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Background: A series of phase 3 clinical trials have demonstrated that elexacaftor plus tezacaftor plus ivacaftor (ELX/TEZ/IVA) is safe and efficacious in people with cystic fibrosis (pwCF) aged ≥12 years with ≥1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impact of this treatment on lifetime clinical outcomes and survival, however, has yet to be assessed., Methods: We used a person-level microsimulation model to estimate the survival and lifetime clinical benefits of ELX/TEZ/IVA treatment versus other CFTR modulator combinations (tezacaftor plus ivacaftor [TEZ/IVA] or lumacaftor plus ivacaftor [LUM/IVA]) or best supportive care (BSC) alone in pwCF aged ≥12 years who are homozygous for F508del-CFTR. Disease progression inputs were derived from published literature; clinical efficacy inputs were derived from an indirect treatment comparison conducted using relevant phase 3 clinical trial data and extrapolations of clinical data., Results: The median projected survival for pwCF homozygous for F508del-CFTR treated with ELX/TEZ/IVA was 71.6 years. This was an increase of 23.2 years versus TEZ/IVA, 26.2 years versus LUM/IVA, and 33.5 years versus BSC alone. Treatment with ELX/TEZ/IVA also reduced disease severity as well as the number of pulmonary exacerbations and lung transplants. In a scenario analysis, the median projected survival for pwCF initiating ELX/TEZ/IVA between the ages of 12 and 17 years was 82.5 years, an increase of 45.4 years compared with BSC alone., Conclusions: The results from our model suggest ELX/TEZ/IVA treatment may substantially increase survival for pwCF, with early initiation potentially allowing pwCF to achieve near-normal life expectancy., Competing Interests: Declaration of Competing Interest Andrea Lopez, Conor Daly, Gabriela Vega-Hernandez, and Jaime L. Ru- bin are employees of Vertex Pharmaceuticals and might own stock or stock options in the company. Gordon MacGre- gor has no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Elexacaftor-tezacaftor-ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing., Methods: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor-tezacaftor-deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV 1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor-tezacaftor-deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor-deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)-tezacaftor-deutivacaftor or tezacaftor-ivacaftor active control for 4 weeks, following a 4-week tezacaftor-ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV 1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete., Findings: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV 1 of 3·1 percentage points (95% CI -0·8 to 7·0) and 2·7 percentage points (-1·0 to 6·5) from baseline at week 12, respectively, versus -0·8 percentage points (-6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)-tezacaftor-deutivacaftor (n=9), vanzacaftor (10 mg)-tezacaftor-deutivacaftor (n=19), vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV 1 of 4·6 percentage points (-1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (-4·1 to 8·0), respectively, in sweat chloride concentration of -42·8 mmol/L (-51·7 to -34·0), -45·8 mmol/L (95% CI -51·9 to -39·7), -49·5 mmol/L (-55·9 to -43·1), and 2·3 mmol/L (-7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (-10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=18) and tezacaftor-ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor-ivacaftor) at day 29 in ppFEV 1 of 15·9 percentage points (11·3 to 20·6) and -0·1 percentage points (-6·4 to 6·1), respectively, in sweat chloride concentration of -45·5 mmol/L (-49·7 to -41·3) and -2·6 mmol/L (-8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and -5·0 points (-16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor-tezacaftor-deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity., Interpretation: Once-daily dosing with vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor-tezacaftor-deutivacaftor in phase 3 clinical trials compared with elexacaftor-tezacaftor-ivacaftor., Funding: Vertex Pharmaceuticals., Competing Interests: Declaration of interests AZU received grants from the Cystic Fibrosis Foundation and the CFF-Therapeutic Development Network for the present work; received payment or honoraria from Vertex Pharmaceuticals for presentations at CF Centers in UK; and participated in advisory boards for Vertex and Eloxx. VI received grant support from CF TDN for the present work; consulting fees from Mylan for CF—TOBI podhaler advisory board; and grant support from CFF for meeting attendance. PA received support from Vertex Pharmaceuticals for lectures, presentations, and materials; meeting attendance; and participation on data safety monitoring boards or advisory boards. MAM received payment from Vertex for the current work and personal fees for serving on an advisory board; grants from Vertex and from the German Ministry for Education and Research; consulting fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Sterna Biologicals, Enterprise Therapeutics, Antabio, and Abbvie; lecture fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, and Vertex Pharmaceuticals; travel reimbursement from Boehringer Ingelheim and Vertex Pharmaceuticals; personal fees for participation in an advisory board from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Enterprise Therapeutics, Antabio, Kither Biotech, Abbvie, and Pari; and serves as an ECFS Board member. EFM received grants and other payments or honoraria from Vertex; and support for meetings or travel from Menarini. BWR received payments from Vertex for the present work, and payments for a presentation in Vancouver, BC, Canada in 2019; and participated on data safety monitoring boards or advisory boards for CF Storm Clinical Trial, Vertex Pharmaceuticals, Janssen, Abbvie, and Insmed. SMR received support for a clinical trial; consulting fees on the design and conduct of clinical trials; support for meeting attendance and for his role as Co-Chair of the Next Generation Steering Committee; received grants or contracts from Novartis, TranslateBio, Galapagos–Abbvie, Synedgen–Synspira, Eloxx, Vertex Pharmaceuticals, and Ionis Astra Zenica; consulting fees from Novartis, Galapagos–Abbvie, Synedgen–Synspira, Vertex Pharmaceuticals, Renovion, Ionis, Cystetic Medicines, and Arcturus; support for meeting attendance from Vertex; has patents planned, issued or pending; serves as a Co-Chair of the Next Generation Steering Committee; and owns stock or stock options with Synedgen–Synspira and Renovion. RCR received clinical trial support and consulting fees from Vertex for the present work; grants from CFF, NIDDK, NHLBI, NICHD, and NIDCD; received consulting fees from Guidepoint Global, Gerson Lehrman Group, and Cystic Fibrosis Foundation; participated on a data safety monitoring or advisory board for NHLBI DSMB. JLT-C received personal consulting fees from Vertex for the present work; received grants from Vertex, Eloxx, and 4DMT for the conduct of a research trial; personal fees from Vertex, Insmed, and 4DMT for trial design consulting; personal fees from Vertex for non-branded speaking; and personal fees from AbbVie for her role as DMC Chair; served as the adult patient care representative to the CFF Board of Trustees, on the CF Foundation's Clinical Research Executive Committee, Clinical Research Advisory Board, and Racial Justice Working Group; as immediate past chair of the CF TDN's Sexual Health, Reproduction and Gender Research Working Group; on the scientific advisory board for Emily's Entourage; on the ATS Respiratory Health Awards Working Group; on the ATS Scientific Grant Review and Clinical Problems Assembly Programming Committees; and served as an associate editor for the Journal of Cystic Fibrosis. ET received payment for the present work and grants for doing clinical trials from Vertex Pharmaceuticals; received payment and reimbursement from Vertex for her role on a steering committee and for presentations at educational events. JB received funding from Vertex Pharmaceuticals for the present work. AH received funding from Vertex Pharmaceuticals for the present work; grant support from NIHR, CF Trust, CF Foundation, and Medical Research Council; payments for educational lectures from Vertex Pharmaceuticals and for an advisory board from Mylan; medical writing support from Vertex; served as Chair of the UK CF Clinical Trials Accelerator Platform and as a board member of the UK CF Medical Association. LMY received salary support from mgH TDN for clinical research activity for the present work. DW has patents planned, issued or pending. DW, LTW, CC, APM, NN, PRS, ST, FVG, and YX are Vertex employees and might own stocks or stock options. GM and CK have nothing to disclose. LV was a clinical pharmacology lead at Vertex during the conduct of this study and conducted PK data analysis for the present study., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Cystic fibrosis is a devastating life-limiting genetic condition characterised by a progressive decline in lung function, respiratory infections and premature death. Tezacaftor-ivacaftor is a combined cystic fibrosis transmembrane conductance regulator (CFTR) modulator that targets the underlying cause of the disease. This study aimed to assess the impact of tezacaftor-ivacaftor use in routine clinical practice for adults with cystic fibrosis., Methods: A retrospective observational longitudinal cohort study design was applied to examine the clinical effect of tezacaftor-ivacaftor in routine practice in the West of Scotland Adult Cystic Fibrosis Unit. Adults receiving tezacaftor-ivacaftor for at least 4 weeks were included in this medicine use evaluation.A standardised data form was used to collect patient-level data: demographics, genotype, complications of cystic fibrosis, medicine access process. Fifty-two weeks pre and post tezacaftor-ivacaftor initiation data: lung function, body mass index (BMI), days spent in hospital, days receiving antibiotic treatment for respiratory exacerbations. Anonymised data were collated and analysed using SPSS V.26., Results: Of 121 potential patients, 45 received treatment with tezacaftor-ivacaftor; median age 30 years (range 17-64) at initiation, 56% were male, 76% were deemed to be homozygote and 41 patients continued treatment for at least 52 weeks. There was no significant change in % predicted FEV 1 ; median difference 0 (IQR -3 to 6). There was a significant improvement in BMI, mean 0.6 kg/m 2 (95% CI 0.2 to 1.0), as well as a median 4 (IQR -17 to 0) day reduction in days in hospital and 21 (IQR -42 to 0) day reduction in days receiving antibiotics., Conclusions: The use of tezacaftor-ivacaftor in routine practice for people with cystic fibrosis was associated with improvements in weight, as well as reducing the number of days people needed to spend in hospital and receive antibiotics., Competing Interests: Competing interests: IP has received payment as an external speaker at a Vertex sponsored scientific event. CJ has no competing interests. GM has been the principal and chief investigator on a variety of Vertex studies, and has received funding from Vertex for investigator-led trials, attended advisory boards and received unrestricted educational grants on behalf of the Scottish Cystic Fibrosis Group., (© European Association of Hospital Pharmacists 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Ivacaftor has shown to be effective in patients with cystic fibrosis (CF) with a G551D mutation., Objectives: This work aims to evaluate ivacaftor's effectiveness and safety in the real world, over 5 years, in the West of Scotland CF population., Methods: We evaluated ivacaftor's effect on pulmonary function, body mass index (BMI), hospital bed occupancy, and adverse effects in patients ≥6 years with at least one G551D mutation., Results: Statistically significant increases from baseline were observed in mean per cent predicted forced expiratory volume in 1 s (FEV 1 ) at year 1 (which was maintained at years 2 and 5) and BMI over 5 years in our adolescent/adult cohort. Improvements were observed in per cent predicted FEV 1 within the paediatric cohort with a suggestion of a plateau effect. The increase in paediatric BMI z-score was nonstatistically significant. There was a reduction in the number of pulmonary exacerbations requiring intravenous antibiotics and hospital bed occupancy. Ivacaftor was well tolerated., Conclusion: Ivacaftor was effective in our population., (© 2023 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Background: Elexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation., Methods: We conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV 1 of 40-90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV 1 , age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV 1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972., Findings: Between Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (-1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], p<0·0001), the mean percent predicted FEV 1 increased by 11·2 percentage points (95% CI 9·8 to 12·6) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·0 percentage points (-0·4 to 2·4) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 10·2 percentage points [8·2 to 12·1], p<0·0001), and the mean sweat chloride concentration decreased by 46·2 mmol/L (95% CI 43·7 to 48·7) in the elexacaftor plus tezacaftor plus ivacaftor group and by 3·4 mmol/L (1·0 to 5·8) in the tezacaftor plus ivacaftor group (least squares mean treatment difference -42·8 mmol/L [-46·2 to -39·3], nominal p<0·0001). Most participants (70 [80%] in the elexacaftor plus tezacaftor plus ivacaftor group and 74 [84%] in the tezacaftor plus ivacaftor group) had adverse events that were mild or moderate in severity; serious adverse events occurred in five (6%) of 87 participants in the elexacaftor plus tezacaftor plus ivacaftor group and 14 (16%) of 88 participants in the tezacaftor plus ivacaftor group. One (1%) participant in the elexacaftor plus tezacaftor plus ivacaftor group discontinued treatment due to an adverse event of anxiety and depression. Two (2%) participants in the tezacaftor plus ivacaftor group discontinued treatment due to adverse events of psychotic disorder (n=1) and obsessive-compulsive disorder (n=1)., Interpretation: The elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population., Funding: Vertex Pharmaceuticals., Competing Interests: Declaration of interests SS received personal fees from Proteostasis Therapeutics, Novartis Pharma, Vertex Pharmaceuticals, Chiesi, and Teva outside of the submitted work; and grants from Galapagos, Proteostasis Therapeutics, Celtaxsys, Flatley, Vertex Pharmaceuticals, Teva, Chiesi, Boehringer Ingelheim, Corbus Pharmaceuticals, and Ionis Pharmaceuticals outside of the submitted work. EFM received personal fees and grants from Vertex Pharmaceuticals during the conduct of the study; personal fees from Roche Pharmaceuticals, Insmed, and Janssen Pharmaceuticals; and other financial support from A Menarini outside of the submitted work. DGD received non-financial support from Vertex Pharmaceuticals during the conduct of the study; personal fees from Vertex Pharmaceuticals, Proteostasis, and Chiesi; and grants from Chiesi outside of the submitted work. JD received advisory board and speaker fees from Vertex Pharmaceuticals outside of the submitted work. EVB received institutional grants from Vertex Pharmaceuticals for the submitted work; and institutional grants from Vertex Pharmaceuticals, Galapagos, and Abbvie for other cystic fibrosis-related trials. MAM received personal fees from Vertex Pharmaceuticals during the conduct of the study; grants from Vertex Pharmaceuticals; and personal fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Galapagos, Sterna Biologicals, Enterprise Therapeutics, Kither Biotech, and Antabio outside of the submitted work. ET received grants and non-financial support from Vertex Pharmaceuticals during the conduct of the study; grants from Abbvie, Boehringer Ingelheim, Bayer, Spyryx, Horizon, Corbus, and Celtaxis; personal fees from Proteostasis and Horizon; and non-financial support from Proteostasis and Spyryx outside of the submitted work. CEW received institutional grants from Vertex Pharmaceuticals during the conduct of the study; grants from Novo Nordisk outside of the submitted work; and personal fees from Vertex Pharmaceuticals, Boehringer Ingelheim, Novartis, DKBmed, Gilead, and In Vivo Academy outside of the submitted work. DWal and SMM have pending patents for methods of treatment for cystic fibrosis, pharmaceutical compositions for treatment of cystic fibrosis, compositions and methods for treatment of cystic fibrosis, and crystalline forms and compositions of CFTR modulators. DWal and SMM have issued patents for crystalline forms and compositions of CFTR modulators. NA, BGB, CH, APL, YL, SMM, ST, JY, and DWal are employees of Vertex Pharmaceuticals and might own stock or stock options in the company. GM and DWat declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Emerging data suggests a possible role for cysteamine as an adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that continue to be a major clinical challenge. There are no studies investigating the use of cysteamine in pulmonary exacerbations of CF. This exploratory randomized clinical trial was conducted to answer the question: In future pivotal trials of cysteamine as an adjunct treatment in pulmonary exacerbations of CF, which candidate cysteamine dosing regimens should be tested and which are the most appropriate, clinically meaningful outcome measures to employ as endpoints?, Methods and Findings: Multicentre double-blind randomized clinical trial. Adults experiencing a pulmonary exacerbation of CF being treated with standard care that included aminoglycoside therapy were randomized equally to a concomitant 14-day course of placebo, or one of 5 dosing regimens of cysteamine. Outcomes were recorded on days 0, 7, 14 and 21 and included sputum bacterial load and the patient reported outcome measures (PROMs): Chronic Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis Questionnaire-Revised (CFQ-R); FEV1, blood leukocyte count, and inflammatory markers. Eighty nine participants in fifteen US and EU centres were randomized, 78 completed the 14-day treatment period. Cysteamine had no significant effect on sputum bacterial load, however technical difficulties limited interpretation. The most consistent findings were for cysteamine 450mg twice daily that had effects additional to that observed with placebo, with improved symptoms, CRISS additional 9.85 points (95% CI 0.02, 19.7) p = 0.05, reduced blood leukocyte count by 2.46x109 /l (95% CI 0.11, 4.80), p = 0.041 and reduced CRP by geometric mean 2.57 nmol/l (95% CI 0.15, 0.99), p = 0.049., Conclusion: In this exploratory study cysteamine appeared to be safe and well-tolerated. Future pivotal trials investigating the utility of cysteamine in pulmonary exacerbations of CF need to include the cysteamine 450mg doses and CRISS and blood leukocyte count as outcome measures., Clinical Trial Registration: NCT03000348; www.clinicaltrials.gov., Competing Interests: The authors have read the journal's policy and have the following competing interests: Deborah A O’Neil (DO) is the CEO, CSO, and shareholder of the trial sponsor NovaBiotics Ltd. Douglas J Fraser-Pitt (DFP) is a Principal Scientist and salaried employee of the trial sponsor NovaBiotics Ltd. Emma Lovie (EL) is a research scientist and Jennifer Robertson (JR) is a laboratory manager/research scientist; Both are salaried employees of the trial sponsor NovaBiotics Ltd. Graham Devereux (GD) received support from NovaBiotics Ltd to attend the 2018 NACFC. Danielle Wrolstad (DW) reports personal fees through her employer (Precision Medicine Group) from NovaBiotics Ltd, during the study. Rose Franco (RF), Stephen J Bourke (SB), Benjamin T Kopp (BK) and Ryan Dougherty (RD) report grant from NovaBiotics Ltd during the conduct of the study. SB & BK report grants from Vertex outside the submitted work. DFP and DO are authors of patent; WO2016198842A1, IL256162D0 - An amino thiol for use in the treatment of an infection caused by the bacterium mycobacterium spp. DO is also author of the following patents; US9364491B2 (and other territories) - Antimicrobial compositions with cysteamine/A composition comprising an antibiotic and a dispersant; WO2016046524A1 - Use of cysteamine in treating infections caused by yeasts/moulds; US9782423B2 (and other territories) - Antibiotic compositions comprising an antibiotic agent and cysteamine; US9339525B2 (and other territories) - Inhibition of biofilm organisms; and US20190175501A1 pending (and other territories) - Microparticles comprising a sulphur-containing compound. (JR, EL, DFP, and DO) are involved in the development of cysteamine bitartrate as a therapy for cystic fibrosis. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Clinical studies demonstrate that ivacaftor (IVA) improves health-related quality of life (HRQoL) in patients aged ≥6 years with cystic fibrosis (CF). The real-world impact of IVA and standard of care (SOC) in groups of patients with G551D and F508del mutations, respectively, was assessed using a survey comprising disease-specific and generic HRQoL measures., Methods: Patients with CF aged ≥12 years, or aged 6-11 years with caregiver support, with either (1) a G551D mutation and receiving IVA (G551D/IVA) for ≥3 months, or (2) homozygous for F508del and receiving SOC before lumacaftor/IVA availability (F508del/SOC), were eligible to participate in a cross-sectional survey. Demographic and clinical characteristics, and HRQoL measures were compared between patient groups, and multiple regression analyses were conducted., Results: After differences in patient demographic and clinical characteristics were controlled for, significantly better scores were observed in the G551D/IVA group than in the F508del/SOC group on multiple domains of the validated Cystic Fibrosis Questionnaire-Revised and the EuroQol 5-dimensions 5-level questionnaire., Conclusions: G551D/IVA patients reported better HRQoL than F508del/SOC patients on generic and disease-specific measures in a real-world setting.

There is a significant unmet need for safe and effective anti-inflammatory treatment for cystic fibrosis. The aim of this study was to evaluate the safety of acebilustat, a leukotriene A4 hydrolase inhibitor, and its effect on inflammation biomarkers in patients with cystic fibrosis. Seventeen patients with mild to moderate cystic fibrosis were enrolled and randomized into groups receiving placebo or doses of 50 mg or 100 mg acebilustat administered orally, once daily for 15 days. Sputum neutrophil counts were reduced by 65% over baseline values in patients treated with 100 mg acebilustat. A modestly significant 58% reduction vs. placebo in sputum elastase was observed with acebilustat treatment. Favorable trends were observed for reduction of serum C-reactive protein and sputum neutrophil DNA in acebilustat-treated patients. No changes in pulmonary function were observed. Acebilustat was safe and well tolerated. The results of this study support further clinical development of acebilustat for treatment of cystic fibrosis., (© 2016 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge., (Copyright © 2016, American Association for the Advancement of Science.)

The host- and bacteria-derived extracellular polysaccharide coating of the lung is a considerable challenge in chronic respiratory disease and is a powerful barrier to effective drug delivery. A low molecular weight 12-15-mer alginate oligosaccharide (OligoG CF-5/20), derived from plant biopolymers, was shown to modulate the polyanionic components of this coating. Molecular modeling and Fourier transform infrared spectroscopy demonstrated binding between OligoG CF-5/20 and respiratory mucins. Ex vivo studies showed binding induced alterations in mucin surface charge and porosity of the three-dimensional mucin networks in cystic fibrosis (CF) sputum. Human studies showed that OligoG CF-5/20 is safe for inhalation in CF patients with effective lung deposition and modifies the viscoelasticity of CF-sputum. OligoG CF-5/20 is the first inhaled polymer therapy, represents a novel mechanism of action and therapeutic approach for the treatment of chronic respiratory disease, and is currently in Phase IIb clinical trials for the treatment of CF.

Background: We set out to determine the magnitude of antigen-specific memory T helper cell responses to Pseudomonas aeruginosa in healthy humans and patients with cystic fibrosis., Methods: Peripheral blood human memory CD4(+) T cells were co-cultured with dendritic cells that had been infected with different strains of Pseudomonas aeruginosa. The T helper response was determined by measuring proliferation, immunoassay of cytokine output, and immunostaining of intracellular cytokines., Results: Healthy individuals and patients with cystic fibrosis had robust antigen-specific memory CD4(+) T cell responses to Pseudomonas aeruginosa that not only contained a Th1 and Th17 component but also Th22 cells. In contrast to previous descriptions of human Th22 cells, these Pseudomonal-specific Th22 cells lacked the skin homing markers CCR4 or CCR10, although were CCR6(+). Healthy individuals and patients with cystic fibrosis had similar levels of Th22 cells, but the patient group had significantly fewer Th17 cells in peripheral blood., Conclusions: Th22 cells specific to Pseudomonas aeruginosa are induced in both healthy individuals and patients with cystic fibrosis. Along with Th17 cells, they may play an important role in the pulmonary response to this microbe in patients with cystic fibrosis and other conditions.

Background: For cystic fibrosis (CF) patients there is a lack of good assays of disease activity and response to new therapeutic interventions, including gene therapy. Current measures of airways inflammation severity are insensitive or non-specific., Methods: Bronchoalveolar lavage fluid from 39 CF children and 38 respiratory disease controls was obtained at bronchoscopy and analysed by surface enhanced laser desorption ionisation time of flight (SELDI-TOF) mass spectrometry. Recognized proteins were assessed for CF disease specificity. Individual protein identification of specific peaks was performed., Results: 1277 proteins/peptides, >4 kDa, were detected using 12 different surfaces and binding conditions. 202 proteins/peptides were differentially expressed in the CF samples (p<0.001), 167 up-regulated and 35 down-regulated. The most discriminatory biomarker had a mass of 5.163 kDa. The most abundant, with a mass of 10.6 kDa, was identified as s100 A8 (calgranulin A)., Conclusions: The application of SELDI-TOF mass spectrometry allows evaluation of proteins in BAL fluid avoiding the limitations of only analysing predetermined proteins and potentially identifying proteins not previously appreciated as biomarkers. Its application to cystic fibrosis should enable appropriate evaluation of evolving illness, of gene therapy and other new therapies.

Background: The cationic lipid Genzyme lipid (GL) 67 is the current "gold-standard" for in vivo lung gene transfer. Here, we assessed, if GL67 mediated uptake of siRNAs and asODNs into airway epithelium in vivo., Methods: Anti-lacZ and ENaC (epithelial sodium channel) siRNA and asODN were complexed to GL67 and administered to the mouse airway epithelium in vivo Transfection efficiency and efficacy were assessed using real-time RT-PCR as well as through protein expression and functional studies. In parallel in vitro experiments were carried out to select the most efficient oligonucleotides., Results: In vitro, GL67 efficiently complexed asODNs and siRNAs, and both were stable in exhaled breath condensate. Importantly, during in vitro selection of functional siRNA and asODN we noted that asODNs accumulated rapidly in the nuclei of transfected cells, whereas siRNAs remained in the cytoplasm, a pattern consistent with their presumed site of action. Following in vivo lung transfection siRNAs were only visible in alveolar macrophages, whereas asODN also transfected alveolar epithelial cells, but no significant uptake into conducting airway epithelial cells was seen. SiRNAs and asODNs targeted to beta-galactosidase reduced betagal mRNA levels in the airway epithelium of K18-lacZ mice by 30% and 60%, respectively. However, this was insufficient to reduce protein expression. In an attempt to increase transfection efficiency of the airway epithelium, we increased contact time of siRNA and asODN using the in vivo mouse nose model. Although highly variable and inefficient, transfection of airway epithelium with asODN, but not siRNA, was now seen. As asODNs more effectively transfected nasal airway epithelial cells, we assessed the effect of asODN against ENaC, a potential therapeutic target in cystic fibrosis; no decrease in ENaC mRNA levels or function was detected., Conclusion: This study suggests that although siRNAs and asODNs can be developed to inhibit gene expression in culture systems and certain organs in vivo, barriers to nucleic acid transfer in airway epithelial cells seen with large DNA molecules may also affect the efficiency of in vivo uptake of small nucleic acid molecules.

Background: The loss of cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride conductance does not fully explain the diverse pathologies evident in patients with cystic fibrosis (CF). Bicarbonate (HCO(3)(-)) secretion is also impaired in CFTR expressing tissues and CFTR is thought to regulate HCO(3)(-) secretion at the apical membrane of epithelial cells. We hypothesised that the epithelial lining fluid (ELF) of patients with CF would be acidified and that this may be worsened during an infective exacerbation due to the increased inflammatory burden., Methods: pH and nitrite levels in exhaled breath condensate (EBC) from 12 healthy non-smoking controls and 30 patients with CF (11 of whom were in an infective exacerbation) were measured. A further nine patients were studied before and after intravenous antibiotic treatment for an exacerbation of CF., Results: The pH of EBC was significantly lower in patients with stable CF than in controls (5.88 (0.32) v 6.15 (0.16), p=0.017), and was further reduced in CF patients with an exacerbation (5.32 (0.38), p=0.001) compared with stable CF patients. EBC pH increased significantly following antibiotic treatment from 5.27 (0.42) to 5.71 (0.42), p=0.049). Nitrite levels in EBC were increased in CF patients with an exacerbation compared with control subjects (4.4 (4.0) micro m v 1.6 (1.6) micro m p=0.047). No correlation was found between EBC pH and nitrite levels., Conclusions: These findings support the hypothesis that airway acidification occurs in CF. This acidity is in part a function of inflammation as the pH of the EBC of patients increased significantly with treatment of an exacerbation, although not to control levels. Acidic pH of the ELF may play a role in the pathophysiology of CF lung disease and requires further investigation.

There is a significant unmet need for safe and effective anti-inflammatory treatment for cystic fibrosis. The aim of this study was to evaluate the safety of acebilustat, a leukotriene A4 hydrolase inhibitor, and its effect on inflammation biomarkers in patients with cystic fibrosis. Seventeen patients with mild to moderate cystic fibrosis were enrolled and randomized into groups receiving placebo or doses of 50 mg or 100 mg acebilustat administered orally, once daily for 15 days. Sputum neutrophil counts were reduced by 65% over baseline values in patients treated with 100 mg acebilustat. A modestly significant 58% reduction vs. placebo in sputum elastase was observed with acebilustat treatment. Favorable trends were observed for reduction of serum C-reactive protein and sputum neutrophil DNA in acebilustat-treated patients. No changes in pulmonary function were observed. Acebilustat was safe and well tolerated. The results of this study support further clinical development of acebilustat for treatment of cystic fibrosis. [ABSTRACT FROM AUTHOR]

Objectives Safe, effective anti-inflammatory treatment (AIT) remains a significant unmet need for CF. Inflammation plays a central role in CF and is a key factor in lung function decline and exacerbations. CTX-4430 is an oral once daily AIT in development for CF. It acts by reducing production of Leukotriene B4, thereby modulating the excessive neutrophil burden characteristic of CF lung disease. Safety and inflammatory biomarkers were assessed over two weeks of treatment in phase 1 study in CF patients. Methods This ascending dose study was conducted at four clinical sites in the United Kingdom (NCT01944735). It included 17 patients with mild to moderate CF. Doses of 50 mg or 100 mg CTX-4430 or placebo were studied during 15 days of treatment. Safety measures were taken on days 1, 8 and 15, including assessments of adverse events, hematology, blood chemistries and pulmonary function. Experimental measures included serum CRP, sputum DNA, elastase and microbial counts. Additional assessments of pharmacokinetics and pharmacodynamics in blood are reported separately. Results Here we report the results of this phase 1 study in CF patients including assessments of safety and tolerability, pulmonary function and inflammatory markers in blood and sputum. In brief, CTX-4430 was safe and well tolerated at both dose levels. No deleterious changes in pulmonary function were observed. Treatment did not affect circulating neutrophil counts. Positive trends were observed in blood and sputum inflammatory markers demonstrating potential use of CTX-4430 to preserve CF lung function over time. Conclusion These results support further clinical development of CTX-4430 for treatment of CF. [ABSTRACT FROM AUTHOR]