NBD1 and NBD2) for channel opening, the thermodynamic basis for the activity potentiation by VX-770 in Trikafta remains unknown. The results demonstrated that comparable thermostability between dimerized NBD1 and NBD2 was required to stabilize an activated intermediate for the channel activity potentiation by VX-770. Thus, a global induced fit across the interdomain interfaces upon ligand binding may optimize cooperative ligand-mediated NBD dimerization and improve the treatment of cystic fibrosis."

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

Targeting programmed death ligand 1 for anticancer therapy using computational drug repurposing and molecular simulations. (PubMed, Sci Rep) - "Two of them, Lumacaftor and Vedaprofen, showed appropriate drug profiles and biological activities and stood out as highly potent binding partners of the PD-L1...While the findings are promising, they remain computational and require experimental validation to confirm biological efficacy and specificity. This study also emphasizes the role of bioinformatics approaches in drug repurposing that can help in the identification of novel anticancer agents."

Journal • Oncology • PD-L1

Structure-guided combination of novel CFTR correctors to improve the function of F508del-CFTR in airway epithelial cells. (PubMed, Biochem Pharmacol) - "Although remarkable rescue has been achieved for treatment of Cystic Fibrosis (CF) by the combination of two correctors (VX-661, VX-445) and one potentiator (VX-770), the stability and trafficking defects induced by the most common mutation, F508del, are not completely reverse...Functional measurements in F508del-CFTR CFBE cells and primary nasal epithelial cells demonstrated that eight of fourteen compounds acted as CFTR correctors and the F508del-CFTR rescue was comparable to the level measured after VX-809 or VX-445 treatment in CFBE cells. Through rational selection based on molecular docking studies and mechanisms of action, we showed that combination of compounds (7a+1b and 2a+2b) targeting distinct domains of CFTR, can additively/synergistically rescue F508del-CFTR function in both CFBE cell line and primary nasal cells. Our study demonstrated that in silico and in vitro approaches to develop and investigate the mechanism of action of novel CFTR correctors could..."

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

Thermodynamic coupling between folding correctors and the first of dimerized nucleotide binding domains in CFTR. (PubMed, Res Sq) - "Although folding correctors elexacaftor/VX-445 and lumacaftor/VX-809 have been combined to correct the NBD1 misfolding, the exact correction pathway is still unknown. However, the binding of folding correctors may allosterically protect the α-subdomain from misfolding until subsequent core formation. This thermodynamic protective mechanism, unlike the chaperone-based one in cotranslational NBD1 folding, may restore posttranslational NBD1 folding for tight Mg/ATP-mediated NBD dimerization in the F508del mutation, and also potentially apply to treating other cystic fibrosis patients with rare mutations."

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

Repurposing FDA-Approved Drugs to Target MTH1 for Anticancer Therapeutics. (PubMed, J Mol Recognit) - "Among these, Lumacaftor and Nilotinib were selected based on their strong binding affinity and pharmacokinetic profiles. The findings suggest that Nilotinib could be repurposed to enhance cancer therapy, particularly in combating drug resistance through the novel mechanism of MTH1 inhibition. This approach provides new avenues for tackling chemoresistance and improving therapeutic outcomes in cancer patients."

FDA event • Journal • Oncology

Small molecules acting as eRF degraders differently rescue G542X and W1282X-CFTR function (ECFS 2025) - " 16HBE14o- cells with the G542X-CFTR mutation were treated for 24 h with different drug combinations containing CC-90009 (0.1 M) or SRI-41315 (15 M) with/without VX-809 (1 M), and ELX-02 (200 M), as a RT agent, or SMG1i (1 M), as a NMD inhibitor. The eRF3a degrader CC-90009 has a role in potentiating RT, since it is effective on G542X-CFTR in combination with ELX-02, while the eRF1 degrader SRI-41315 is particularly active on W1282X-CFTR together with SMG1i. These results suggest that eRF degraders have different involvement in RT and NMD mechanisms. This work was supported by: the Cystic Fibrosis Foundation (GALIET22I0), the Italian Cystic Fibrosis Foundation (FFC#9/2022 and GMRF#1/2024), and the Italian Ministry of Health (GR-2018-12367126)."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • GSPT1

Pharmacokinetics of Ivacaftor, Tezacaftor, Elexacaftor, and Lumacaftor in Special Cystic Fibrosis Populations: A Systematic Review. (PubMed, Clin Pharmacokinet) - "The PK of CFTR modulators have been more extensively studied in adults, pwCF with mild/moderate hepatic impairment, and children. However, ensuring adequate dosing remains challenging. Knowledge gaps persist for adults with severe hepatic impairment (Child-Pugh Class C), children with CF-induced hepatic impairment, and pregnant or lactating pwCF. Future research addressing these gaps, through incorporating routine clinical data, is crucial for improving clinical guidelines and optimizing dosing regimens, thereby advancing towards evidence-based utilization of CFTR modulators."

Journal • PK/PD data • Review • Cystic Fibrosis • Genetic Disorders • Hepatology • Immunology • Pediatrics • Pulmonary Disease • Respiratory Diseases • CFTR

Lumacaftor inhibits channel activity of rescued F508del cystic fibrosis transmembrane conductance regulator. (PubMed, Am J Physiol Lung Cell Mol Physiol) - "At 37°C, rF508del channel activity is significantly inhibited in CFBE-DF cells by acute exposure to 5mM lumacaftor, but not to 5mM tezacaftor or 1mM elexacaftor, the two correctors of Trikafta. Taken together, despite its strong corrector activity, lumacaftor inhibits rF508del channel activity, compromising the degree of functional rescue. This effect may contribute to the limited clinical efficacy of Orkambi."

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

Identification of potential SARS-CoV-2 inhibitors among well-tolerated drugs using drug repurposing and in vitro approaches. (PubMed, Sci Rep) - "Furthermore, dual combination experiments revealed that amcinonide, pimozide, lumacaftor, and eltrombopag acted as potent inhibitors at nanomolar concentrations when combined with candesartan. This study highlights lumacaftor, candesartan, and nelfinavir as effective inhibitors of SARS-CoV-2 replication in vitro and emphasizes their potential for repurposing as antiviral treatments. These findings support future clinical trials and may lead to breakthroughs in COVID-19 treatment strategies."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Quantification of Ivacaftor, Tezacaftor, Elexacaftor, and Lumacaftor and their active metabolites in plasma using UHPLC-MS/MS: Doors open to the application of therapeutic drug monitoring in cystic fibrosis treatment. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "All seven components were stable in EDTA plasma for ten days in the autosampler after sample preparation and through four freeze-thaw cycles. The developed assay was applied in routine TDM analysis to investigate exposure to elexacaftor, tezacaftor, ivacaftor and their metabolites in people with CF undergoing treatment with Kaftrio®."

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

Unraveling PPARβ/δ nuclear receptor agonists via a drug-repurposing approach: HTVS-based ligand identification, molecular dynamics, pharmacokinetics, and in vitro anti-steatotic validation. (PubMed, RSC Adv) - "The top five ligands with strong binding affinity towards PPARβ/δ were canagliflozin > empagliflozin > lumacaftor > eprosartan > dapagliflozin. Canagliflozin showed significant (P < 0.001) dose-dependent decrease in lipid accumulation and the associated oxidative stress-inflammatory response, suggesting its promising anti-steatotic potential. These outcomes pave the way for further validation and development of PPAR activity-modulating therapeutics."

Journal • PK/PD data • Preclinical • Addiction (Opioid and Alcohol) • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology

Unraveling the Mechanism of Action, Binding Sites, and Therapeutic Advances of CFTR Modulators: A Narrative Review. (PubMed, Curr Issues Mol Biol) - "Currently, four CFTR modulators are clinically approved: the potentiator ivacaftor (VX-770), either as monotherapy or in combination with the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Among these, the triple combination VX-445/VX-661/VX-770 (marketed as Trikafta® in the US and Kaftrio® in Europe) has emerged as the most effective CFTR modulator therapy to date, demonstrating significant clinical benefits in phase III trials for patients with at least one F508del CFTR allele...A deeper understanding of these mechanisms could provide essential insights for developing more potent and effective modulators, particularly in combination therapies. This narrative review delves into the mechanism of action, binding sites, and combinatorial effects of approved and investigational CFTR modulators, highlighting ongoing efforts to broaden therapeutic options for individuals with CF."

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

Defective Cystic Fibrosis Transmembrane Conductance Regulator Accelerates Skeletal Muscle Aging by Impairing Autophagy/Myogenesis. (PubMed, J Cachexia Sarcopenia Muscle) - "Age-related reduction in skeletal muscle expression of CFTR impairs autophagy and myogenesis, exacerbating skeletal muscle aging. Enhancing CFTR might be a potential treatment strategy for age-related skeletal muscle disorders."

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

Structure-based virtual screening and drug repurposing studies indicate potential inhibitors of bovine papillomavirus E6 oncoprotein. (PubMed, Microbiol Immunol) - "Our results reveal that Lumacaftor and MK-3207 are promising candidates for controlling BPV1 infection. The findings of this study may contribute to the development of E6 oncoprotein blockers in an accelerated and cost-effective manner."

Journal • Infectious Disease • Oncology

Adeno-Associated Virus 1 (AAV1) CFTR Gene Therapy Successfully Reduces Cysts in a Mouse Model of Autosomal Dominant Polycystic Kidney Disease (KIDNEY WEEK 2024) - "We showed that CFTR correctors such as VX-809 alter the location of CFTR in cystic epithelia from the apical to the basolateral membrane, thereby reducing cyst formation... These experiments demonstrate convincingly that kidneys of RC/RC animals can be transduced by AAV1 and that phenotypic correction of defective function can be achieved by over expression of CFTR. Also the data suggests that CFTR plays a critical role in ADPKD."

Gene therapy • Preclinical • Autosomal Dominant Polycystic Kidney Disease • Gene Therapies • Genetic Disorders • Nephrology • Polycystic Kidney Disease • Renal Disease • Solid Organ Transplantation • CFTR

E-pharmacophore based virtual screening of potent lead molecules against Cystic Fibrosis: An in silico study. (PubMed, Comput Biol Chem) - "The compound Anguibactin (NPC41982) has been identified as a top lead that exhibits higher binding affinity and stability than the reference compound Lumacaftor, suggesting their potential to bind to the active site of the CFTR protein. These compounds could serve as starting points for the development of drug-like molecules for treating cystic fibrosis."

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