lumacaftor (VX-809) / Vertex - LARVOL DELTA

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

Pd-Catalyzed C(sp2)-C(sp3) Suzuki Coupling and Synthesis of Lumacaftor Using Designed Monophosphine Ligands. (PubMed, Org Lett) - "The aryl thianthrene salt was further applied for late-stage methylation in 97% yield. The active pharmaceutical ingredient lumacaftor was synthesized by aryl-alkyl and aryl-aryl Suzuki coupling reactions using L1 and L2."

Journal

Rescue of CFTR nonsense mutations is enhanced under inflammatory stimuli (NACFC 2024) - "Cells were also treated in the last 24 hours with ELX-02 (200 µM) plus VX-809 (1 µM) with or without CC-90009 (0.1 µM). We found that cytokine-treated epithelia had an enhanced response to the triple compound combination containing the eRF3a degrader CC-90009. We are investigating the molecular basis of this behavior because the cytokine treatment may change expression of genes controlling protein synthesis, thus potentiating the effect of readthrough maneuvers."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • GSPT1 • IL17A • IL4 • TNFA

The ER Stress Induced in Human Neuroblastoma Cells Can Be Reverted by Lumacaftor, a CFTR Corrector. (PubMed, Curr Issues Mol Biol) - "Here, we evaluated the activity of Vx-809 (Lumacaftor), a drug used in cystic fibrosis, in SH-SY5Y neuronal cells, in which an ER stress condition was induced by Thapsigargin, to verify whether the drug could improve protein folding, suggesting its possible therapeutic use in proteinopathies, such as neurodegenerative diseases (NDs). Our data show that Vx-809 is involved in the significant reduction in protein produced under ER stress, particularly in the levels of Bip, ATF4, and ATF6 by Western blotting analysis, the reduction in ROS in the cytosol and mitochondria, and the reduction in the activation of the apoptotic pathway, measured by flow cytofluorimetry analysis and in restoring calcium homeostasis."

Journal • CNS Disorders • CNS Tumor • Cystic Fibrosis • Genetic Disorders • Immunology • Neuroblastoma • Oncology • Proteinopathy • Pulmonary Disease • Respiratory Diseases • Solid Tumor • ATF4 • ATF6 • CASP4 • HSPA5

Development of a drug testing platform for CFTR premature termination codon variants based on rectal organoids (NACFC 2024) - "Incubation with the aminoglycoside G418, as expected from the literature, caused a significantly greater in FIS rate than control (vehicle) and ELX-02 or PTC124, with further improvement in combination with CFTR modulators (elexacaftor/tezacaftor/ivacaftor [ETI]). Our preliminary data indicate that the levels of swelling induced by G418+ETI reached reference AUC values of F508del/F508del organoids treated with VX809/ VX770 (mean 2,487.9 ± 504). Our data show that this platform may be able to evaluate the drug response that reflects variability in genotypes and individual response to pharmacological treatment to direct clinical research toward a rapid, reliable evaluation of the most promising compounds for CFTR PTC variants. Additional candidate readthrough molecules are being studied using this screening and validation platform."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Partial rescue of p.Phe08del-CFTR trafficking and stability defects by dual and triple corrector combinations (NACFC 2024) - "The additive correction of PTI-801 to type I (ABBV-2222, FDL-169, VX-661, VX-809), type II (Corr-4a), and type III (VX-445) correctors was also assessed. The lack of additivity of PTI-801 with VX-445 suggests that these compounds may act by a similar MoA to rescue p.Phe508del-CFTR. Nevertheless, despite the higher level of functional rescue by dual- and triple-corrector combinations, p.Phe508del-CFTR still presents instability and accelerated degradation."

CFTR

Off-target identification of cystic fibrosis pharmacological correctors using functionalized photocrosslinker analogs (NACFC 2024) - "Background: Cystic fibrosis (CF) pharmacological correctors such as VX-809 and VX-445 are used widely in combinations as highly effective modulator therapy (HEMT) at CF clinics because of their efficacy in improving CFTR protein trafficking and function, yet several side-effects from these correctors and adverse drug interactions have been reported, emphasizing the need to understand the etiology of side-effects that may arise from off-target use. The off targets identified may provide insights into indirect correction mechanisms and provide explanations for the side-effects observed in patients at the cellular level, allowing further optimization of corrector combinations to enhance efficacy and decrease adverse effects."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Development and clinical implementation of an LC-HRMS method for ivacaftor, lumacaftor, tezacaftor and elexacaftor in human plasma and breast milk. (PubMed, Anal Bioanal Chem) - "The validated quantification range for ivacaftor is 0.0050-10 µg/mL with a coefficient of variation < 6% and a mean accuracy of 97-106%; for lumacaftor, tezacaftor, and elexacaftor, the validated quantification range is 0.050-100 µg/mL with a coefficient of variation < 8% and a mean accuracy 93-106%. A simple and sensitive quantification method for CFTR modulators has been developed and used for routine analysis of human plasma and breast milk samples since 2022."

Journal • Cystic Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Failure • Pulmonary Disease • Respiratory Diseases

Synthesis and Biological Evaluation of Pyrazole-Pyrimidones as a New Class of Correctors of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). (PubMed, J Med Chem) - "We previously identified compound 4172 that synergistically rescued the F508del-CFTR folding defect in combination with the existing corrector drugs VX-809 and VX-661. Molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted to propose a plausible binding site and design more potent and effective analogs. We identified three optimized compounds, which, in combination with VX-809 and the investigational corrector 3151, increased the plasma membrane density and function of F508del-CFTR and other rare CFTR mutants resistant to the currently approved therapies."

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

Identification of 6,9-dihydro-5H-pyrrolo[3,2-h]quinazolines as a new class of F508del-CFTR correctors for the treatment of cystic fibrosis. (PubMed, Eur J Med Chem) - "Although substantial advances have been obtained in the pharmacological treatment of cystic fibrosis (CF) with the approval of Kaftrio, a combination of two correctors (VX-661, VX-445) and one potentiator (VX-770), new modulators are still needed to rescue F508del and other CFTR mutants with trafficking defects. Synergy was also observed with corr-4a (class 2 corrector) but not with VX-445 and PP028 (class 3 correctors) indicating that the new compounds behave as class 3 correctors. These results suggest that tricyclic pyrrolo-quinazolines interact with CFTR at a site different from that of VX-809 and represent a novel class of CFTR correctors suitable for combinatorial pharmacological treatments for the basic defect in CF."

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

Inhibition of DUSP18 impairs cholesterol biosynthesis and promotes anti-tumor immunity in colorectal cancer. (PubMed, Nat Commun) - "Finally, the combination of an anti-PD-1 antibody and Lumacaftor, an FDA-approved small molecule inhibitor of DUSP18, inhibits CRC growth in mice and synergistically enhances anti-tumor immunity. Collectively, our findings support the idea that a combination of immune checkpoint and metabolic blockade represents a rationally-designed, mechanistically-based and potential therapy for CRC."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • DUSP1 • KRAS • SREBF2 • USF1 • USP18

Lumacaftor as a potential repurposed drug in targeting breast cancer stem cells: insights from in silico study. (PubMed, J Mol Model) - "This study opens avenues for further investigation and may pave the way for developing therapeutic potential in breast cancer treatment. Further confirmation is warranted through in vitro and clinical studies to validate the findings of this study."

Cancer stem • Journal • Breast Cancer • Oncology • Solid Tumor • CTNNB1

Partial Rescue of p.Phe08del-CFTR Trafficking and Stability Defects by Dual and Triple Corrector Combinations (ECFS 2024) - "The additive correction of PTI-801 to type I (ABBV-2222, FDL-169, VX-661, VX-809), type II (Corr-4a) and type III (VX-445) was also assessed. The lack of additivity of PTI-801 with VX-445 suggests that these compounds may act by a similar MoA to rescue p.Phe508del-CFTR. Nevertheless, despite the higher level of functional rescue by dual and triple corrector combinations, p.Phe508del-CFTR still presents instability and accelerated degradation."

CFTR