- |||||||||| lumacaftor (VX-809) / Vertex, Alverix (amiloride hydrochloride) / Remedica, tezacaftor (VX-661) / Vertex
Clinical, Journal: Functional Profiling of CFTR-Directed Therapeutics Using Pediatric Patient-Derived Nasal Epithelial Cell Models. (Pubmed Central) - Oct 7, 2020
Amiloride-sensitive sodium currents were robust and ranged between 20-80 μA/cm depending on the subject. In addition to characterizing the electrophysiological profile of mutant CFTR activity in cultures for five genotypes, our study exemplifies the promising paradigm of bed-to-bench side cooperation and personalized medicine.
- |||||||||| lumacaftor (VX-809) / Vertex, Orkambi (lumacaftor/ivacaftor) / Vertex
Clinical, Journal: From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2. (Pubmed Central) - Sep 30, 2020
Lumacaftor + Ivacaftor shortened significantly the QTc in the two LQT2 patients with a trafficking defect, largely confirming the findings in their iPSC-CMs but with smaller quantitative changes. The findings are encouraging but immediate translation into clinical practice, without validation in more patients, would be premature.
- |||||||||| lumacaftor (VX-809) / Vertex, Olysio (simeprevir) / J&J, Medivir
Journal: An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors. (Pubmed Central) - Sep 10, 2020
We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein - ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Deciphering the role of protein kinase CK2 in the maturation/stability of CFTR F508del. (Pubmed Central) - Aug 4, 2020
Here, by using immortalized cell lines, primary human cells, and knockout cell lines deprived of CK2 subunits, we do not disclose any direct correlation between F508del-CFTR proteostasis and CK2 expression/activity. Rather, our data indicate that the CK2α' catalytic subunit should be preserved rather than inhibited for F508del rescue by the correctors of class-1, such as VX-809, disclosing new important features in CF therapeutic approaches.
- |||||||||| ensifentrine (RPL554) / Verona Pharma
Journal: The dual phosphodiesterase 3/4 inhibitor RPL554 stimulates rare class III and IV CFTR mutants. (Pubmed Central) - Jul 29, 2020
Furthermore, we provide biochemical evidence that VX-809 causes surprisingly robust correction of several class III and IV CFTR mutants. Together, our findings further support the therapeutic potential of RPL554 for CF patients with class III/IV mutations and emphasize the potential of PDEs as potential drug targets that could benefit CF patients.
- |||||||||| galicaftor (GLPG2222) / AbbVie
Journal: Biological characterization of F508delCFTR protein processing by the CFTR Corrector ABBV-2222/GLPG2222. (Pubmed Central) - Jul 16, 2020
SIGNIFICANCE STATEMENT: To address the most prevalent defect of the defective CFTR protein (i.e. F508del mutation) in Cystic Fibrosis, Abbvie-Galapagos has developed ABBV-2222/GLPG2222, a novel, potent and orally bioavailable C1 corrector of this protein. ABBV-2222/GLPG2222 exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR and is currently in clinical trials that exhibits substantial improvements over the existing C1 correctors.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex, Orkambi (lumacaftor/ivacaftor) / Vertex
Clinical, Journal, Combination therapy: Safety and efficacy of treatment with lumacaftor in combination with ivacaftor in younger patients with cystic fibrosis. (Pubmed Central) - Jun 29, 2020
Expert opinion: Orkambi somewhat improves clinical outcomes for people with CF who are homozygous for the F508del mutation, and does so with a reasonable safety profile. This therapy represents a major advance in the therapy for CF, but further advances are needed, perhaps with addition of a third agent to this combination small molecule therapy, in order to expand both the targeted population and beneficial effects.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
The last 10%: small molecule screening for correctors of rare CFTR processing mutations () - Jun 29, 2020 - Abstract #ECFS2020ECFS_60;
We aimed at screening compounds directly on refractory mutations N1303 K and G85E. Currently, we have identified several hits with corrector efficacy in the low μM range for N1303 K. FIS experiments are ongoing to confirm if positive hits can rescue CFTR trafficking and possibly function in organoids.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
HspB5 is a phospho-regulated corrector of F508del-CFTR () - Jun 29, 2020 - Abstract #ECFS2020ECFS_28;
These activities are enhanced in presence of VX-770, VX-809 and VX-770 + VX- 809. Moreover, in CF disease we have shown that HspB5 acts in a very different way compared to HspB1 and HspB4.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
Role of cholesterol in the function of current cystic fibrosismedications () - Jun 29, 2020 - Abstract #ECFS2020ECFS_26;
Our studies suggest an important role played by cholesterol in the functioning of CF drugs. The impact of our findings will not only bridge the gap in knowledge relating to existing CF drugs, but also provide a platform for the design of novel CF therapeutics.
- |||||||||| Kalydeco (ivacaftor) / Vertex
AVX-770 binding site within CFTR membrane spanning domain 2 enables ATP-independent channel activation () - Jun 29, 2020 - Abstract #ECFS2020ECFS_25;
During these last years, modulators of CFTR channel have been developed to target some defects associated with specific mutations, affecting the folding of CFTR protein (correctors; e.g. VX809) or the opening probability of the channel (potentiators; e.g. VX-770). Altogether, these results give new insights into our funda- mental understanding of the mode of action of potentiators and open new perspectives for CFTR-specific, structure-based drug design.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: The anion transporter SLC26A9 localizes to tight junctions and is degraded by the proteasome when co-expressed with F508del-CFTR. (Pubmed Central) - Jun 25, 2020
Apical SLC26A9 expression increased when F508del-CFTR trafficking was partially corrected by low temperature or with the CFTR modulator VX-809...Immunofluorescence staining of endogenous SLC26A9 and transfection of a 3HA-tagged construct into well-differentiated cells revealed that SLC26A9 is mostly present at tight junctions. We conclude that SLC26A9 interacts with CFTR in both the ER and Golgi and that its interaction with F508del-CFTR increases proteasomal SLC26A9 degradation.
- |||||||||| lumacaftor (VX-809) / Vertex, tezacaftor (VX-661) / Vertex
Journal: Slowing ribosome velocity restores folding and function of mutant CFTR. (Pubmed Central) - Jun 25, 2020
Rpl12 knockdown also partially restored maturation of specific CFTR variants in addition to F508del, and WT Cftr biogenesis was enhanced in the pancreas, colon, and ileum of Rpl12 haplosufficient mice. Modulation of ribosome velocity therefore represents a robust method for understanding both CF pathogenesis and therapeutic response.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
Review, Journal: Pharmacological analysis of CFTR variants of cystic fibrosis using stem cell-derived organoids. (Pubmed Central) - Jun 12, 2020
In this review, we shed light on the pharmacogenomics of diverse CFTR mutations and the emerging role of stem cell-based organoids in predicting the CF drug response. We discuss mechanisms that underlie differential CF drug responses both in organoid-based assays and in CF clinical trials, thereby facilitating the precision design of safer and more effective therapies for individual patients with CF.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
Journal: Structural mechanisms for defective CFTR gating caused by the Q1412X mutation, a severe Class VI pathogenic mutation in cystic fibrosis. (Pubmed Central) - May 27, 2020
Detailed comparisons of several mutations with different degrees of truncation in the C-terminal region of NBD2 reveal the importance of the last two beta-strands in NBD2 in maintaining proper gating functions. Our studies also show that the application of clinically-approved drugs (VX-770 and VX-809) can greatly enhance the function of Q1412X, providing in vitro evidence for a therapeutic strategy employing both reagents for patients bearing Q1412X or similar truncation mutations.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: CK19 stabilizes CFTR at the cell surface by limiting its endocytic pathway degradation. (Pubmed Central) - May 27, 2020
CK19 overexpression stabilized both wild-type (WT)-CFTR and Lumacaftor (VX-809)-rescued F508del-CFTR (where F508del is the deletion of the phenylalanine residue at position 508) at the plasma membrane (PM), promoting Cl secretion across human bronchial epithelial (HBE) cells...Unexpectedly, CK19 expression was decreased by ∼40% in primary HBE cells from homogenous F508del patients with CF relative to non-CF controls. CK19 also positively regulated multidrug resistance-associated protein 4 expression at the PM, suggesting that this keratin may regulate the apical expression of other ATP-binding cassette proteins as well as CFTR.-Hou, X., Wu, Q., Rajagopalan, C., Zhang, C., Bouhamdan, M., Wei, H., Chen, X., Zaman, K., Li, C., Sun, X., Chen, S., Frizzell, R. A., Sun, F. CK19 stabilizes CFTR at the cell surface by limiting its endocytic pathway degradation.
- |||||||||| lumacaftor (VX-809) / Vertex, Orkambi (lumacaftor/ivacaftor) / Vertex
Clinical, Journal: Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis. (Pubmed Central) - May 23, 2020
Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often due to adverse events, were found at high risk of clinical deterioration.
- |||||||||| Review, Journal: Cystic fibrosis precision therapeutics: Emerging considerations. (Pubmed Central) - May 11, 2020
In addition to describing the remarkable progress that has occurred regarding CF precision medicine, this review outlines some of the remaining challenges. The CF experience is emblematic of many conditions for which personalized interventions are actively being sought.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
Clinical, Journal: iPSC-Derived Intestinal Organoids from Cystic Fibrosis Patients Acquire CFTR Activity upon TALEN-Mediated Repair of the p.F508del Mutation. (Pubmed Central) - May 8, 2020
Gene-edited iPSCs were subsequently used to produce intestinal organoids on which the physiological activity of the restored gene was tested in forskolin-induced swelling tests. The seamless restoration of the p.F508del mutation resulted in normal expression of the mature CFTR glycoprotein, full recovery of CFTR activity, and a normal response of the repaired organoids to treatment with two approved CF therapies: VX-770 and VX-809.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex, Orkambi (lumacaftor/ivacaftor) / Vertex
Journal: Continuous glucose monitoring in youth with cystic fibrosis treated with lumacaftor-ivacaftor. (Pubmed Central) - Apr 24, 2020
The current study demonstrates how endogenous pathways can be utilized for the development of companion therapy in CF. Glycemic abnormalities persisted in CF patients treated with lumacaftor-ivacaftor, although sex-dependent differences in glycemic response to treatment may exist.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex, Orkambi (lumacaftor/ivacaftor) / Vertex
Clinical, Journal: Lumacaftor/Ivacaftor reduces pulmonary exacerbations in patients irrespective of initial changes in FEV. (Pubmed Central) - Apr 24, 2020
P3
Glycemic abnormalities persisted in CF patients treated with lumacaftor-ivacaftor, although sex-dependent differences in glycemic response to treatment may exist. LUM/IVA significantly reduced PEx, even in patients without early lung function improvement.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex, Orkambi (lumacaftor/ivacaftor) / Vertex
Journal, Combination therapy: Combination Therapy with Lumacaftor-Ivacaftor in CF: Keeping it Real. (Pubmed Central) - Apr 22, 2020
Efficacy studies using LQT2 variant-specific iPSC-CMs may be a useful pre-LUM treatment screening strategy. No abstract available
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
Journal: High-Throughput Screening for Modulators of CFTR Activity Based on Genetically Engineered Cystic Fibrosis Disease-Specific iPSCs. (Pubmed Central) - Apr 16, 2020
CFTR function was partially rescued by treatment with VX-770 and VX-809, and seamless gene correction of the p.Phe508del mutation resulted in full restoration of CFTR function. The identification of a series of validated primary hits that improve the function of p.Phe508del CFTR from a library of ∼42,500 chemical compounds demonstrates that the advantages of complex iPSC-derived culture systems for disease modeling can also be utilized for drug screening in a true HT format.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex, Orkambi (lumacaftor/ivacaftor) / Vertex
Clinical, Journal: CFTR Modulator Use is Associated with Higher Hemoglobin Levels in Individuals with Cystic Fibrosis. (Pubmed Central) - Apr 10, 2020
The identification of a series of validated primary hits that improve the function of p.Phe508del CFTR from a library of ∼42,500 chemical compounds demonstrates that the advantages of complex iPSC-derived culture systems for disease modeling can also be utilized for drug screening in a true HT format. Ivacaftor and lumacaftor/ivacaftor use are both associated with higher Hgb levels in CF patients.
- |||||||||| lumacaftor (VX-809) / Vertex
Journal: Characterization of Cystic Fibrosis Airway Smooth Muscle Cell Proliferative and Contractile Activities. (Pubmed Central) - Apr 10, 2020
The combination CFTR corrector and potentiator, VX-809/770, was used to restore proper CFTR function in CF ASM which resulted in a reduction in proliferation and in a normalization of calcium reuptake kinetics. These results show that improper CFTR function in ASM cause intrinsic changes in their proliferative and contractile properties.
- |||||||||| Kalydeco (ivacaftor) / Vertex, lumacaftor (VX-809) / Vertex
Journal: Functional and Pharmacological Characterization of the Rare CFTR Mutation W361R. (Pubmed Central) - Apr 9, 2020
Analysis of the 3D structure of CFTR within a lipid environment indicated that W361, together with other mutations located in this hotspot, is at the edge of a groove which stably accommodates lipid acyl chains. We suggest this lipid environment impacts CFTR folding, maturation and response to CFTR modulators.
- |||||||||| lumacaftor (VX-809) / Vertex, Orkambi (lumacaftor/ivacaftor) / Vertex
Clinical, Journal: Pathogen acquisition in patients with cystic fibrosis receiving ivacaftor or lumacaftor/ivacaftor. (Pubmed Central) - Mar 24, 2020
Patients receiving ivacaftor or lumacaftor/ivacaftor for CF had significantly delayed acquisition of P. aeruginosa and S. aureus after these drugs were released. This method for analyzing incident infections may be useful for future studies of CFTR modulators and bacterial acquisition in CF registry cohorts.
- |||||||||| Amino Acids Regulate Defective CFTR Trafficking and Gating in Primary Human F508del-Bronchial Epithelial Cells Similar to Cystic Fibrosis Correctors and Potentiators (PENNSYLVANIA CONVENTION CENTER, Hall D-E (200 Level), Area J) - Mar 15, 2020 - Abstract #ATS2020ATS_10138;
Here, we compare the efficiency or additive efficiency of our AA to treatment with VX809/VX770 or VX661/VX770 alone in trafficking defective CFTR and increasing chloride secretion in primary human bronchial epithelial cells with homozygous F508del (HBEC-F508del)...After blocking ENaC with benzamil, chloride secretion was stimulated using GLPG1837 (VX770-analogue) with or without forskolin... A proprietary AA mixture increases apical anion secretion similar to correctors and potentiators rendering these AA a potential additive or stand-alone treatment option in CF patients following additional preclinical and clinical studies.
- |||||||||| lumacaftor (VX-809) / Vertex, Orkambi (lumacaftor/ivacaftor) / Vertex
Variation in Use of Lumacaftor/Ivacaftor (PENNSYLVANIA CONVENTION CENTER, Hall D-E (200 Level), Area K) - Mar 15, 2020 - Abstract #ATS2020ATS_9134;
There was a high degree of readmission among hospitalized cystic fibrosis patients that received lumacaftor/ivacaftor during their stays, and the stays were generally lengthy. Further study will elucidate other impacts of lumacaftor/ivacaftor, including visits that did not include use of lumacaftor/ivacaftor.
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