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Steven M. Rowe - One of the best experts on this subject based on the ideXlab platform.
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Ataluren/Ivacaftor combination therapy: Two N-of-1 trials in cystic fibrosis patients with nonsense mutations.
Pediatric Pulmonology, 2020Co-Authors: Jacelyn E. Peabody Lever, Venkateshwar Mutyam, Heather Hathorne, Ning Peng, Jyoti Sharma, Lloyd J. Edwards, Steven M. RoweAbstract:: Premature termination codons (PTCs) in cystic fibrosis transmembrane conductance regulator (CFTR) produce nonfunctional protein. No approved therapies exist for PTC mutations, including W1282X. We hypothesized that Ivacaftor, combined with readthrough therapy, may benefit W1282X patients. Two N-of-1 clinical trials were conducted with ataluren and Ivacaftor in various combinations. No meaningful clinical benefit was observed in either patient with Ivacaftor alone or ataluren/Ivacaftor combination. However, isolated improvements of uncertain significance were noted by a nasal potential difference (NPD) and FEV1 % with Ivacaftor in Patient-1 and with ataluren/Ivacaftor combination by NPD and body mass index in Patient-2. Drug regimen composed of readthrough agents and potentiators warrant further development for W1282X and other CFTR nonsense mutations.
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variable cellular Ivacaftor concentrations in people with cystic fibrosis on modulator therapy
Journal of Cystic Fibrosis, 2020Co-Authors: Jennifer S. Guimbellot, Steven M. Rowe, Kevin J Ryan, Justin D Anderson, Latona Kersh, Charles R Esther, Edward P. AcostaAbstract:Abstract The development of CFTR modulators has transformed the care of patients with cystic fibrosis (CF). Although the clinical efficacy of modulators depends on their concentrations in target tissues, the pharmacokinetic properties of these drugs in epithelia are not utilized to guide patient care. We developed assays to quantitate Ivacaftor in cells and plasma from patients on modulator therapy, and our analyses revealed that cellular Ivacaftor concentrations differ from plasma concentrations measured concurrently, with evidence of in vivo accumulation of Ivacaftor in the cells of patients. While the nature of this study is exploratory and limited by a small number of patients, these findings suggest that techniques to measure modulator concentrations in vivo will be essential to interpreting their clinical impact, particularly given the evidence that Ivacaftor concentrations influence the activity and stability of restored CFTR protein.
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efficacy and safety of the elexacaftor plus tezacaftor plus Ivacaftor combination regimen in people with cystic fibrosis homozygous for the f508del mutation a double blind randomised phase 3 trial
The Lancet, 2019Co-Authors: H.g.m. Heijerman, Steven M. Rowe, Edward F. Mckone, Marcus A. Mall, Bonnie W. Ramsey, Elizabeth Tullis, D G Downey, Eva Van Braeckel, John J Welter, Charlotte M MckeeAbstract:BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus Ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus Ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus Ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus Ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus Ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus Ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. FINDINGS: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus Ivacaftor group and 52 in the tezacaftor plus Ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus Ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus Ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus Ivacaftor and in one (2%) receiving tezacaftor plus Ivacaftor. INTERPRETATION: Elexacaftor plus tezacaftor plus Ivacaftor provided clinically robust benefit compared with tezacaftor plus Ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. FUNDING: Vertex Pharmaceuticals.
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The effect of CFTR modulators on a cystic fibrosis patient presenting with recurrent pancreatitis in the absence of respiratory symptoms: a case report
BMC Gastroenterology, 2019Co-Authors: J. Dixon Johns, Steven M. RoweAbstract:Background Cystic fibrosis (CF) is a genetic disorder of the epithelial CFTR apical chloride channel resulting in multi-organ manifestations, including pancreatic exocrine secretion. In the pancreas, CFTR abnormality results in abnormally viscous secretions that obstruct proximal ducts leading to fibrotic injury and ultimately pancreatic insufficiency in 85% of the CF population. CFTR modulators, including the potentiator Ivacaftor, augment channel gating to restore 30–50% of CFTR-mediated anion transport. While CFTR modulation has been shown to alkalinize the pH of the alimentary tract and potentially augment pancreatic enzyme activity, the effect of Ivacaftor on recurrent pancreatitis is emerging. Here we describe a case of a patient with CF ( R117H/7 T/F508del ) who presented with recurrent pancreatitis who was effectively treated with Ivacaftor in the absence of respiratory symptoms. Case presentation A 24-year-old white male with past medical history of recurrent acute pancreatitis presented for evaluation following a referral from an outside hospital. The patient reported a lifetime of gastrointestinal symptoms requiring over 20 hospitalizations for pancreatitis in the last 10 years. Prior U/S and CT imaging for pancreatitis ruled out gallstones or anatomical etiologies. Family history included a brother with CF carrier status who suffered from recurrent acute pancreatitis. Sweat chloride testing was suggestive of CFTR dysfunction (57 mmol/L). Genetic testing demonstrated disease causing CFTR mutations: R1117H/7 T/F508del . Patient was prescribed pancrelipase, however, he reported worsened gas and diarrhea symptoms. Pancrelipase was discontinued and the patient was prescribed Ivacaftor 150 mg BID. After 6 weeks of Ivacaftor treatment, patient reported improved gastrointestinal symptoms. For an additional 19 months, patient reported no episodes of pancreatitis until he discontinued Ivacaftor. Over the next 3 weeks, patient experienced progressive nausea and sharp epigastric pain and laboratory studies confirmed pancreatitis. Patient was subsequently lost to follow up. Conclusions These findings support a possible relationship between the use of CFTR modulators, such as Ivacaftor, in the management of recurrent pancreatitis in the setting of patients with cystic fibrosis and a CFTR mutation with residual CFTR activity or otherwise known to be responsive in vitro. Ivacaftor may be useful for recurrent pancreatitis, even in the absence of respiratory morbidity.
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effectiveness of Ivacaftor in cystic fibrosis patients with non g551d gating mutations
Journal of Cystic Fibrosis, 2019Co-Authors: Jennifer S. Guimbellot, Sonya L Heltshe, Arthur Baines, George M Solomon, Scott D Sagel, Jill Vandalfsen, Elizabeth Joseloff, Steven M. RoweAbstract:Abstract Background The cystic fibrosis transmembrane conductance regulator (CFTR) potentiator Ivacaftor is approved for patients with CF with gating and residual function CFTR mutations. We report the results of an observational study investigating its effects in CF patients with non- G551D gating mutations. Methods Patients with non- G551D gating mutations were recruited to an open-label study evaluating Ivacaftor. Primary outcomes included: lung function, sweat chloride, weight gain, and quality of life scores. Results Twenty-one subjects were enrolled and completed 6 months follow-up on Ivacaftor; mean age was 25.6 years with 52% 1 was 68% and mean sweat chloride 89.6 mEq/L. Participants experienced significant improvements in ppFEV 1 (mean absolute increase of 10.9% 95% CI = [2.6,19.3], p = 0.0134), sweat chloride (−48.6 95% CI = [−67.4,-29.9], p Conclusions Patients with non- G551D gating mutations experienced improved lung function, nutritional status, and quality of life. This study supports ongoing use of Ivacaftor for patients with these mutations.
Bonnie W. Ramsey - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of the elexacaftor plus tezacaftor plus Ivacaftor combination regimen in people with cystic fibrosis homozygous for the f508del mutation a double blind randomised phase 3 trial
The Lancet, 2019Co-Authors: H.g.m. Heijerman, Steven M. Rowe, Edward F. Mckone, Marcus A. Mall, Bonnie W. Ramsey, Elizabeth Tullis, D G Downey, Eva Van Braeckel, John J Welter, Charlotte M MckeeAbstract:BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus Ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus Ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus Ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus Ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus Ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus Ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. FINDINGS: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus Ivacaftor group and 52 in the tezacaftor plus Ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus Ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus Ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus Ivacaftor and in one (2%) receiving tezacaftor plus Ivacaftor. INTERPRETATION: Elexacaftor plus tezacaftor plus Ivacaftor provided clinically robust benefit compared with tezacaftor plus Ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. FUNDING: Vertex Pharmaceuticals.
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elexacaftor tezacaftor Ivacaftor for cystic fibrosis with a single phe508del allele
The New England Journal of Medicine, 2019Co-Authors: Peter G Middleton, Edward F. Mckone, Marcus A. Mall, Bonnie W. Ramsey, Elizabeth Tullis, Jennifer L Taylorcousar, Pavel Dřevinek, Larry C Lands, Deepika Polineni, F VermeulenAbstract:BACKGROUND: Cystic 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. METHODS: We 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. RESULTS: A 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. CONCLUSIONS: Elexacaftor-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.).
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VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.
The New England Journal of Medicine, 2018Co-Authors: Dominic Keating, Steven M. Rowe, Edward F. Mckone, Gautham Marigowda, Lucy D. Burr, Cori L. Daines, Marcus A. Mall, Bonnie W. Ramsey, Laura A. Sass, Elizabeth TullisAbstract:BACKGROUND: VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and Ivacaftor (VX-445-tezacaftor-Ivacaftor). METHODS: We evaluated the effects of VX-445-tezacaftor-Ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-Ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-Ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline. RESULTS: In vitro, VX-445-tezacaftor-Ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-Ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del-MF group (P
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vx 445 tezacaftor Ivacaftor in patients with cystic fibrosis and one or two phe508del alleles
The New England Journal of Medicine, 2018Co-Authors: D Keating, Steven M. Rowe, Edward F. Mckone, Gautham Marigowda, Lucy D. Burr, Cori L. Daines, Marcus A. Mall, Bonnie W. Ramsey, Laura A. Sass, Elizabeth TullisAbstract:BACKGROUND: VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and Ivacaftor (VX-445-tezacaftor-Ivacaftor). METHODS: We evaluated the effects of VX-445-tezacaftor-Ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-Ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-Ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline. RESULTS: In vitro, VX-445-tezacaftor-Ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-Ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del-MF group (P<0.001). In patients in the Phe508del-Phe508del group, who were already receiving tezacaftor-Ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV1 (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire-Revised. CONCLUSIONS: The use of VX-445-tezacaftor-Ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Funded by Vertex Pharmaceuticals; VX16-445-001 ClinicalTrials.gov number, NCT03227471 ; and EudraCT number, 2017-000797-11 .).
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vx 659 tezacaftor Ivacaftor in patients with cystic fibrosis and one or two phe508del alleles
The New England Journal of Medicine, 2018Co-Authors: Jane C Davies, Edward F. Mckone, Marcus A. Mall, Bonnie W. Ramsey, B J Plant, Samuel M Moskowitz, Cynthia Brown, A Horsley, Dario Prais, Jennifer L TaylorcousarAbstract:Abstract Background The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and Ivacaftor (VX-659–tezacaftor–Ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis. Methods We evaluated the effects of VX-659–tezacaftor–Ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659–tezacaftor–Ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del–MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1). Results VX-6...
Edward F. Mckone - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of the elexacaftor plus tezacaftor plus Ivacaftor combination regimen in people with cystic fibrosis homozygous for the f508del mutation a double blind randomised phase 3 trial
The Lancet, 2019Co-Authors: H.g.m. Heijerman, Steven M. Rowe, Edward F. Mckone, Marcus A. Mall, Bonnie W. Ramsey, Elizabeth Tullis, D G Downey, Eva Van Braeckel, John J Welter, Charlotte M MckeeAbstract:BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus Ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus Ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus Ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus Ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus Ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus Ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. FINDINGS: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus Ivacaftor group and 52 in the tezacaftor plus Ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus Ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus Ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus Ivacaftor and in one (2%) receiving tezacaftor plus Ivacaftor. INTERPRETATION: Elexacaftor plus tezacaftor plus Ivacaftor provided clinically robust benefit compared with tezacaftor plus Ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. FUNDING: Vertex Pharmaceuticals.
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elexacaftor tezacaftor Ivacaftor for cystic fibrosis with a single phe508del allele
The New England Journal of Medicine, 2019Co-Authors: Peter G Middleton, Edward F. Mckone, Marcus A. Mall, Bonnie W. Ramsey, Elizabeth Tullis, Jennifer L Taylorcousar, Pavel Dřevinek, Larry C Lands, Deepika Polineni, F VermeulenAbstract:BACKGROUND: Cystic 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. METHODS: We 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. RESULTS: A 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. CONCLUSIONS: Elexacaftor-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.).
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VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.
The New England Journal of Medicine, 2018Co-Authors: Dominic Keating, Steven M. Rowe, Edward F. Mckone, Gautham Marigowda, Lucy D. Burr, Cori L. Daines, Marcus A. Mall, Bonnie W. Ramsey, Laura A. Sass, Elizabeth TullisAbstract:BACKGROUND: VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and Ivacaftor (VX-445-tezacaftor-Ivacaftor). METHODS: We evaluated the effects of VX-445-tezacaftor-Ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-Ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-Ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline. RESULTS: In vitro, VX-445-tezacaftor-Ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-Ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del-MF group (P
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vx 445 tezacaftor Ivacaftor in patients with cystic fibrosis and one or two phe508del alleles
The New England Journal of Medicine, 2018Co-Authors: D Keating, Steven M. Rowe, Edward F. Mckone, Gautham Marigowda, Lucy D. Burr, Cori L. Daines, Marcus A. Mall, Bonnie W. Ramsey, Laura A. Sass, Elizabeth TullisAbstract:BACKGROUND: VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and Ivacaftor (VX-445-tezacaftor-Ivacaftor). METHODS: We evaluated the effects of VX-445-tezacaftor-Ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-Ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-Ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline. RESULTS: In vitro, VX-445-tezacaftor-Ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-Ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del-MF group (P<0.001). In patients in the Phe508del-Phe508del group, who were already receiving tezacaftor-Ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV1 (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire-Revised. CONCLUSIONS: The use of VX-445-tezacaftor-Ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Funded by Vertex Pharmaceuticals; VX16-445-001 ClinicalTrials.gov number, NCT03227471 ; and EudraCT number, 2017-000797-11 .).
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vx 659 tezacaftor Ivacaftor in patients with cystic fibrosis and one or two phe508del alleles
The New England Journal of Medicine, 2018Co-Authors: Jane C Davies, Edward F. Mckone, Marcus A. Mall, Bonnie W. Ramsey, B J Plant, Samuel M Moskowitz, Cynthia Brown, A Horsley, Dario Prais, Jennifer L TaylorcousarAbstract:Abstract Background The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and Ivacaftor (VX-659–tezacaftor–Ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis. Methods We evaluated the effects of VX-659–tezacaftor–Ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659–tezacaftor–Ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del–MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1). Results VX-6...
Jane C Davies - One of the best experts on this subject based on the ideXlab platform.
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restoration of exocrine pancreatic function in older children with cystic fibrosis on Ivacaftor
Paediatric Respiratory Reviews, 2020Co-Authors: A L Nichols, Jane C Davies, D Jones, S B CarrAbstract:Abstract Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Improvement in pancreatic function on Ivacaftor has been reported in open label studies in 1–5 year olds. The mechanism by which Ivacaftor might improve exocrine pancreatic function is unclear. Although the effect of Ivacaftor on pancreatic function may be more significant in younger children, evidence is mounting that there may still be potential for improvement in older children on long term therapy.
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vx 659 tezacaftor Ivacaftor in patients with cystic fibrosis and one or two phe508del alleles
The New England Journal of Medicine, 2018Co-Authors: Jane C Davies, Edward F. Mckone, Marcus A. Mall, Bonnie W. Ramsey, B J Plant, Samuel M Moskowitz, Cynthia Brown, A Horsley, Dario Prais, Jennifer L TaylorcousarAbstract:Abstract Background The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and Ivacaftor (VX-659–tezacaftor–Ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis. Methods We evaluated the effects of VX-659–tezacaftor–Ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659–tezacaftor–Ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del–MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1). Results VX-6...
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VX-659–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles
The New England Journal of Medicine, 2018Co-Authors: Jane C Davies, Edward F. Mckone, Marcus A. Mall, Bonnie W. Ramsey, Alex Horsley, Samuel M Moskowitz, Cynthia Brown, Dario Prais, Barry J. Plant, Jennifer L Taylor-cousarAbstract:Abstract Background The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and Ivacaftor (VX-659–tezacaftor–Ivacaftor), was developed to restore the function of Phe508del CFTR protein in patients with cystic fibrosis. Methods We evaluated the effects of VX-659–tezacaftor–Ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659–tezacaftor–Ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del–MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del–Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV1). Results VX-6...
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safety pharmacokinetics and pharmacodynamics of Ivacaftor in patients aged 2 5 years with cystic fibrosis and a cftr gating mutation kiwi an open label single arm study
The Lancet Respiratory Medicine, 2016Co-Authors: Jane C Davies, Sarah Robertson, William T Harris, Gregory S Sawicki, Steve Cunningham, Allen Lapey, Warren E Regelmann, K W Southern, Yulia Green, J CookeAbstract:Summary Background Ivacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of Ivacaftor in children aged 2–5 years. Methods In the two-part KIWI study, we enrolled children aged 2–5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada. Participants received oral Ivacaftor 50 mg (if bodyweight Z scores, and pharmacokinetic parameter estimation of Ivacaftor. This study is registered with ClinicalTrials.gov, number NCT01705145. Findings Between Jan 8, 2013, and March 1, 2013, nine patients were enrolled onto part A of the study, all of whom completed the 4 day treatment period, and eight of whom took part in part B. Between June 28, 2013, and Sept 26, 2013, 34 patients were enrolled in part B, 33 of whom completed the 24 week treatment period. All patients received at least one dose of Ivacaftor. Results of Ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults (median C min were 536 ng/mL for the 50 mg dose; 580 ng/mL for the 75 mg dose; median Ivacaftor AUC values were 9840 ng × h/mL and 10 200 ng × h/mL, respectively). Common adverse events in part B included cough (in 19 [56%] of 34 patients) and vomiting (in ten [29%]). Five (15%) patients had liver function test (LFT) results that were more than eight times higher than the upper limit of normal, four of whom had study drug interrupted, and one of whom had study drug discontinued. Six (18%) of 34 patients had seven serious adverse events; a raised concentration of transaminases was the only serious adverse event regarded as related to Ivacaftor and the only adverse event that resulted in study treatment discontinuation. At week 24, in patients for whom we had data, sweat chloride had changed from baseline by a mean of −46·9 mmol/L (SD 26·2, p Z score by 0·2 (0·3; p Z score by 0·4 (0·4, p Z score by −0·01 (0·3; p=0·84). Interpretation Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2–5 years with cystic fibrosis with a gating mutation followed up for 24 weeks, although the frequency of elevated LFTs suggests that monitoring should be frequent in young children, particularly those with a history of elevated LFTs. Results of an ongoing extension study assessing durability of these effects and longer-term safety are warranted. Funding Vertex Pharmaceuticals Incorporated.
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lumacaftor Ivacaftor in patients with cystic fibrosis homozygous for phe508del cftr
The New England Journal of Medicine, 2015Co-Authors: Claire E Wainwright, Gautham Marigowda, Bonnie W. Ramsey, J S Elborn, Xiaohong Huang, M Cipolli, Carla Colombo, Jane C Davies, K De Boeck, Patrick A FlumeAbstract:A total of 1108 patients underwent randomization and received study drug. The mean baseline FEV 1 was 61% of the predicted value. In both studies, there were significant improvements in the primary end point in both lumacaftor–Ivacaftor dose groups; the difference between active treatment and placebo with respect to the mean absolute improvement in the percentage of predicted FEV 1 ranged from 2.6 to 4.0 percentage points (P<0.001), which corresponded to a mean relative treatment difference of 4.3 to 6.7% (P<0.001). Pooled analyses showed that the rate of pulmonary exacerbations was 30 to 39% lower in the lumacaftor–Ivacaftor groups than in the placebo group; the rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor–Ivacaftor groups as well. The incidence of adverse events was generally similar in the lumacaftor–Ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor–Ivacaftor versus 1.6% among those who received placebo. CONCLUSIONS These data show that lumacaftor in combination with Ivacaftor provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. (Funded by Vertex Pharmaceuticals and others; TRAFFIC and TRANSPORT ClinicalTrials.gov numbers, NCT01807923 and NCT01807949.)
Elizabeth Tullis - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of the elexacaftor plus tezacaftor plus Ivacaftor combination regimen in people with cystic fibrosis homozygous for the f508del mutation a double blind randomised phase 3 trial
The Lancet, 2019Co-Authors: H.g.m. Heijerman, Steven M. Rowe, Edward F. Mckone, Marcus A. Mall, Bonnie W. Ramsey, Elizabeth Tullis, D G Downey, Eva Van Braeckel, John J Welter, Charlotte M MckeeAbstract:BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus Ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus Ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40-90%, inclusive. After a 4-week tezacaftor plus Ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus Ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus Ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus Ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. FINDINGS: Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus Ivacaftor group and 52 in the tezacaftor plus Ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus Ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference -45·1 mmol/L [95% CI -50·1 to -40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus Ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus Ivacaftor and in one (2%) receiving tezacaftor plus Ivacaftor. INTERPRETATION: Elexacaftor plus tezacaftor plus Ivacaftor provided clinically robust benefit compared with tezacaftor plus Ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. FUNDING: Vertex Pharmaceuticals.
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elexacaftor tezacaftor Ivacaftor for cystic fibrosis with a single phe508del allele
The New England Journal of Medicine, 2019Co-Authors: Peter G Middleton, Edward F. Mckone, Marcus A. Mall, Bonnie W. Ramsey, Elizabeth Tullis, Jennifer L Taylorcousar, Pavel Dřevinek, Larry C Lands, Deepika Polineni, F VermeulenAbstract:BACKGROUND: Cystic 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. METHODS: We 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. RESULTS: A 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. CONCLUSIONS: Elexacaftor-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.).
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VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles.
The New England Journal of Medicine, 2018Co-Authors: Dominic Keating, Steven M. Rowe, Edward F. Mckone, Gautham Marigowda, Lucy D. Burr, Cori L. Daines, Marcus A. Mall, Bonnie W. Ramsey, Laura A. Sass, Elizabeth TullisAbstract:BACKGROUND: VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and Ivacaftor (VX-445-tezacaftor-Ivacaftor). METHODS: We evaluated the effects of VX-445-tezacaftor-Ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-Ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-Ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline. RESULTS: In vitro, VX-445-tezacaftor-Ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-Ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del-MF group (P
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vx 445 tezacaftor Ivacaftor in patients with cystic fibrosis and one or two phe508del alleles
The New England Journal of Medicine, 2018Co-Authors: D Keating, Steven M. Rowe, Edward F. Mckone, Gautham Marigowda, Lucy D. Burr, Cori L. Daines, Marcus A. Mall, Bonnie W. Ramsey, Laura A. Sass, Elizabeth TullisAbstract:BACKGROUND: VX-445 is a next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector designed to restore Phe508del CFTR protein function in patients with cystic fibrosis when administered with tezacaftor and Ivacaftor (VX-445-tezacaftor-Ivacaftor). METHODS: We evaluated the effects of VX-445-tezacaftor-Ivacaftor on Phe508del CFTR protein processing, trafficking, and chloride transport in human bronchial epithelial cells. On the basis of in vitro activity, a randomized, placebo-controlled, double-blind, dose-ranging, phase 2 trial was conducted to evaluate oral VX-445-tezacaftor-Ivacaftor in patients heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-MF) and in patients homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del) after tezacaftor-Ivacaftor run-in. Primary end points were safety and absolute change in percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline. RESULTS: In vitro, VX-445-tezacaftor-Ivacaftor significantly improved Phe508del CFTR protein processing, trafficking, and chloride transport to a greater extent than any two of these agents in dual combination. In patients with cystic fibrosis, VX-445-tezacaftor-Ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. The treatment also resulted in an increased percentage of predicted FEV1 of up to 13.8 points in the Phe508del-MF group (P<0.001). In patients in the Phe508del-Phe508del group, who were already receiving tezacaftor-Ivacaftor, the addition of VX-445 resulted in an 11.0-point increase in the percentage of predicted FEV1 (P<0.001). In both groups, there was a decrease in sweat chloride concentrations and improvement in the respiratory domain score on the Cystic Fibrosis Questionnaire-Revised. CONCLUSIONS: The use of VX-445-tezacaftor-Ivacaftor to target Phe508del CFTR protein resulted in increased CFTR function in vitro and translated to improvements in patients with cystic fibrosis with one or two Phe508del alleles. This approach has the potential to treat the underlying cause of cystic fibrosis in approximately 90% of patients. (Funded by Vertex Pharmaceuticals; VX16-445-001 ClinicalTrials.gov number, NCT03227471 ; and EudraCT number, 2017-000797-11 .).
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effect of Ivacaftor therapy on exhaled nitric oxide in patients with cystic fibrosis
Journal of Cystic Fibrosis, 2015Co-Authors: Hartmut Grasemann, Elizabeth Tullis, Tanja Gonska, Julie Avolio, Michelle Klingel, Felix RatjenAbstract:Abstract Airways of patients with cystic fibrosis are deficient for nitric oxide. Low nitric oxide in cystic fibrosis has been shown to be associated with poor pulmonary function and risk of infection with certain pathogens. Treatment of cystic fibrosis patients with the cystic fibrosis transmembrane conductance regulator (CFTR)-targeting drug Ivacaftor results in improved pulmonary function. The effect of Ivacaftor on airway nitric oxide has not been assessed. Methods In this observational trial, fractional exhaled nitric oxide (FE NO ) was measured before and 4weeks after initiation of Ivacaftor therapy, in patients with cystic fibrosis and a CFTR gating mutation. The effect of Ivacaftor on FE NO was compared to treatment with inhaled dornase alfa or hypertonic saline for 4weeks, respectively. Results A total of 15 patients on Ivacaftor therapy were studied. Pulmonary function improved significantly and mean (±SD) FE NO increased from 8.5±5.0 to 16.2±15.5ppb. The effect was more pronounced in pediatric compared to adult patients. There was no linear correlation between changes in FE NO , pulmonary function or sweat chloride concentration. Neither treatment with inhaled dornase alfa (n=15) or hypertonic saline (n=16) resulted in a change in FE NO . Conclusion Therapy with Ivacaftor results in an increase in nitric oxide formation in cystic fibrosis airways, while dornase alfa or hypertonic saline has no effect on airway nitric oxide. Some beneficial effects of CFTR targeting therapy in CF may result from improved airway nitric oxide production.
