Ivacaftor Research Articles

Long-Term Outcomes in Real Life of Lumacaftor-Ivacaftor Treatment in Adolescents With Cystic Fibrosis.

Background: The combination of the CFTR corrector lumacaftor (LUM) and potentiator ivacaftor (IVA) has been labeled in France since 2015 for F508del homozygote cystic fibrosis (CF) patients over 12 years. In this real-life study, we aimed (i) to compare the changes in lung function, clinical (e.g., body mass index and pulmonary exacerbations) and radiological parameters, and in sweat chloride concentration before and after initiation of LUM/IVA treatment; (ii) to identify factors associated with response to treatment; and (iii) to assess the tolerance to treatment.Materials and Methods: In this tri-center, non-interventional, and observational cohort study, children (12–18 years old) were assessed prospectively during the 2 years of therapy, and retrospectively during the 2 years preceding treatment. Data collected and analyzed for the study were exclusively extracted from the medical electronic system records of the patients.Results: Forty adolescents aged 12.0–17.4 years at LUM/IVA initiation were included. The lung function decreased significantly during and prior to treatment and increased after LUM/IVA initiation, becoming significant after 2 years of treatment. LUM/IVA significantly improved the BMI Z-score and sweat chloride concentration. By contrast, there was no significant change in exacerbation rates, antibiotic use, or CT scan scores. Age at LUM/IVA initiation was lower in good responders and associated with greater ppFEV1 change during the 2 years of treatment. LUM/IVA was well-tolerated.Conclusion: In F508del homozygote adolescents, real-life long-term LUM/IVA improved the ppFEV1 trajectory, particularly in the youngest patients, nutritional status, and sweat chloride concentration but not exacerbation rates or radiological scores. LUM/IVA was generally well-tolerated and safe.

Triple Therapy for Cystic Fibrosis Phe508del–Gating and –Residual Function Genotypes

BackgroundElexacaftor–tezacaftor–ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor–ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear.MethodsWe conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del–gating or Phe508del–residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor–ivacaftor, patients were randomly assigned to receive elexacaftor–tezacaftor–ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor–tezacaftor–ivacaftor group.ResultsAfter the run-in period, 132 patients received elexacaftor–tezacaftor–ivacaftor and 126 received active control. Elexacaftor–tezacaftor–ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire–Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor–tezacaftor–ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, −0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor–tezacaftor–ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group.ConclusionsElexacaftor–tezacaftor–ivacaftor was efficacious and safe in patients with Phe508del–gating or Phe508del–residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.)

Response to elexacaftor/tezacaftor/ivacaftor in intestinal organoids derived from people with cystic fibrosis

Superior efficacy of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) over tezacaftor/ivacaftor (TEZ/IVA) in people with cystic fibrosis (CF) and Phe508del/Phe508del genotype was shown in clinical trials. We utilized intestinal organoid approach to compare in vitro responses to these 2 CFTR modulator drug combinations and to check potential inter-individual variability in therapeutic response to the triple combination. Organoids from 17 subjects with Phe508del/Phe508del were screened with forskolin induced swelling assay. Significantly larger swelling, when exposed to ELX/TEZ/IVA as compared to TEZ/IVA, was observed in 16 of them. However, 1 sample showed no additional effect of ELX. The finding of unique CFTR variants in this sample indicates that genetic traits other than CF-causing CFTR mutation are worth exploring as they may have an impact on the definitive modulator drug response.

A Review of Trikafta: Triple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Therapy.

Cystic fibrosis (CF) is a potentially fatal genetic disease that causes serious lung damage. With time, researchers have a more complete understanding of the molecular-biological defects that underlie CF. This knowledge is leading to alternative approaches regarding the treatment of this condition. Trikafta is the third FDA-approved drug that targets the F508del mutation of the CFTR gene. The drug is a combination of three individual drugs which are elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA). This trio increases the activity of the cystic fibrosis transmembrane conductance regulator (CFTR) protein and reduces the mortality and morbidity rates in CF patients. The effectiveness of Trikafta, seen in clinical trials, outperforms currently available therapies in terms of lung function, quality of life, sweat chloride reduction, and pulmonary exacerbation reduction. The safety and efficacy of CFTR modulators in children with CF have also been studied. Continued evaluation of patient data is needed to confirm its long-term safety and efficacy. In this study, we will focus on reviewing data from clinical trials regarding the benefits of CFTR modulator therapy. We address the impact of Trikafta on lung function, pulmonary exacerbations, and quality of life. Adverse events of the different CFTR modulators are discussed.

A rapid RP-HPLC method for the simultaneous estimation of Ivacaftor and Tezacaftor and in silico study of their metabolitic products

BackgroundThis study was designed to develop a reliable method for estimation of Ivacaftor and Tezacaftor in pure and its pharmaceutical dosage form by RP-HPLC in human plasma. Molecular docking studies were carried out and the results were visualized using PyMol and Discovery studio visualizer (Discovery studio visualizer ver. 2.5). The pharmacokinetic properties such as Swiss ADME and pKCSM of the Ivacaftor and its metabolites Ivacaftor M1, M6 and Tezacaftor and metabolites Tezacaftor M1, M2 were predicted. In admetSAR, web-based query tools incorporating a molecular built-in interface enable the database to be queried by SMILES.ResultsA simple, linear, precise, and accurate RP-HPLC method was developed and validated for the determination of Ivacaftor (IVA) and Tezacaftor (TEZ) in human plasma. Chromatographic separation was achieved isocratically on Inspire C18, (4.6 × 250 mm, 5 μm) column at 30 °C. Mobile phase consisting of methanol and 0.05% formic acid in ratio of 95:5 with flow rate of 1 mL/min with injection volume 20 μl detector used is PDA at 235 nm. The developed method was validated according to ICH guidelines and found to be linearity range was found to be for TEZ (10–50 μg/mL) and IVA (15–75 μg/mL). IVA and TEZ drugs and its metabolites were retrieved from the PubChem database and the 2D chemical structures were generated from SMILES notation by using the Chemsketch Software. The structure was viewed using Swiss-PDB Viewer to form a better understanding of the molecule for toxicity and biological activity prediction.ConclusionThe results obtained by the proposed method from validation parameters and from assay confirmed that the determination of Tezacaftor (TEZ) and Ivacaftor (IVA) in their combined dosage form in human plasma was sensitive and selective method. In silico study has revealed that IVA and its metabolites IVA M1, IVA M6 are according to Lipinski rule. The oral bioactivity of IVA was found to be more when compared to its metabolites (Molinspiration) and TEZ and its metabolites TEZ M1, TEZ M2 even though they have the molecular weight > 500, but all other parameters from Molinspiration revealed better oral bioactivity of TEZ M2. Validation of the developed isocratic RP-HPLC procedure revealed that, regardless of how the sample was purified, the method was characterized by good linearity, sensitivity, reproducibility, specificity, and low values of LOD (0.090 μg/mL) and LOQ (0.275 μg/mL). From the in silico docking results, it is quite evident that metabolites of TEZ and IVA have the great potential against cystic fibrosis.

PRS31 Modelling Survival of People with Cystic Fibrosis (PWCF) Aged ≥12 YEARS Homozygous for the F508DEL Mutation Treated with Ivacaftor/Tezacaftor/Elexacaftor and Ivacaftor (IVA/TEZ/ELX)

IVA/TEZ/ELX is a novel cystic fibrosis transmembrane conductance modulator (CFTRm) therapy approved by the European Medicines Agency to treat the underlying cause of disease for pwCF aged ≥12 years homozygous for the F508del mutation (F/F) or heterozygous for F508del and a minimal function mutation. A simulation model was used to estimate survival benefit of IVA/TEZ/ELX in F/F pwCF. A validated, lifetime, patient-level simulation model was used to estimate median survival in a simulated cohort of F/F pwCF aged ≥12 years in the United Kingdom (UK) treated with: IVA/TEZ/ELX+best supportive care (BSC), tezacaftor/ivacaftor (TEZ/IVA)+BSC, and BSC-alone. Age-specific mortality hazards from the 2008 UK CF Registry were combined with a Cox proportional hazards model to predict survival based on several risk factors in pwCF. Clinical efficacy inputs for IVA/TEZ/ELX+BSC and TEZ/IVA+BSC were derived from an indirect treatment comparison conducted using data from the IVA/TEZ/ELX Phase 3b study (NCT04105972) and TEZ/IVA Phase 3 study (NCT02347657). CFTRm impact on long-term lung function decline was based on TEZ/IVA data. Median projected survival in BSC-treated pwCF was 37.8 years; median projected survival increased to 47.9 years in TEZ/IVA-treated pwCF and 59.1 years in IVA/TEZ/ELX+BSC-treated pwCF, leading to an incremental survival increase with IVA/TEZ/ELX+BSC of 11.2 years versus TEZ/IVA+BSC and 21.3 years versus BSC-alone. Patients initiating IVA/TEZ/ELX+BSC treatment at age 12 years were projected to live 15.6 years more than TEZ/IVA+BSC-treated (74.4 vs 58.8 years) and 37.5 years more than BSC-alone–treated (74.4 vs 36.9 years) pwCF. At 10 years, 83% of IVA/TEZ/ELX+BSC-treated pwCF were alive versus 73% and 57% of TEZ/IVA+BSC-treated and BSC-alone–treated pwCF, respectively. Based on these simulations, treatment with IVA/TEZ/ELX+BSC is projected to substantially increase survival for pwCF aged ≥12 years with the F/F genotype in the UK. Treatment initiation at the youngest indicated age is projected to provide even greater survival benefit.

Long-Term Outcomes in Real Life of Lumacaftor-Ivacaftor Treatment in Adolescents with Cystic Fibrosis

Background: The combination of the CFTR corrector Lumacaftor (LUM) and potentiator Ivacaftor (IVA) has been labelled in France since 2015 for F508del homozygote cystic fibrosis (CF) patients over 12 years. Aims: Main: to compare the changes in ppFEV1 2 years before and after initiation of LUM/IVA treatment. Secondary: to assess (i) the evolution of clinical (weight, height, BMI, pulmonary exacerbations, antibiotic use), biological (sweat chloride concentration) and radiological parameters; (ii) to identify parameters associated with response to treatment; (iii) to assess the tolerance to treatment. Methods: In this tri-centre non-interventional observational cohort study, children (12-18 years old) were assessed prospectively during the two years of therapy, and retrospectively during the two years preceding treatment. Data collected and analysed for the study were exclusively extracted from the patients' medical electronic system. Findings: Forty adolescents aged 12.0 to 17.4 years at LUM/IVA initiation were included. Regarding ppFEV1, a decrease was present during the two years prior to treatment, followed by a significant increase after LUM/IVA initiation, becoming significant after 2 years of treatment. LUM/IVA significantly improved the BMI Z-score and sweat chloride concentration. By contrast, there was no significant change in exacerbation rates, antibiotic use or CT-scan scores. Age at LUM/IVA initiation was lower in good responders and was associated with greater ppFEV1 change during the 2 years of treatment. LUM/IVA was well tolerated. Interpretation: In F508del homozygote adolescents, real-life long-term LUM/IVA improves the ppFEV1 trajectory (in particular if introduced early), nutritional status and sweat chloride concentration but not exacerbation rates or radiological scores. LUM/IVA was generally well tolerated and safe. Funding Information: This study did not receive any specific funding. Declaration of Interests: SB, FG, CC, RE, FB, MF conduct clinical trials with Vertex pharmacological agents, on behalf of the European Cystic Fibrosis Society – Clinical Trials Network (ECFS-CTN) and within the scope of ECFS-CTN activities. The other authors have no conflicts of interest to declare. Ethics Approval Statement: The use of the data collected and analysed for the study were exclusively extracted from the patients' medical records (MUCODOMEOS, https://www.vaincrelamuco.org/2019/05/09/mucodomeos-un-logiciel-adapte-aux-besoins-des-crcm-2684) after having obtained their informed consent. In this context and according to the French law in force, the approval of an ethics committee was not required.

Rapid Improvement after Starting Elexacaftor-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease.

Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1) <40 who initiated elexacaftor-tezacaftor-ivacaftor from December 2019 to August 2020 in France was conducted. Clinical characteristics were collected at initiation and at 1 and 3 months. Safety and effectiveness were evaluated by September 2020. National-level transplantation and mortality figures for 2020 were obtained from the French CF and transplant centers and registries. Measurements and Main Results: Elexacaftor-tezacaftor- ivacaftor was initiated in 245 patients with a median (interquartile range) ppFEV1 = 29 (24-34). The mean (95% confidence interval) absolute increase in the ppFEV1 was +15.1 (+13.8 to +16.4; P < 0.0001), and the mean (95% confidence interval) in weight was +4.2 kg (+3.9 to +4.6; P < 0.0001). The number of patients requiring long-term oxygen, noninvasive ventilation, and/or enteral tube feeding decreased by 50%, 30%, and 50%, respectively (P < 0.01). Although 16 patients were on the transplant waiting list and 37 were undergoing transplantation evaluation at treatment initiation, only 2 received a transplant, and 1 died. By September 2020, only five patients were still on the transplantation path. Compared with the previous 2 years, a twofold decrease in the number of lung transplantations in patients with CF was observed in 2020, whereas the number of deaths without transplantation remained stable. Conclusions: In patients with advanced disease, elexacaftor-tezacaftor-ivacaftor is associated with rapid clinical improvement, often leading to the indication for lung transplantation being suspended.

Development of elexacaftor – tezacaftor – ivacaftor: Highly effective CFTR modulation for the majority of people with Cystic Fibrosis

ABSTRACT Introduction: Cystic fibrosis (CF), the most common life-shortening inherited disorder in people of European descent, also occurs in other ethnicities. The identification of the disease, the isolation of the causative gene, termed the cystic fibrosis transmembrane conductance regulator (CFTR) and the improved survival from comprehensive multidisciplinary treatment is one of the success stories of modern medicine. Survival has increased dramatically over the last 50 years, from 10 years in the 1960s to 30 years in the 1990s and approximately 50 years currently. Areas covered: This review will examine the development of highly effective modulators for CF which will revolutionize therapy for more than 90% of the people with CF. This review summarizes the development of triple combination CFTR modulator elexacaftor–tezacaftor–ivacaftor. Expert opinion: The development of this highly effective CFTR modulator for the majority of people with CF will likely change the landscape of CF care. The challenge is to now find highly effective therapy for the remaining 10% of the people with CF who may need other therapeutic agents to correct their primary defect.

Long-term safety and efficacy of tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years or older who are homozygous or heterozygous for Phe508del CFTR (EXTEND): an open-label extension study

Tezacaftor-ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8-24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor-ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor-ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor-ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor-ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914). Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor-ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor-ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor-ivacaftor-treated F/F participants versus untreated matched historical controls. Tezacaftor-ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor-ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor-ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Vertex Pharmaceuticals Incorporated.

How Clinically Efficient Is Lumacaftor/Ivacaftor for Cystic Fibrosis Patients? An Updated Literature Review.

Cystic fibrosis (CF) is an autosomal recessive illness caused by the defective cystic fibrosis transmembrane conductance regulator (CFTR) gene. These patients suffer from repeated chronic sinuses and lung infections, resulting in frequent hospital admissions and antibiotic (Abx) courses. These are the major contributing factors responsible for a low health-related quality of life (HRQoL) and increasing the disease burden. The introduction and approval of CFTR modulators-lumacaftor (LUM) and ivacaftor (IVA) in 2015 by the US Food and Drug Administration (FDA) reduced the mortality and morbidity rates associated with the disease. In 2018, the FDA approved these drugs from age two and five years with two copies of F5806 del. This literature review aims to present the studies centered on the clinical effects of LUM/IVA. We searched for the relevant articles, from 2016 to 2020, in PubMed Central (PMC), Google Scholars, and Journal of Cystic Fibrosis. LUM/IVA has a broader range of effects. They showed marked improvement in the reduction of pulmonary exacerbations (PEx), Hospitalization rates, Abx use, and modification in forced expiratory volume in one second (FEV1) status of pre-existing severe lung disease. Now, there is a need for an initiative to conduct more clinical trials and studies in the future to assess and evaluate the long-term clinical benefits and safety of LUM/IVA therapy in all age groups.

Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies target the underlying cause of cystic fibrosis (CF), and are generally well-tolerated; however, real-world studies indicate the frequency of discontinuation and adverse events (AEs) may be higher than what was observed in clinical trials. The objectives of this systematic review were to summarize real-world AEs reported for market-available CFTR modulators (i.e., ivacaftor (IVA), lumacaftor/ivacaftor (LUM/IVA), tezacaftor/ivacaftor (TEZ/IVA), and elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA)), and to identify ways in which the pharmacist on CF healthcare teams may contribute to mitigating and managing these AEs. The MEDLINE, EMBASE, CINAHL, and Web of Science Core Collection online databases were searched from 2012 to 1 Aug 2020. Full manuscripts or conference abstracts of observational studies, case series, and case reports were eligible for inclusion. The included full manuscripts and conference abstracts comprised of 54 observational studies, 5 case series, and 9 case reports. The types of AEs reported generally aligned with what have been observed in clinical trials. LUM/IVA was associated with a higher frequency of respiratory-related AE and discontinuation in real-world studies. A signal for mental health and neurocognitive AEs was identified with all 4 CFTR modulators. A systematic approach to monitoring for AEs in people with CF on CFTR modulators in the real-world setting is necessary to help better understand potential AEs, as well as patient characteristics that may be associated with higher risk of certain AEs. Pharmacists play a key role in the safe initiation and monitoring of people with CF on CFTR modulator therapies.

A phase 3, randomized, double-blind, parallel-group study to evaluate tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for F508del-CFTR and a gating mutation

BackgroundTezacaftor (TEZ)/ivacaftor (IVA) is an approved CFTR modulator shown to be efficacious and generally safe and well tolerated in people ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous for the F508del-CFTR mutation and a residual function mutation. Although previous studies with IVA alone showed clinical benefits in people with CFTR gating mutations, TEZ/IVA has not yet been evaluated in a Phase 3 study of participants heterozygous for F508del-CFTR and a gating mutation (F/gating genotypes). Here, we present results from a randomized, double-blind, IVA-controlled, parallel-group, Phase 3 study assessing the efficacy, safety, and pharmacokinetics (PK) of TEZ/IVA in participants ≥12 years of age with F/gating genotypes. MethodsEnrolled participants entered a 4-week IVA run-in period to create a stable IVA baseline. Participants were then randomized to receive IVA or TEZ/IVA for 8 weeks in an active comparator treatment period (ACTP). The primary endpoint was absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1). Key secondary endpoints were relative change in ppFEV1 and absolute change in CF Questionnaire–Revised respiratory domain score. Secondary endpoints included absolute change in sweat chloride (SwCl) concentration, PK parameters, and safety. All endpoints except PK parameters and safety were assessed from baseline through Week 8. ResultsSixty-nine participants (92.0%) in the IVA group and 75 participants (98.7%) in the TEZ/IVA group completed treatment. No improvements were seen in efficacy endpoints from baseline at the end of the IVA run-in period through the end of the ACTP in the IVA group. No significant differences in ppFEV1 or any key secondary endpoint were observed between the IVA and TEZ/IVA groups. SwCl concentrations decreased more in the TEZ/IVA versus IVA group during the ACTP. The safety profile and PK parameters of TEZ/IVA were consistent with those of previous studies in participants ≥12 years of age with CF. ConclusionsThis Phase 3 study showed that the dual-combination regimen of TEZ/IVA demonstrated clinical efficacy but did not have significantly greater clinical efficacy than IVA alone in participants ≥12 years of age with F/gating genotypes. However, as reported in other studies, TEZ/IVA was generally safe and well tolerated (NCT02412111).

Cystic fibrosis drug approved for patients aged 6-11years worked well in clinical practice.

Ivacaftor (IVA) and lumacaftor (LUM) modulate the cystic fibrosis (CF) transmembrane conductance regulator protein. IVA targets gating defects and LUM improves the conformational stability of the F508del mutation. This combined drug was approved for homozygous F508del CF patients aged 12 years or more in 2015 and was extended to children aged 6-11 in 2018.

Living and dying with cystic fibrosis

Throughout history, it has been recognised a ‘salty’ child would die in infancy. Over the past 80 years, knowledge about cystic fibrosis (CF), including genetic mutations and healthcare interventions, has...

From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis.

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.

The preclinical discovery and development of the combination of ivacaftor + tezacaftor used to treat cystic fibrosis

ABSTRACT Introduction Cystic Fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. The most common mutation, F508del, induces protein misprocessing and loss of CFTR function. The discovery through in vitro studies of the CFTR correctors (i.e. lumacaftor, tezacaftor) that partially rescue the misprocessing of F508del-CFTR with the potentiator ivacaftor is promising in giving an unprecedented clinical benefit in affected patients. Areas covered Online databases were searched using key phrases for CF and CFTR modulators. Tezacaftor–ivacaftor treatment has proved to be safer than lumacaftor–ivacaftor, although clinical efficacy is similar. Further clinical efficacy has ensued with the introduction of triple therapy, i.e. applying second-generation correctors, such as VX-569 and VX-445 (elexacaftor) to tezacaftor–ivacaftor. The triple combinations will herald the availability of etiologic therapies for patients for whom no CFTR modulators are currently applied (i.e. F508del/minimal function mutations) and enhance CFTR modulator therapy for patients homozygous for F508del. Expert opinion CF patient-derived tissue models are being explored to determine donor-specific response to current approved and future novel CFTR modulators for F508del and other rare mutations. The discovery and validation of biomarkers of CFTR modulation will complement these studies in the long term and in real-life world.

The Extrapulmonary Effects of Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Cystic Fibrosis.

The effects of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators on lung function, pulmonary exacerbations, and quality of life have been well documented. However, CF is a multiorgan disease, and therefore an evidence base is emerging on the systemic effects of CFTR modulators beyond the pulmonary system. This is of great clinical importance, as many of these studies provide proof of concept that CFTR modulators might be used one day to prevent or treat extrapulmonary manifestations stemming from CFTR dysfunction. In this concise review of the literature, we summarize the results of key publications that have evaluated the effects of CFTR modulators on weight and growth, pancreatic function, the gastrointestinal and hepatobiliary systems, sinus disease, bone disease, exercise tolerance, fertility, mental health, and immunity. Although many of these studies have reported beneficial extrapulmonary effects related to the use of ivacaftor (IVA) in patients with CF with at least one gating mutation, most of the evidence is low or very low quality, given the limited number of patients evaluated and the lack of control groups. Based on an even smaller number of studies evaluating the extrapulmonary effects of lumacaftor-IVA, the benefits are less clear. Although limited, these studies may provide the basis for future clinical trials to evaluate CFTR modulators on the extrapulmonary manifestations of CF.

Stability Indicating RP-HPLC Method Development and Validation for the Simultaneous Estimation of Tezacaftor and Ivacaftor in Bulk and Pharmaceutical Dosage Form

Stability Indicating RP-HPLC Method Development and Validation for the Simultaneous Estimation of Tezacaftor and Ivacaftor in Bulk and Pharmaceutical Dosage Form

Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

BackgroundCystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del–minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.MethodsWe conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor–tezacaftor–ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del–minimal function genotypes. Patients were randomly assigned to receive elexacaftor–tezacaftor–ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.ResultsA total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor–tezacaftor–ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire–Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor–tezacaftor–ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor–tezacaftor–ivacaftor group.ConclusionsElexacaftor–tezacaftor–ivacaftor was efficacious in patients with cystic fibrosis with Phe508del–minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.)