ABSTRACT
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapy has previously been contraindicated in solid organ transplant recipients. This was due to lack of data and concern for interactions with immunosuppressive drug regimens. However, in post-lung transplant recipients, CFTR modulators may improve extrapulmonary manifestations of cystic fibrosis without impacting graft function or immunosuppressive drug levels. Herein, we present our single center experience with the use of elexacaftor/tezacaftor/ivacaftor, Trikafta, in adult post-lung transplant recipients.
Subject(s)
Aminophenols/therapeutic use , Benzodioxoles/therapeutic use , Chloride Channel Agonists/therapeutic use , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis/drug therapy , Cystic Fibrosis/surgery , Indoles/therapeutic use , Lung Transplantation , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Quinolines/therapeutic use , Adult , Blood Glucose , Body Mass Index , Drug Combinations , Female , Forced Expiratory Volume , Humans , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: Half of adults with cystic fibrosis (CF) develop CF-related diabetes (CFRD). CFRD contributes to worsened pulmonary function and malnutrition. We undertook this study to determine the effect of cystic fibrosis transmembrane regulator (CFTR) modulators on CRFD. METHODS: We reviewed the medical records of adults with CF who followed in the CF clinic at Oklahoma University Medical Center. We collected data for age at diagnosis of CF and CFRD, CF mutations present, first date of ivacaftor therapy either alone or in combination, insulin use, pulmonary function, body mass index data, and home glucose monitoring results. Clinical resolution of CFRD was taken as discontinuation of routine insulin and resolution of high interstitial home glucose values. RESULTS: We identified 69 adult CF patients, of whom 31 had CFRD. Among these 14 CFRD patients taking ivacaftor alone or in combination, four patients completely stopped using insulin. Another patient went from three times a day pre-prandial insulin to using insulin once a week. Home blood glucose and hemoglobin A1c values supported resolution of CFRD. Three patients continued to have hypoglycemia despite stopping insulin. No CFRD patient not taking CFTR modulators markedly changed the insulin regimen. Pulmonary function was preserved in those patients with resolved CFRD (FEV1 +6.75% ±7.6), whereas it worsened in CFRD patients who either were not taking CFTR modulators (FEV1 -2.09% ±3.9) or who had no response of CFRD status (FEV1 -4.9% ±7.6). CONCLUSIONS: About one-third of patients on CFTR modulator therapy had resolution or near resolution of CFRD.
Subject(s)
Aminophenols/therapeutic use , Chloride Channel Agonists/therapeutic use , Cystic Fibrosis , Diabetes Mellitus , Quinolones/therapeutic use , Adult , Blood Glucose , Blood Glucose Self-Monitoring , Cystic Fibrosis/complications , Cystic Fibrosis/drug therapy , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Diabetes Mellitus/drug therapy , Humans , Insulin/therapeutic useABSTRACT
Premature-termination codons (PTCs) in CFTR (cystic fibrosis [CF] transmembrane conductance regulator) result in nonfunctional CFTR protein and are the proximate cause of â¼11% of CF-causing alleles, for which no treatments exist. The CFTR corrector lumacaftor and the potentiator ivacaftor improve CFTR function with terminal PTC mutations and enhance the effect of readthrough agents. Novel correctors GLPG2222 (corrector 1 [C1]), GLPG3221 (corrector 2 [C2]), and potentiator GLPG1837 compare favorably with lumacaftor and ivacaftor in vitro. Here, we evaluated the effect of correctors C1a and C2a (derivatives of C1 and C2) and GLPG1837 alone or in combination with the readthrough compound G418 on CFTR function using heterologous Fischer rat thyroid (FRT) cells, the genetically engineered human bronchial epithelial (HBE) 16HBE14o- cell lines, and primary human cells with PTC mutations. In FRT lines pretreated with G418, GLPG1837 elicited dose-dependent increases in CFTR activity that exceeded those from ivacaftor in FRT-W1282X and FRT-R1162X cells. A three-mechanism strategy consisting of G418, GLPG1837, and two correctors (C1a + C2a) yielded the greatest functional improvements in FRT and 16HBE14o- PTC variants, noting that correction and potentiation without readthrough was sufficient to stimulate CFTR activity for W1282X cells. GLPG1837 + C1a + C2a restored substantial function in G542X/F508del HBE cells and restored even more function for W1282X/F508del cells, largely because of the corrector/potentiator effect, with no additional benefit from G418. In G542X/R553X or R1162X/R1162X organoids, enhanced forskolin-induced swelling was observed with G418 + GLPG1837 + C1a + C2a, although GLPG1837 + C1a + C2a alone was sufficient to improve forskolin-induced swelling in W1282X/W1282X organoids. Combination of CFTR correctors, potentiators, and readthrough compounds augments the functional repair of CFTR nonsense mutations, indicating the potential for novel correctors and potentiators to restore function to truncated W1282X CFTR.
Subject(s)
Benzoates/pharmacology , Benzopyrans/pharmacology , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/genetics , Epithelial Cells/drug effects , Protein Biosynthesis/drug effects , Pyrans/pharmacology , Pyrazoles/pharmacology , Aminophenols/pharmacology , Aminopyridines/pharmacology , Animals , Benzodioxoles/pharmacology , Cell Line , Chlorides/metabolism , Codon, Nonsense , Cystic Fibrosis/drug therapy , Cystic Fibrosis/metabolism , Cystic Fibrosis/pathology , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis Transmembrane Conductance Regulator/deficiency , Epithelial Cells/metabolism , Humans , Ion Transport/drug effects , Quinolones/pharmacology , Rats , Recovery of Function , Thyroid Epithelial Cells/drug effects , Thyroid Epithelial Cells/metabolismABSTRACT
DISCLOSURES: No funding contributed to the writing of this commentary. Both authors are employed by the Cystic Fibrosis Foundation. The Cystic Fibrosis Foundation has entered into therapeutic development award agreements and licensing agreements to assist with the development of CFTR modulators that may result in intellectual property rights, royalties, and other forms of consideration provided to CFF. Some of these agreements are subject to confidentiality restrictions and, thus, CFF cannot comment on them.
Subject(s)
Chloride Channel Agonists/therapeutic use , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis/drug therapy , Drug Costs , Aminophenols/economics , Aminophenols/therapeutic use , Benzodioxoles/economics , Benzodioxoles/therapeutic use , Chloride Channel Agonists/economics , Cystic Fibrosis/economics , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Drug Approval/economics , Drug Combinations , Humans , Indoles/economics , Indoles/therapeutic use , Medical Assistance , Mutation , Pyrazoles/economics , Pyrazoles/therapeutic use , Pyridines/economics , Pyridines/therapeutic use , Quinolines/economics , Quinolines/therapeutic use , Quinolones/economics , Quinolones/therapeutic use , Treatment Outcome , United States , United States Food and Drug AdministrationABSTRACT
DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Seidner, Rind, and Pearson are employed by ICER. Tice reports contracts to his institution, University of California, San Francisco, from ICER during the conduct of this study. Wherry has nothing to disclose.
Subject(s)
Chloride Channel Agonists/therapeutic use , Cost-Benefit Analysis , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis/drug therapy , Models, Economic , Adolescent , Aminophenols/economics , Aminophenols/therapeutic use , Aminopyridines/economics , Aminopyridines/therapeutic use , Benzodioxoles/economics , Benzodioxoles/therapeutic use , Child , Chloride Channel Agonists/economics , Cystic Fibrosis/economics , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Drug Approval/economics , Drug Combinations , Drug Costs , Health Policy/economics , Humans , Indoles/economics , Indoles/therapeutic use , Mutation , Pyrazoles/economics , Pyrazoles/therapeutic use , Pyridines/economics , Pyridines/therapeutic use , Quinolines/economics , Quinolines/therapeutic use , Quinolones/economics , Quinolones/therapeutic use , Treatment Outcome , United States , United States Food and Drug AdministrationABSTRACT
We previously identified a spiro [piperidine-4,1-pyrido [3,4-b]indole] class of co-potentiators that function in synergy with existing CFTR potentiators such as VX-770 or GLGP1837 to restore channel activity of a defined subset of minimal function cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Here, structure-activity studies were conducted to improve their potency over the previously identified compound, 20 (originally termed CP-A01). Targeted synthesis of 37 spiro [piperidine-4,1-pyrido [3,4-b]indoles] was generally accomplished using versatile two or three step reaction protocols with each step having high efficiency. Structure-activity relationship studies established that analog 2i, with 6'-methoxyindole and 2,4,5-trifluorobenzyl substituents, had the greatest potency for activation of N1303K-CFTR, with EC50 â¼600 nM representing an â¼17-fold improvement over the original compound identified in a small molecule screen.
Subject(s)
Chloride Channel Agonists/chemistry , Chloride Channel Agonists/pharmacology , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Indoles/chemistry , Indoles/pharmacology , Aminophenols/pharmacology , Animals , Cell Line , Chloride Channel Agonists/chemical synthesis , Cystic Fibrosis/drug therapy , Cystic Fibrosis/genetics , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Humans , Indoles/chemical synthesis , Models, Molecular , Mutation , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Quinolones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Exocrine pancreatic insufficiency (EPI), which leads to malabsorption and poor weight gain, is seen in 85% of patients with cystic fibrosis (CF). EPI is treated with pancreatic enzyme replacement therapy taken with each meal. The highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator, ivacaftor, restores CFTR function in patients with responsive mutations. It is a widely held view that EPI in CF is irreversible due to the complete destruction of pancreatic ducts and acinar cells. We describe three pediatric CF patients with EPI who were started on ivacaftor, and subsequently showed evidence of restored exocrine pancreatic function with clinical and biochemical parameters.
Subject(s)
Aminophenols/therapeutic use , Chloride Channel Agonists/therapeutic use , Cystic Fibrosis/drug therapy , Exocrine Pancreatic Insufficiency/drug therapy , Quinolones/therapeutic use , Child , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Female , Humans , Male , Mutation , Pancreas/drug effectsABSTRACT
BACKGROUND: Several studies have assessed safety and efficacy outcomes for lumacaftor/ivacaftor therapy. We report on lumacaftor/ivacaftor's impact on lung function, physical performance, and health-related quality of life (HRQOL) in a subpopulation of Danish people with Cystic Fibrosis (CF; PWCF) with advanced pulmonary disease who would not fulfill inclusion criteria for these studies. METHODS: This follow-up study examined lumacaftor/ivacaftor's effect in a highly selected CF population. Inclusion criteria included low percent predicted forced expiratory volume in one second (ppFEV1 ), fast deteriorating ppFEV1 , low body mass index (BMI), and difficult-to-treat infections. Primary endpoints included change in ppFEV1 slope, cardiopulmonary exercise testing (CPET), and all domains of the Cystic Fibrosis Questionnaire-Revised (CFQ-R). Secondary outcomes included change in ppFEV1 , BMI Z-score, and sweat chloride concentration. RESULTS: A total of 21 patients homozygous for the F508del mutation and a median ppFEV1 of 38.7 were included. We found significant improvements in ppFEV1 (+4.2 p < .01, +5.8 p < .01, +4.8 p < .01 and +3.8 p = .03 ppFEV1 after 3, 6, 9, and 12 months of treatment compared to baseline), ppFEV1 slope (+6.84 ppFEV1 /year between the year before and the year after treatment initiation; p = .02), and saturation at CPET initiation (+1.4%, p < .02) and termination (+2.6%, p < .01) after 6 months of treatment. Finally, HRQOL improved significantly in all CFQ-R domains except Emotion and Treat. CONCLUSIONS: Our findings suggest that lumacaftor/ivacaftor reduces lung function decline, improves lung function, physical performance, and HRQOL to a greater extent in PWCF with severe lung disease than previously recognized.
Subject(s)
Aminophenols/therapeutic use , Aminopyridines/therapeutic use , Benzodioxoles/therapeutic use , Chloride Channel Agonists/therapeutic use , Cystic Fibrosis/drug therapy , Quinolones/therapeutic use , Adolescent , Adult , Cystic Fibrosis/genetics , Cystic Fibrosis/physiopathology , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Drug Combinations , Female , Forced Expiratory Volume , Humans , Lung/drug effects , Lung/physiopathology , Male , Middle Aged , Quality of Life , Young AdultABSTRACT
Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR modulators for different genetic subsets of patients with CF. Two investigators independently performed the search on PubMed and included phase 2 and 3 clinical trials published in the study period 1 January 2005-31 January 2020. A final pool of 23 papers was included in the systematic review for a total of 4219 patients. For each paper data of interest were extracted and reported in table. In terms of lung function, patients who had the most beneficial effects from CFTR modulation were those patients with one gating mutation receiving IVA (ivacaftor) and patients with p.Phe508del mutation, both homozygous and heterozygous, receiving ELX/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor) had the most relevant beneficial effects in term of lung function, pulmonary exacerbation decrease, and symptom improvement. CFTR modulators showed an overall favorable safety profile. Next steps should aim to systematize our comprehension of scientific data of efficacy and safety coming from real life observational studies.
Subject(s)
Aminophenols/therapeutic use , Chloride Channel Agonists/therapeutic use , Clinical Trials as Topic , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis/drug therapy , Quinolones/therapeutic use , Aminophenols/administration & dosage , Aminophenols/adverse effects , Child , Chloride Channel Agonists/administration & dosage , Chloride Channel Agonists/adverse effects , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Drug Combinations , Humans , Quinolones/administration & dosage , Quinolones/adverse effectsSubject(s)
Aminophenols/therapeutic use , Cystic Fibrosis/drug therapy , Epithelial Cells/drug effects , Lung/drug effects , Quinolones/therapeutic use , Cystic Fibrosis/physiopathology , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Humans , Lung/physiopathology , Proof of Concept StudyABSTRACT
In this paper the innovative approach of nano into micro dry powders (NiM) was applied to incorporate into mannitol or mannitol/cysteamine micromatrices ivacaftor-loaded nanoparticles for pulmonary delivery in CF. Nanoparticles composed by a mixture of two polyhydrohydroxyethtylaspartamide copolymers containing loaded with ivacaftor at 15.5% w/w were produced. The nanoparticles were incorporated into microparticles to obtain NiM that were fully characterized in terms of size, morphology, interactions with artificial Cf mucus (CF-AM) as well as for aerodynamic behaviour. Finally the activity of ivacaftor-containing NiM was evaluated by in vitro preliminary experiments. NiM at matrix composed by a mixture of mannitol:cysteamine showed greater ability to reduce CF-AM viscosity whereas that based on just mannitol showed better aerodynamic properties with a FPF of about 25%. All produced NiM showed very good cytocompatibility and the released ivacaftor was able to restore the chroride transport in vitro.
Subject(s)
Aminophenols/administration & dosage , Chloride Channel Agonists/administration & dosage , Cysteamine/administration & dosage , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis/drug therapy , Expectorants/administration & dosage , Mannitol/administration & dosage , Nanoparticles , Peptides/chemistry , Quinolones/administration & dosage , Administration, Inhalation , Aminophenols/chemistry , Animals , Cells, Cultured , Chloride Channel Agonists/chemistry , Cysteamine/chemistry , Cystic Fibrosis/genetics , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Drug Compounding , Drug Liberation , Expectorants/chemistry , Mannitol/chemistry , Mutation , Powders , Quinolones/chemistry , Rats, Inbred F344ABSTRACT
Over 2,000 mutations have been reported in the cystic fibrosis transmembrane conductance regulator (cftr) gene, many of which cause disease but are rare and have no effective treatment. Thus, there is an unmet need for new, mutation-agnostic therapies for cystic fibrosis (CF). Phosphodiesterase (PDE) inhibitors are one such class of therapeutics that have been shown to elevate intracellular cAMP levels and stimulate CFTR-dependent anion secretion in human airway epithelia; however, the number of people with CF that could be helped by PDE inhibitors remains to be determined. Here we used Fisher rat thyroid (FRT) cells stably transduced with rare human CFTR mutants and studied their responsiveness to the dual phosphodiesterase 3/4 inhibitor RPL554 (Verona Pharma). Through its inhibitory effect on PDE4D, we find that RPL554 can elevate intracellular cAMP leading to a potentiation of forskolin-stimulated current mediated by R334W, T338I, G551D, and S549R mutants of CFTR when used alone or in combination with CFTR modulators. We also were able to reproduce these effects of RPL554 on G551D-CFTR when it was expressed in primary human bronchial epithelial cells, indicating that RPL554 would have stimulatory effects on rare CFTR mutants in human airways and validating FRT cells as a model for PDE inhibitor studies. 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 patients with CF with class III/IV mutations and emphasize the potential of PDEs as potential drug targets that could benefit patients with CF.
Subject(s)
Cyclic AMP/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Isoquinolines/pharmacology , Phosphodiesterase 3 Inhibitors/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacology , Pyrimidinones/pharmacology , Thyroid Epithelial Cells/drug effects , Aminopyridines/pharmacology , Animals , Benzodioxoles/pharmacology , Bronchi/cytology , Bronchi/drug effects , Bronchi/metabolism , Cell Line , Colforsin/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 3/genetics , Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis Transmembrane Conductance Regulator/classification , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Humans , Mutation , Primary Cell Culture , Rats , Rats, Inbred F344 , Thyroid Epithelial Cells/cytology , Thyroid Epithelial Cells/metabolism , TransgenesABSTRACT
Purpose: Dry eye disorders are a major health care burden. We previously reported the identification of N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine [cystic fibrosis transmembrane conductance regulator (CFTR)act-K267], which activated human wild-type CFTR chloride conductance with EC50 â¼ 30 nM. Here, we report in vivo evidence for CFTRact-K267 efficacy in an experimental mouse model of dry eye using a human compatible ophthalmic vehicle. Methods: CFTR activation in mice in vivo was demonstrated by ocular surface potential difference (OSPD) measurements. Ocular surface pharmacodynamics was measured in tear fluid samples obtained at different times after topical administration of CFTRact-K267. Dry eye was produced by lacrimal duct cautery (LDC) and corneal epithelial injury and was assessed by Lissamine green (LG) staining. Results: OSPD measurements demonstrated a hyperpolarization of -8.6 ± 3 mV (standard error of the mean, 5 mice) in response to CFTRact-K267 exposure in low chloride solution that was reversed by a CFTR inhibitor. Following single-dose topical administration of 2 nmol CFTRact-K267, tear fluid CFTRact-K267 concentration was >500 nM for more than 6 h. Following LDC, corneal surface epithelial injury, as assessed by LG staining, was substantially reversed in 10 of 12 eyes receiving 2 nmol CFTRact-K267 3 times daily starting on day 2, when marked epithelial injury had already occurred. Improvement was seen in 3 of 12 vehicle-treated eyes. Conclusion: These studies provide in vivo evidence in mice for the efficacy of a topical, human use compatible CFTRact-K267 formulation in stimulating chloride secretion and reversing corneal epithelial injury in dry eye.
Subject(s)
Corneal Injuries/drug therapy , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Dry Eye Syndromes/drug therapy , Triazines/pharmacology , Administration, Topical , Animals , Benzoates/administration & dosage , Benzoates/pharmacology , Cautery/adverse effects , Chloride Channels/drug effects , Disease Models, Animal , Female , Lacrimal Apparatus/physiopathology , Lissamine Green Dyes/chemistry , Mice , Mice, Inbred BALB C , Nanotechnology , Tears/drug effects , Thiazolidines/administration & dosage , Thiazolidines/pharmacology , Treatment Outcome , Triazines/administration & dosage , Triazines/pharmacokinetics , Triazines/therapeutic useSubject(s)
Chloride Channel Agonists/therapeutic use , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis/drug therapy , Drug Development , Chloride Channel Agonists/economics , Chloride Channel Agonists/pharmacology , Cystic Fibrosis/economics , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Drug Costs , Humans , Loss of Function MutationABSTRACT
A fixed-dose combination tablet of the cystic fibrosis transmembrane conductance regulator (CFTR) corrector tezacaftor and the CFTR potentiator ivacaftor with the next-generation CFTR corrector elexacaftor (hereafter referred to as elexacaftor/ivacaftor/tezacaftor) [Trikafta™] has been developed by Vertex Pharmaceuticals Inc. to treat patients with the most common cystic fibrosis mutation (F508del). Its use has been associated with statistically significant and/or clinically meaningful improvements in lung function and respiratory-related quality of life compared with comparator regimens (placebo or ivacaftor/tezacaftor) in multinational phase II and III studies, and in October 2019 elexacaftor/ivacaftor/tezacaftor was approved by the US FDA for the treatment of cystic fibrosis in patients aged ≥ 12 years who have ≥ 1 F508del mutation in the CFTR gene. A regulatory assessment for elexacaftor/ivacaftor/tezacaftor as a treatment for cystic fibrosis is underway in the EU. This article summarizes the milestones in the development of elexacaftor/ivacaftor/tezacaftor leading to this first approval for the treatment of cystic fibrosis in patients aged ≥ 12 years who have ≥ 1 F508del mutation in the CFTR gene.
Subject(s)
Aminophenols/pharmacology , Benzodioxoles/pharmacology , Chloride Channel Agonists/pharmacology , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis/drug therapy , Drug Approval , Indoles/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Pyrrolidines/pharmacology , Quinolones/pharmacology , Cystic Fibrosis/genetics , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Humans , Mutation , United States , United States Food and Drug AdministrationABSTRACT
BACKGROUND: Approximately 1 in 5 patients with pancreas sufficient cystic fibrosis (PS-CF) will develop acute pancreatitis (AP). It is not known whether ivacaftor alone or in combination with other CFTR (cystic transmembrane regulator) modulators (tezacaftor or lumacaftor) can reduce the risk of AP in patients with PS-CF and AP history. METHODS: We retrospectively queried the CF registry at our institution for adult patients with PS-CF, a documented history of AP and initiation of CFTR modulators for pulmonary indications. Patient characteristics including demographics, CFTR genotype, pancreatitis risk factors, pancreatic exocrine function and other relevant laboratory, imaging parameters were obtained from the time of the sentinel AP episode through the follow-up period. RESULTS: A total of 15 adult CF patients were identified with mean age of 44.1 years (SD⯱â¯13.8). In the 24 months preceding CFTR modulator initiation, six of these patients had at least 1 episode of AP with median of 2 episodes [1.75, 2.5]. None of the patients had evidence of pancreatic calcifications or exocrine pancreas insufficiency at the time of CFTR modulator initiation. The mean duration of follow-up after CFTR modulator initiation was 36.7 months (SD⯱â¯21.5). None of the patients who remained on CFTR modulators developed an episode of AP or required hospitalization for AP related abdominal pain during follow-up. CONCLUSIONS: CFTR modulators, alone or in combination, substantially reduce the risk of recurrent AP over a mean follow-up period of 3 years in adult patients with PS-CF and a history of prior AP. These data suggest that any augmentation of CFTR function can reduce the risk of pancreatitis.
Subject(s)
Aminophenols/therapeutic use , Aminopyridines/therapeutic use , Benzodioxoles/therapeutic use , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis/complications , Exocrine Pancreatic Insufficiency/prevention & control , Indoles/therapeutic use , Quinolones/therapeutic use , Adult , Aged , Aminophenols/administration & dosage , Aminopyridines/administration & dosage , Benzodioxoles/administration & dosage , Exocrine Pancreatic Insufficiency/etiology , Female , Humans , Indoles/administration & dosage , Male , Middle Aged , Quinolones/administration & dosage , Retrospective StudiesABSTRACT
To determine if ivacaftor (Kalydeco) influences non-CF human CFTR function in vivo, we measured CFTR-dependent (C-sweat) and CFTR-independent (M-sweat) rates from multiple identified sweat glands in 8 non-CF adults. The two types of sweating were stimulated sequentially with intradermal injections of appropriate reagents; each gland served as its own control via alternating off-on drug tests on both arms, given at weekly intervals with 3 off and 3 on tests per subject. We compared drug effects on C-sweating stimulated by either high or low concentrations of ß-adrenergic cocktail, and on methacholine-stimulated M-sweating. For each subject we measured ~700 sweat volumes from ~75 glands per arm (maximum 12 readings per gland), and sweat volumes were log-transformed for statistical analysis. T-tests derived from linear mixed models (LMMs) were more conservative than the familiar paired sample t-tests, and show that ivacaftor significantly increased C-sweating stimulated by both levels of agonist, with a larger effect in the low cocktail condition; ivacaftor did not increase M-sweat. Concurrent sweat chloride tests detected no effect of ivacaftor. We conclude that ivacaftor in vivo increases the open channel probability (PO) of WT CFTR, provided it is not already maximally stimulated.
Subject(s)
Aminophenols/administration & dosage , Chloride Channel Agonists/administration & dosage , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Quinolones/administration & dosage , Sweat Glands/drug effects , Sweating/drug effects , Adult , Chlorides/analysis , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Dose-Response Relationship, Drug , Female , Humans , Male , Sweat/chemistry , Sweat Glands/metabolismSubject(s)
Aminophenols/administration & dosage , Benzodioxoles/administration & dosage , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis/drug therapy , Indoles/administration & dosage , Lung/drug effects , Membrane Transport Modulators/administration & dosage , Quinolones/administration & dosage , Administration, Oral , Aminophenols/adverse effects , Aminophenols/pharmacokinetics , Aminopyridines/administration & dosage , Benzodioxoles/adverse effects , Benzodioxoles/pharmacokinetics , Cystic Fibrosis/diagnosis , Cystic Fibrosis/genetics , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Drug Administration Schedule , Drug Combinations , Drug Interactions , Humans , Indoles/adverse effects , Indoles/pharmacokinetics , Lung/metabolism , Membrane Transport Modulators/adverse effects , Membrane Transport Modulators/pharmacokinetics , Mutation , Quinolones/adverse effects , Quinolones/pharmacokinetics , Treatment OutcomeABSTRACT
BACKGROUND: N1303K, one of the common, severe disease-causing mutations in the CFTR gene, causes both defective biogenesis and gating abnormalities of the CFTR protein. The goals of the present study are to quantitatively assess the gating defects associated with the N1303K mutation and its pharmacological response to CFTR modulators including potentiators VX-770 and GLPG1837 and correctors VX-809, and VX-661. METHODS: Gating behavior and pharmacological responses to CFTR potentiators were assessed using patch-clamp technique in the excised, inside-out mode. We also examined the effects of GLPG1837, VX-770, VX-809 and VX-661 on N1303K-CFTR surface expression using Western blot analysis. RESULTS: Like wild-type (WT) CFTR, N1303K-CFTR channels were activated by protein kinase A-dependent phosphorylation, but the open probability (Po) of phosphorylated N1303K-CFTR was extremely low (~0.03 vs ~0.45 in WT channels). N1303K mutants showed abnormal responses to ATP analogs or mutations that disrupt ATP hydrolysis and/or dimerization of CFTR's two nucleotide-binding domains (NBDs). However, the Po of N1303K-CFTR was dramatically increased by GLPG1837 (~17-fold) and VX-770 (~8-fold). VX-809 or VX-661 enhanced N1303K-CFTR maturation by 2-3 fold, and co-treatment with GLPG1837 or VX-770 did not show any negative drug-drug interaction. CONCLUSION: N1303K has a severe gating defect, reduced ATP-dependence and aberrant response to ATP analogs. These results suggest a defective function of the NBDs in N1303K-CFTR. An improvement of channel function by GLPG1837 or VX-770 and an increase of Band C protein by VX-809 or VX-661 support a therapeutic strategy of combining CFTR potentiator and corrector for patients carrying the N1303K mutation.
Subject(s)
Chloride Channel Agonists/pharmacology , Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Mutant Proteins/drug effects , Adenosine Triphosphate/physiology , Aminophenols , Aminopyridines , Animals , Benzodioxoles , Blotting, Western , CHO Cells , Cricetinae , Cricetulus , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Indoles , Ion Channel Gating/drug effects , Mutation , Patch-Clamp Techniques , Phosphorylation , Quinolones , Structure-Activity RelationshipABSTRACT
Cystic fibrosis (CF) is a genetic disorder driven by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. While different mutations lead to varying levels of disease severity, the most common CFTR F508del mutation leads to defects in protein stability, trafficking to the cell membrane and gating of chloride ions. Recently, advances in medicinal chemistry have led to the identification small-molecule drugs that result in significant clinical efficacy in improving lung function in CF patients. Multiple CFTR modulators are required to fix the various defects in the CFTR protein. Small-molecule potentiators increase the open-channel probability and improve the gating of ions through CFTR. Small-molecule correctors stabilize the protein fold of the mutant channel, facilitating protein maturation and translocation to the cellular membrane. Recent data suggest that triple-combination therapy consisting of a potentiator and two correctors that operate through distinct mechanisms will be required to deliver highly significant clinical efficacy for most CF patients. The progress in medicinal chemistry that has led to the identification of novel CFTR potentiators and correctors is presented in this chapter.