Use of elexacaftor/tezacaftor/ivacaftor combination in pregnancy.

INTRODUCTION: Management of cystic fibrosis has recently stepped forward with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, although data on potential adverse effects are lacking for many categories of patients, such as pregnant women. METHODS: We report one of the first reports on the outcome of pregnancy in a woman treated with Elexacaftor/Tezacaftor/Ivacaftor during the second and third trimester of pregnancy, showing a significant improvement of respiratory status, compared with the first trimester when the medication was discontinued due to unknown and, therefore, potential teratogenic effects. Also, we performed the review of the existing literature on the topic. RESULTS: The course of pregnancy was uneventful, with reference to major obstetric complications, and the patient delivered a healthy neonate. These results were similar to those coming from other short series of pregnant women affected by cystic fibrosis and treated with CFTR modulators during pregnancy. CONCLUSIONS: Thus, despite the lack of evidence on the topic, the use of Elexacaftor/Tezacaftor/Ivacaftor in pregnancy seems to be apparently not associated with major adverse events, thus opening optimistic scenarios in terms of management of these patients.

A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators.

WHAT IS KNOWN AND OBJECTIVE: Treatment with cystic fibrosis transmembrane conductance regulator (CFTR) modulators has led to improved clinical outcomes and an increase in lifespans of cystic fibrosis (CF) patients. As CF patients continue to live longer, they are at risk for developing adverse drug reactions associated with polypharmacy and CFTR modulators. COMMENT: The authors aim to describe safety concerns of the current combination CFTR modulators, based upon a literature review, including notable safety concerns and recommendations for drug-drug interactions. WHAT IS NEW AND CONCLUSION: Cystic fibrosis transmembrane conductance regulator agents are generally well tolerated with low discontinuation rates when compared to placebo. Elevations in liver enzymes and drug-drug interactions are the most notable safety concerns. Additionally, lumacaftor/ivacaftor has shown more respiratory-related adverse events and drug-drug interactions compared to elexacaftor/tezacaftor/ivacaftor and tezacaftor/ivacaftor. Postmarketing studies are needed to determine long-term safety concerns.

Tezacaftor-Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis.

BACKGROUND: Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene that lead to progressive respiratory decline. Some mutant CFTR proteins show residual function and respond to the CFTR potentiator ivacaftor in vitro, whereas ivacaftor alone does not restore activity to Phe508del mutant CFTR. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3, crossover trial to evaluate the efficacy and safety of ivacaftor alone or in combination with tezacaftor, a CFTR corrector, in 248 patients 12 years of age or older who had cystic fibrosis and were heterozygous for the Phe508del mutation and a CFTR mutation associated with residual CFTR function. Patients were randomly assigned to one of six sequences, each involving two 8-week intervention periods separated by an 8-week washout period. They received tezacaftor-ivacaftor, ivacaftor monotherapy, or placebo. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from the baseline value to the average of the week 4 and week 8 measurements in each intervention period. RESULTS: The number of analyzed intervention periods was 162 for tezacaftor-ivacaftor, 157 for ivacaftor alone, and 162 for placebo. The least-squares mean difference versus placebo with respect to the absolute change in the percentage of predicted FEV1 was 6.8 percentage points for tezacaftor-ivacaftor and 4.7 percentage points for ivacaftor alone (P<0.001 for both comparisons). Scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised, a quality-of-life measure, also significantly favored the active-treatment groups. The incidence of adverse events was similar across intervention groups; most events were mild or moderate in severity, with no discontinuations of the trial regimen due to adverse events for tezacaftor-ivacaftor and few for ivacaftor alone (1% of patients) and placebo (<1%). CONCLUSIONS: CFTR modulator therapy with tezacaftor-ivacaftor or ivacaftor alone was efficacious in patients with cystic fibrosis who were heterozygous for the Phe508del deletion and a CFTR residual-function mutation. (Funded by Vertex Pharmaceuticals and others; EXPAND ClinicalTrials.gov number, NCT02392234 .).

Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del.

BACKGROUND: Combination treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators tezacaftor (VX-661) and ivacaftor (VX-770) was designed to target the underlying cause of disease in patients with cystic fibrosis. METHODS: In this phase 3, randomized, double-blind, multicenter, placebo-controlled, parallel-group trial, we evaluated combination therapy with tezacaftor and ivacaftor in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation. Patients were randomly assigned in a 1:1 ratio to receive either 100 mg of tezacaftor once daily and 150 mg of ivacaftor twice daily or matched placebo for 24 weeks. The primary end point was the absolute change in the percentage of the predicted forced expiratory volume in 1 second (FEV1) through week 24 (calculated in percentage points); relative change in the percentage of the predicted FEV1 through week 24 (calculated as a percentage) was a key secondary end point. RESULTS: Of the 510 patients who underwent randomization, 509 received tezacaftor-ivacaftor or placebo, and 475 completed 24 weeks of the trial regimen. The mean FEV1 at baseline was 60.0% of the predicted value. The effects on the absolute and relative changes in the percentage of the predicted FEV1 in favor of tezacaftor-ivacaftor over placebo were 4.0 percentage points and 6.8%, respectively (P<0.001 for both comparisons). The rate of pulmonary exacerbation was 35% lower in the tezacaftor-ivacaftor group than in the placebo group (P=0.005). The incidence of adverse events was similar in the two groups. Most adverse events were of mild severity (in 41.8% of patients overall) or moderate severity (in 40.9% overall), and serious adverse events were less frequent with tezacaftor-ivacaftor (12.4%) than with placebo (18.2%). A total of 2.9% of patients discontinued the assigned regimen owing to adverse events. Fewer patients in the tezacaftor-ivacaftor group than in the placebo group had respiratory adverse events, none of which led to discontinuation. CONCLUSIONS: The combination of tezacaftor and ivacaftor was efficacious and safe in patients 12 years of age or older who had cystic fibrosis and were homozygous for the CFTR Phe508del mutation. (Funded by Vertex Pharmaceuticals; EVOLVE ClinicalTrials.gov number, NCT02347657 .).

Experience With Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Disease.

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) was used through the early access programme in Spain from December 2019 in cystic fibrosis (CF) patients with homozygous or heterozygous F508del mutation with advanced lung disease. METHODOLOGY: Multicentre, ambispective, observational, study in which 114 patients in follow-up in 16 national CF units were recruited. Clinical data, functional tests, nutritional parameters, quality of life questionnaires, microbiological isolates, number of exacerbations, antibiotic treatments and side effects were collected. The study also compared patients with homozygous and heterozygous F508del mutations. RESULTS: Of the 114 patients, 85 (74.6%) were heterozygous for F508del mutation, and the mean age was 32.2±9.96 years. After 30 months of treatment, lung function measured by FEV1% showed improvement from 37.5 to 48.6 (p<0.001), BMI increased from 20.5 to 22.3 (p<0.001), and all isolated microorganisms decreased significantly. The total number of exacerbations was also significantly reduced from 3.9 (±2.9) to 0.9 (±1.1) (p<0.001). All items in the CFQ-R questionnaire showed improvement, except for the digestive domain. Oxygen therapy use decreased by 40%, and only 20% of patients referred for lung transplantation remained on the active transplant list. ETI was well-tolerated, with only 4 patients discontinuing treatment due to hypertransaminemia. CONCLUSIONS: ETI decreases the number of exacerbations, increases lung function and nutritional parameters, decrease in all isolated microorganisms, for 30 months of treatment. There is an improvement in the CFQ-R questionnaire score except for the digestive item. It is a safe and well-tolerated drug.

Acneiform Eruption Following Elexacaftor-Tezacaftor-Ivacaftor Treatment in Patients With Cystic Fibrosis.

Importance: A new treatment for cystic fibrosis combining 3 CFTR modulators-elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA)-has recently been approved for cystic fibrosis treatment. The cutaneous adverse effects following treatment with this combination are poorly described in the literature. Objective: To describe the clinicopathological features and treatment response of ELX-TEZ-IVA-associated acneiform eruptions in patients with cystic fibrosis. Design, Setting, and Participants: This case series study was conducted in the Dermatology Department of Cochin Hospital, Paris, France, from July 2021 to June 2022 in collaboration with the Cochin Reference Center for Cystic Fibrosis. Referred patients were examined by senior dermatologists. All patients with cystic fibrosis treated with ELX-TEZ-IVA and referred for an acneiform rash were included. Exposures: Treatment with ELX-TEZ-IVA. Main Outcomes and Measures: Onset of acneiform rash, type of lesions, and degree of severity, as well as treatments initiated and response, were evaluated. When performed, skin biopsies were reviewed. Results: This study included 16 patients (11 women [68.7%]) with a median (range) age of 27 (22-38) years. Six patients (37.5%) developed new-onset acneiform rashes, whereas 10 patients (62.5%) had a relapse (5 patients) or worsening (5 patients) of previous acne. The median (range) onset of acneiform rash was 45 (15-150) days. At inclusion, 11 patients (68.7%) had facial hyperseborrhea, 15 patients (93.7%) had noninflammatory lesions, and 14 (87.5%) had inflammatory lesions of seborrheic regions. Four patients (25.0%) had severe acne with deep inflammatory lesions and pitted scars. A specific pathological pattern of necrotizing infundibular crystalline folliculitis was observed in 4 patients. Topical acne treatments, antibiotics, and isotretinoin were used successfully in these patients, resulting in partial or complete remission in 12 patients (85.7% of patients reevaluated). Conclusions and Relevance: This case series study found that acneiform eruption is an adverse event associated with ELX-TEZ-IVA treatment in patients with cystic fibrosis. Most patients developed mild lesions. However, isotretinoin treatment may be necessary in some patients. The mechanism of ELX-TEZ-IVA-associated acneiform eruption is currently unknown, but the observation of necrotizing infundibular crystalline folliculitis in biopsied patients may guide further exploration.

[Alveolar macrophages in rats with chronic obstructive pulmonary disease (COPD) promotes proliferation, mucin and inflammatory factors secretion of airway epithelial cells and its mechanism].

Objective To explore how alveolar macrophages from chronic obstructive pulmonary disease (COPD)-model rats affect proliferation and secretion of 16HBE human bronchial epithelial cells and investigate the associated mechanism. Methods Alveolar macrophages were extracted from COPD rats induced by cigarette smoke exposure and LPS instillation through bronchoalveolar lavage, then co-cultured with 16HBE cells in vitro. Exosomes were extracted from alveolar macrophages of rats with exosome isolation kit. The differentially expressed miRNA in exosomes derived from macrophages of rats in COPD group and control group was detected by PCR. miR-380 was overexpressed with miR-380 mimic while the expression of cystic fibrosis transmembrane transduction regulator (CFTR) was knocked down with siRNA in 16HBE cells. The proliferation of 16HBE cells was detected with CCK-8 assay. The migration ability of 16HBE cells was evaluated with TranswellTM migration assay. The levels of mucins (MUC5AC, MUC5B, MUC2) and CFTR expressed by 16HBE cells were detected with Western blot analysis. The expression of TNF-α and IL-6 in the supernatant of 16HBE cells was detected with ELISA. Results The alveolar macrophages from COPD rats enhanced the proliferation and migration of 16HBE cells. The production of mucins and TNF-α as well as IL-6 in 16HBE cells were increased by COPD macrophages. The expression of miR-380 was significantly elevated in exosomes derived from COPD alveolar macrophages. Both overexpression of miR-380 and inhibition of CFTR decreased the expression of CFTR, resulting in the significantly enhanced proliferation and migration of 16HBE cells as well as increased expression of MUC5AC, MUC5B, MUC2 and TNF-α, IL-6. Conclusion The alveolar macrophages from COPD rats can enhance the proliferation and mucin expression as well as inflammatory cytokine secretion of 16HBE cells. This process may be involved with abnormal expression of miR-380 in exosomes of COPD alveolar macrophages and down-regulation of CFTR in bronchial epithelial cells.

Repurposing calcium-sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas.

Diarrhea is a major cause of global mortality, and outbreaks of secretory diarrhea such as cholera remain an important problem in the developing world. Current treatment of secretory diarrhea primarily involves supportive measures, such as fluid replacement. The calcium-sensing receptor (CaSR) regulates multiple biological activities in response to changes in extracellular Ca2+. The FDA-approved drug cinacalcet is an allosteric activator of CaSR used for treatment of hyperparathyroidism. Here, we found by short-circuit current measurements in human colonic T84 cells that CaSR activation by cinacalcet reduced forskolin-induced Cl- secretion by greater than 80%. Cinacalcet also reduced Cl- secretion induced by cholera toxin, heat-stable E. coli enterotoxin, and vasoactive intestinal peptide (VIP). The cinacalcet effect primarily involved indirect inhibition of cystic fibrosis transmembrane conductance regulator-mediated (CFTR-mediated) Cl- secretion following activation of CaSR and downstream phospholipase C and phosphodiesterases. In mice, cinacalcet reduced fluid accumulation by more than 60% in intestinal closed loop models of cholera and traveler's diarrhea. The cinacalcet effect involved both inhibition of CFTR-mediated secretion and stimulation of sodium-hydrogen exchanger 3-mediated absorption. These findings support the therapeutic utility of the safe and commonly used drug cinacalcet in CFTR-dependent secretory diarrheas, including cholera, traveler's diarrhea, and VIPoma.

Manifestaciones hepáticas en niños con fibrosis quística y uso de moduladores CFTR. ¿Qué debemos monitorizar? / Hepatic manifestations in children with cystic fibrosis and use of CFTR modulators. What should we monitor?

La enfermedad hepática relacionada con fibrosis quística se observa en el 10% de las personas portadoras de la enfermedad. La terapia con moduladores ha mejorado la morbimortalidad, pero teniendo en cuenta que presentan efectos secundarios infrecuentes es necesario monitorizar. Se analiza el algoritmo propuesto por Eldredge et al, que sugiere las decisiones a tomar basado en el resultado de perfil hepático y su aplicación en la práctica clínica.

Cystic fibrosis-related liver disease is seen in 10% of people with the disease. Therapy with modulators has improved morbidity and mortality, but taking into account that they present infrequent side effects, monitoring is necessary. The algorithm proposed by Eldredge et al is analyzed, which suggests the decisions to be made based on the liver profile result and its application in clinical practice.

Experience With Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Disease

Introduction: Elexacaftor/tezacaftor/ivacaftor (ETI) was used through the early access programme in Spain from December 2019 in cystic fibrosis (CF) patients with homozygous or heterozygous F508del mutation with advanced lung disease. Methodology: Multicentre, ambispective, observational, study in which 114 patients in follow-up in 16 national CF units were recruited. Clinical data, functional tests, nutritional parameters, quality of life questionnaires, microbiological isolates, number of exacerbations, antibiotic treatments and side effects were collected. The study also compared patients with homozygous and heterozygous F508del mutations. Results: Of the 114 patients, 85 (74.6%) were heterozygous for F508del mutation, and the mean age was 32.2±9.96 years. After 30 months of treatment, lung function measured by FEV1% showed improvement from 37.5 to 48.6 (p<0.001), BMI increased from 20.5 to 22.3 (p<0.001), and all isolated microorganisms decreased significantly. The total number of exacerbations was also significantly reduced from 3.9 (±2.9) to 0.9 (±1.1) (p<0.001). All items in the CFQ-R questionnaire showed improvement, except for the digestive domain. Oxygen therapy use decreased by 40%, and only 20% of patients referred for lung transplantation remained on the active transplant list. ETI was well-tolerated, with only 4 patients discontinuing treatment due to hypertransaminemia. Conclusions: ETI decreases the number of exacerbations, increases lung function and nutritional parameters, decrease in all isolated microorganisms, for 30 months of treatment. There is an improvement in the CFQ-R questionnaire score except for the digestive item. It is a safe and well-tolerated drug. (AU)

A double-blind, placebo controlled, dose ranging study to evaluate the safety and biological efficacy of the lipid-DNA complex GR213487B in the nasal epithelium of adult patients with cystic fibrosis.

UNLABELLED: GTAB1001: A Double-Blind, Placebo Controlled, Dose Ranging Study to Evaluate the Safety and Biological Efficacy of the Lipid-DNA Complex GR213487B in the Nasal Epithelium of Adult Patients with Cystic Fibrosis. OBJECTIVES: To evaluate the effectiveness of various dosages of the lipid-DNA complex GR213487B (0.4375mg and either 4.0mg or 0.0625mg) for producing CFTR gene transfer and correcting the chloride ion transport defect in the nasal epithelium of patients with cystic fibrosis. To assess the safety and tolerability of the lipid-DNA complex GR213487B when applied to the nasal epithelium of patients with cystic fibrosis. DESIGN: Single-center, double-blind, placebo controlled, dose ranging study. DURATION: Pre-treatment evaluations will be performed during two outpatient study visits (ie. between Day -7 to -3 and at Day -2). Patients will be admitted to the Clinical Research Unit (CRU) at the University of North Carolina at Chapel Hill on Day -1 for additional pre-treatment evaluations performed the day prior to administration of double-blind treatment (ie. gene transfer) on Treatment Day 0. Patients will remain in the CRU for 7 days (Day -1 to Day 6) and will be discharged on Day 6. Patients will subsequently be followed on an outpatient basis but will return for another assessment between Days 9-11, and may also return to the CRU for two optional study visits on Days 14 and 21. All patients will return to the CRU on an out-patient basis for follow-up evaluations on Day 28 +/- 3. SETTING: Patients will receive in-patient treatment in the CRU at the University of North Carolina at Chapel Hill and will remain in the CRU for 7 days. PATIENTS: A target enrollment of 12 evaluable patients is planned. STUDY TREATMENTS: Patients who meet all entry criteria will complete pre-treatment assessments, which will take place between Day -7 to Day -1, and will serve as a baseline for specific evaluations and to ensure clinical stability. Patients will return on Day -1 for admission to the CRU the day prior to gene transfer. Each nostril of the patients will be randomly assigned in a double blind manner to receive either GR213487B liquid nasal spray or the lipid alone (ie. control administered as liposome), by topical application directed at the inferior turbinate. The first four patients will receive an initial dosage of GR213487B containing 0.4375 mg of DNA. The decision to proceed to administer a higher dose (ie. 4.0mg DNA) or a lower dose (ie. 0.0625mg DNA) in the subsequent eight patients will be determined by the Principal Investigator in association with an FDA officer serving as an independent Clinical Ombudsman, according to the study plan (see Section 5.5 and Appendix 3-Dosing Flow Chart). MEASUREMENTS: Efficacy Evaluations The primary variables to determine the efficacy of transgene expression will be: * Evidence of vector derived CFTR (cystic fibrosis transmembrane conductance regulator) mRNA, as measured by reverse transcriptase polymerase chain reaction (RT-PCR) in nasal epithelial cells obtained from nasal scrapes on Day 3 and, nasal biopsies on Day 5, if sufficient tissue is available. * Correction of chloride ion transport across the nasal epithelium as measured by the transepithelial electrical potential difference (TEPD). The baseline TEPD will initially be measured, and again subsequently following perfusion of: --zero chloride perfusion containing amiloride (to induce chloride secretion) --zero chloride perfusion containing amiloride and isoproterenol (to increase cAMP-mediated chloride secretion) Secondary measures to determine the efficacy of gene transfer will be: * Evidence of delivery of plasmid DNA in the nasal lavage (Day 1-5, Day 9-11 and Day 28) * Evidence of vector derived CFTR mRNA from nasal scrapes performed after the nasal biopsy (ie. Day 9-11 and/or Day 28) * Percentage of cells from nasal biopsies expressing vector derived CFTR mRNA as measured by in situ hybridization * Evidence of vector derived CFTR

Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution.

A double-blind, dose escalation gene transfer trial was conducted in subjects with cystic fibrosis (CF), among whom placebo (saline) or compacted DNA was superfused onto the inferior turbinate of the right or left nostril. The vector consisted of single molecules of plasmid DNA carrying the cystic fibrosis transmembrane regulator- encoding gene compacted into DNA nanoparticles, using polyethylene glycol-substituted 30-mer lysine peptides. Entry criteria included age greater than 18 years, FEV1 exceeding 50% predicted, and basal nasal potential difference (NPD) isoproterenol responses (> or = -5 mV) that are typical for subjects with classic CF. Twelve subjects were enrolled: 2 in dose level I (DLI) (0.8 mg DNA), 4 in DLII (2.67 mg), and 6 in DLIII (8.0 mg). The primary trial end points were safety and tolerability, and secondary gene transfer end points were assessed. In addition to routine clinical assessments and laboratory tests, subjects were serially evaluated for serum IL-6, complement, and C-reactive protein; nasal washings were taken for cell counts, protein, IL-6, and IL-8; and pulmonary function and hearing tests were performed. No serious adverse events occurred, and no events were attributed to compacted DNA. There was no association of serum or nasal washing inflammatory mediators with administration of compacted DNA. Day 14 vector polymerase chain reaction analysis showed a mean value in DLIII nasal scraping samples of 0.58 copy per cell. Partial to complete NPD isoproterenol responses were observed in eight subjects: one of two in DLI, three of four in DLII, and four of six in DLIII. Corrections persisted for as long as 6 days (1 subject to day 28) after gene transfer. In conclusion, compacted DNA nanoparticles can be safely administered to the nares of CF subjects, with evidence of vector gene transfer and partial NPD correction.

Is gene therapy in cystic fibrosis a realistic expectation?

To date there are 11 human protocols either ongoing or approved for gene therapy for cystic fibrosis (CF) in the United States. There are also two protocols in the United Kingdom and one in France. Of these, results have been published in four. The protocols vary in the cells targeted, the vectors used, and the frequency of administration, but despite these differences all have contributed toward answering the key questions that will determine the future of gene therapy for CF: the questions of efficacy and safety. These studies have demonstrated that it is feasible to transfer the normal human CF transmembrane conductance regulator complementary DNA to the respiratory epithelium and that this will lead to production of normal CF transmembrane conductance regulator protein and in some cases to a physiologic response. The most frequently used vector is the adenovirus. Obstacles to be overcome with this system include the need for improved and prolonged expression, efficacy on repeat administration, and decreased inflammation. Recent work on the immune response to adenoviral vectors may help achieve these goals. The cationic lipid method of gene delivery is less likely than adenovirus to cause inflammation, at least in the nose, but improved efficacy of gene transfer is necessary as well as improved complex stability. Furthermore, this system has yet to be tested in the lungs of individuals with CF. Finally, the adeno-associated virus, the other vector approved for human gene therapy studies in CF, has shown some promise in preclinical studies but remains to be tested in humans. The results of these studies give some cause for guarded optimism, but point out a number of problems that must be overcome before gene therapy for CF delivers on the promise of a safe effective treatment for this condition.