Imperial College London

ProfessorJaneDavies

Faculty of MedicineNational Heart & Lung Institute

Professor of Paediatric Respirology & Experimental Medicine
 
 
 
//

Contact

 

+44 (0)20 7594 7973j.c.davies

 
 
//

Assistant

 

Mrs Gina Rivellini +44 (0)20 7594 7986

 
//

Location

 

G44Emmanuel Kaye BuildingRoyal Brompton Campus

//

Summary

 

Publications

Publication Type
Year
to

414 results found

Davies J, Southern KW, Barben J, Goldring S, Kneen R, Southward S, Rajeev Y, Bush Aet al., 2023, Raised intracranial pressure in three children with cystic fibrosis receiving elexacaftor-tezacaftor-ivacaftor modulator therapy, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Journal article

Wainwright C, McColley SA, McNally P, Powers M, Ratjen F, Rayment JH, Retsch-Bogart G, Roesch E, Ahluwalia N, Chin A, Chu C, Lu M, Menon P, Waltz D, Weinstock T, Zelazoski L, Davies JC, VX19-445-107 Study Groupet al., 2023, Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged ≥6 Years with Cystic Fibrosis and At Least One F508del Allele: A Phase 3, Open-Label Clinical Trial., Am J Respir Crit Care Med

RATIONALE: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6 through 11 years with cystic fibrosis and ≥1 F508del-CFTR allele. OBJECTIVES: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial. METHODS: In this phase 3, two-part (Part A and Part B), open-label extension study, children aged ≥6 years with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours while children weighing ≥30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose). The 96-week analysis of Part A of this extension study is reported here. MEASUREMENTS AND MAIN RESULTS: Sixty-four children (F/MF genotypes, n=36; F/F genotype, n=28) were enrolled and received ≥1 dose of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of cystic fibrosis disease. Overall, exposure-adjusted rates of adverse events and serious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04 and 8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. From parent study baseline at Week 96 of this extension study, mean ppFEV1 increased (11.2 [95% CI 8.3, 14.2] percentage points), sweat chloride concentration decreased (-62.3 [95% CI 65.9, -58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI 11.4, 15.1] poi

Journal article

Davies J, Dobra R, Wilson G, Matthews J, Boeri M, Elborn S, Kee F, Madge Set al., 2023, A systematic review to identify and collate factors influencing patient journeys through clinical trials, JRSM Open, ISSN: 2054-2704

Journal article

Davies J, Morales S, Alton E, Martin Iet al., 2023, Lytic bacteriophage is a promising adjunct to common antibiotics across cystic fibrosis clinical strains and culture models of Pseudomonas aeruginosa infection, Antibiotics, Vol: 12, Pages: 1-14, ISSN: 2079-6382

Bacteriophages (phages) are antimicrobials with resurgent interest that are being investigated for the treatment of antibiotic refractory infection, including for Pseudomonas aeruginosa (Pa) lung infection in cystic fibrosis (CF). In vitro work supports the use of this therapy in planktonic and biofilm culture models; however, consistent data are lacking for efficacy across different clinical Pa strains, culture models, and in combination with antibiotics in clinical use. We first examined the efficacy of a 4-phage cocktail as an adjunct to our CF centre’s first-line systemic combination antibiotic therapy (ceftazidime + tobramycin) for 16 different clinical Pa strains and then determined subinhibitory interactions for a subset of these strains with each antibiotic in planktonic and biofilm culture. When a 4-phage cocktail (4 × 108 PFU/mL) was added to a ceftazidime-tobramycin combination (ceftazidime 16 mg/mL + tobramycin 8 mg/mL), we observed a 1.7-fold and 1.3-fold reduction in biofilm biomass and cell viability, respectively. The four most antibiotic resistant strains in biofilm were very susceptible to phage treatment. When subinhibitory concentrations of antibiotics and phages were investigated, we observed additivity/synergy as well as antagonism/inhibition of effect that varied across the clinical strains and culture model. In general, more additivity was seen with the phage-ceftazidime combination than with phage-tobramycin, particularly in biofilm culture, where no instances of additivity were seen when phages were combined with tobramycin. The fact that different bacterial strains were susceptible to phage treatment when compared to standard antibiotics is promising and these results may be relevant to ongoing clinical trials exploring the use of phages, in particular in the selection of subjects for clinical trials.

Journal article

Davies J, Hughes D, Rosenthal M, Cuthbertson L, ramadan N, Felton I, Simmonds N, Loebinger M, price H, Armstrong-James D, elborn S, Cookson W, Moffatt Met al., 2023, An invisible threat? Aspergillus positive cultures and co-infecting bacteria in airway sample, Journal of Cystic Fibrosis, Vol: 22, Pages: 320-326, ISSN: 1569-1993

BackgroundAspergillus fumigatus (Af) infection is associated with poor lung health in chronic suppurative lung diseases but often goes undetected. We hypothesised that inhibition of Af growth by Pseudomonas aeruginosa (Pa) increases the frequency of false-negative Af culture in co-infected people. Using a substantial group of cystic fibrosis (CF) airway samples, we assessed the relationship between Af and bacterial pathogens, additionally comparing fungal culture with next-generation sequencing.MethodsFrequency of co-culture was assessed for 44,554 sputum/BAL cultures, from 1,367 CF patients between the years 2010–2020. In a subgroup, Internal Transcribed Spacer-2 (ITS2) fungal sequencing was used to determine sequencing-positive, culture-negative (S+/C-) rates.ResultsPa+ samples were nearly 40% less likely (P<0.0001) than Pa- samples to culture Af, an effect that was also seen with some other Gram-negative isolates. This impact varied with Pa density and appeared to be moderated by Staphylococcus aureus co-infection. Sequencing identified Af-S+/C- for 40.1% of tested sputa. Samples with Pa had higher rates of Af-S+/C- (49.3%) than those without (35.7%; RR 1.38 [1.02–1.93], P<0.05). Af-S+/C- rate was not changed by other common bacterial infections. Pa did not affect the S+/C- rates of Candida, Exophiala or Scedosporium.ConclusionsPa/ Af co-positive cultures are less common than expected in CF. Our findings suggest an Af-positive culture is less likely in the presence of Pa. Interpretation of negative cultures should be cautious, particularly in Pa-positive samples, and a companion molecular diagnostic could be useful. Further work investigating mechanisms, alternative detection techniques and other chronic suppurative lung diseases is needed.

Journal article

Allen L, Allen L, Carr SB, Davies G, Downey D, Egan M, Forton JT, Gray R, Haworth C, Horsley A, Smyth AR, Southern KW, Davies JCet al., 2023, Future therapies for cystic fibrosis., Nat Commun, Vol: 14

We are currently witnessing transformative change for people with cystic fibrosis with the introduction of small molecule, mutation-specific drugs capable of restoring function of the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). However, despite being a single gene disorder, there are multiple cystic fibrosis-causing genetic variants; mutation-specific drugs are not suitable for all genetic variants and also do not correct all the multisystem clinical manifestations of the disease. For many, there will remain a need for improved treatments. Those patients with gene variants responsive to CFTR modulators may have found these therapies to be transformational; research is now focusing on safely reducing the burden of symptom-directed treatment. However, modulators are not available in all parts of the globe, an issue which is further widening existing health inequalities. For patients who are not suitable for- or do not have access to- modulator drugs, alternative approaches are progressing through the trials pipeline. There will be challenges encountered in design and implementation of these trials, for which the established global CF infrastructure is a major advantage. Here, the Cystic Fibrosis National Research Strategy Group of the UK NIHR Respiratory Translational Research Collaboration looks to the future of cystic fibrosis therapies and consider priorities for future research and development.

Journal article

Robinson L, Collins A, Murphy R, Davies J, Allsopp Let al., 2023, Diversity and prevalence of type VI secretion system effectors in clinical Pseudomonas aeruginosa isolates, Frontiers in Microbiology, Vol: 13, ISSN: 1664-302X

Pseudomonas aeruginosa is an opportunistic pathogen and a major driver of morbidity and mortality in people with Cystic Fibrosis (CF). The Type VI secretion system (T6SS) is a molecular nanomachine that translocates effectors across the bacterial membrane into target cells or the extracellular environment enabling intermicrobial interaction. P. aeruginosa encodes three T6SS clusters, the H1-, H2- and H3-T6SS, and numerous orphan islands. Genetic diversity of T6SS-associated effectors in P. aeruginosa has been noted in reference strains but has yet to be explored in clinical isolates. Here, we perform a comprehensive bioinformatic analysis of the pangenome and T6SS effector genes in 52 high-quality clinical P. aeruginosa genomes isolated from CF patients and housed in the Personalised Approach to P. aeruginosa strain repository. We confirm that the clinical CF isolate pangenome is open and principally made up of accessory and unique genes that may provide strain-specific advantages. We observed genetic variability in some effector/immunity encoding genes and show that several well-characterised vgrG and PAAR islands are absent from numerous isolates. Our analysis shows clear evidence of disruption to T6SS genomic loci through transposon, prophage, and mobile genetic element insertions. We identified an orphan vgrG island in P. aeruginosa strain PAK and five clinical isolates using in silico analysis which we denote vgrG7, predicting a gene within this cluster to encode a Tle2 lipase family effector. Close comparison of T6SS loci in clinical isolates compared to reference P. aeruginosa strain PAO1 revealed the presence of genes encoding eight new T6SS effectors with the following putative functions: cytidine deaminase, lipase, metallopeptidase, NADase, and pyocin. Finally, the prevalence of characterised and putative T6SS effectors were assessed in 532 publicly available P. aeruginosa genomes, which suggests the existence of accessory effectors. Our in silico study of

Journal article

Southern KW, Castellani C, Lammertyn E, Smyth A, VanDevanter D, van Koningsbruggen-Rietschel S, Barben J, Bevan A, Brokaar E, Collins S, Connett GJ, Daniels TWV, Davies J, Declercq D, Gartner S, Gramegna A, Hamilton N, Hauser J, Kashirskaya N, Kessler L, Lowdon J, Makukh H, Martin C, Morrison L, Nazareth D, Noordhoek J, O'Neill C, Owen E, Oxley H, Raraigh KS, Raynal C, Robinson K, Roehmel J, Schwarz C, Sermet I, Shteinberg M, Sinha I, Takawira C, van Mourik P, Verkleij M, Waller MD, Duff Aet al., 2023, Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosi, JOURNAL OF CYSTIC FIBROSIS, Vol: 22, Pages: 17-30, ISSN: 1569-1993

Journal article

Mall MA, Brugha R, Gartner S, Legg J, Moeller A, Mondejar-Lopez P, Prais D, Pressler T, Ratjen F, Reix P, Robinson PD, Selvadurai H, Stehling F, Ahluwalia N, Arteaga-Solis E, Bruinsma BG, Jennings M, Moskowitz SM, Noel S, Tian S, Weinstock TG, Wu P, Wainwright CE, Davies JCet al., 2022, Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation A Phase 3b, Randomized, Placebo-controlled Study, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 206, Pages: 1361-1369, ISSN: 1073-449X

Journal article

Gifford AH, Taylor-Cousar JL, Davies JC, McNally Pet al., 2022, Update on Clinical Outcomes of Highly Effective Modulator Therapy, CLINICS IN CHEST MEDICINE, Vol: 43, Pages: 677-695, ISSN: 0272-5231

Journal article

Drevinek P, Canton R, Johansen HK, Hoffman L, Coenye T, Burgel P-R, Davies JCet al., 2022, New concepts in antimicrobial resistance in cystic fibrosis respiratory infections, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 937-945, ISSN: 1569-1993

Journal article

Dobra RA, Davies JC, Elborn JS, Kee F, Madge S, Boeri Met al., 2022, A DISCRETE CHOICE EXPERIMENT (DCE) TO QUANTIFY THE INFLUENCE OF TRIAL FEATURES ON THE DECISION TO PARTICIPATE IN CYSTIC FIBROSIS (CF) TRIALS, Publisher: BMJ PUBLISHING GROUP, Pages: A114-A115, ISSN: 0040-6376

Conference paper

Mahenthiralingam E, Weiser R, Floto RA, Davies JC, Fothergill JLet al., 2022, Selection of relevant bacterial strains for novel therapeutic testing: a guidance document for priority cystic fibrosis lung pathogens, Current Clinical Microbiology Reports, Vol: 9, Pages: 33-45, ISSN: 2196-5471

Purpose of ReviewPeople with cystic fibrosis (CF) suffer chronic lung infections with a range of antimicrobial-resistant bacterial pathogens. There is an urgent need for researchers to develop novel anti-infectives to treat these problematic infections, but how can we select bacterial strains which are relevant for robust testing and comparative research?Recent FindingsPseudomonas aeruginosa, Burkholderia cepacia complex and Burkholderia gladioli, Mycobacterium abscessus complex, Staphylococcus aureus, Haemophilus influenza, and several multidrug-resistant Gram-negative species were selected as key CF infections that urgently require new therapeutics. Reference isolates and strain panels were identified, and a summary of the known genotypic diversity of each pathogen was provided.SummaryHere, we summarise the current strain resources available for priority CF bacterial pathogens and highlight systematic selection criteria that researchers can use to select strains for use in therapeutic testing.

Journal article

Short C, Abkir M, Pinnell S, Proctor O, Saunders CJ, Davies JCet al., 2022, Migration is not the perfect answer: How the cross-talk error correction for multiple breath nitrogen washout (MBWN2) parameters differs on directly collected vs. legacy data, PEDIATRIC PULMONOLOGY, Vol: 58, Pages: 328-331, ISSN: 8755-6863

Journal article

Hine C, Desai M, Davies J, Sapey E, Nagakumar Pet al., 2022, A systematic review of lung clearance index in non-cystic fibrosis, non-primary ciliary dyskinesia bronchiectasis, Respiratory Medicine, Vol: 201, Pages: 1-8, ISSN: 0954-6111

BackgroundNon cystic fibrosis, non primary ciliary dyskinesia bronchiectasis (nCFnPCD-BE) results in significant morbidity with few evidence-based treatments.Objectiveassessments are required to assess severity and evaluate treatment. Lung clearance index (LCI) measures ventilation inhomogeneity and is a sensitive test of disease in CF; its use in nCFnPCD-BE is unclear.MethodsA systematic review of LCI in nCFnPCD-BE was performed using standard methodology (protocol registered on PROSPERO, University of York).ResultsOf 276 records identified, 12 articles, describing 519 adult and paediatric patients in cross-sectional studies were included, addressing several domains.1: What is the utility of LCI in detecting disease and severity?LCI detected disease in adults, differentiating bronchiectasis from controls (AUC 0.90 to 0.96) and mild from moderate/severe bronchiectasis on CT (AUC 0.73).2: Does LCI correlate with spirometry and imaging?LCI correlated with spirometry in adult (r = −0.37 to −0.61) and paediatric (r = −0.6) groups, signs of bronchiectasis on CT, and CT scoring systems (modified Reiff).3: Does LCI relate to subjective scores of severity?In adults, LCI correlated with St. George's Respiratory Questionnaire (r = 0.18) and Bronchiectasis Severity Index (r = 0.45).4: Does LCI identify response to intervention?LCI did not change in studies examining LCI pre-post intervention (adults treated for exacerbation and undergoing physiotherapy).Overall study quality was variable.ConclusionContrary to data in CF, the review did not identify good quality studies defining the role of LCI in children with bronchiectasis. In adults, LCI was a sensitive measure of disease severity and correlated with clinical assessment tools.

Journal article

McLachlan G, Alton EWFW, Boyd AC, Clarke NKK, Davies JCC, Gill DRR, Griesenbach U, Hickmott JWW, Hyde S, Miah KMM, Molina CJet al., 2022, Progress in Respiratory Gene Therapy, HUMAN GENE THERAPY, Vol: 33, Pages: 893-912, ISSN: 1043-0342

Journal article

Stanford GE, Jones M, Charman SC, Bilton D, Usmani OS, Davies JC, Simmonds NJet al., 2022, Clinimetric analysis of outcome measures for airway clearance in people with cystic fibrosis: a systematic review, Therapeutic Advances in Respiratory Disease, Vol: 16, Pages: 1-12, ISSN: 1753-4666

Background:Airway clearance techniques (ACTs) are integral to cystic fibrosis (CF) management. However, there is no consensus as to which outcome measures (OMs) are best for assessing ACT efficacy.Objectives:To summarise OMs that have been assessed for their clinimetric properties (including validity, feasibility, reliability, and reproducibility) within the context of ACT research in CF.Design and Methods:A systematic review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) standards. Any parallel or cross-over randomised controlled trial (RCT) investigating outcome measures for ACT in the CF population were eligible for inclusion. The search was performed in five medical databases, clinicaltrials.gov, and abstracts from international CF conferences. The authors planned to independently assess study quality and risk of bias using the COnsensus-based Standards for the selection of health status Measurement InstrumeNts (COSMIN) risk of bias checklist with external validity assessment based upon study details (participants and study intervention). Two review authors (GS and MJ) independently screened search results against inclusion criteria, and further data extraction were planned but not required.Results:No completed RCTs from the 187 studies identified met inclusion criteria for the primary or post hoc secondary objective. Two ongoing trials were identified.Discussion and conclusion:This empty systematic review highlights that high-quality RCTs are urgently needed to investigate and validate the clinimetric properties of OMs used to assess ACT efficacy. With the changing demographics of CF combined with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, an accurate assessment of the current benefit of ACT or the effect of ACT withdrawal is a high priority for clinical practice and future research; OMs which have been validated for this purpose are essenti

Journal article

Sawicki GS, Chilvers M, McNamara J, Naehrlich L, Saunders C, Sermet-Gaudelus I, Wainwright CE, Ahluwalia N, Campbell D, Harris RS, Paz-Diaz H, Shih JL, Davies JCet al., 2022, A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children >= 6 years of age homozygous for F508del or heterozygous for F508del and a residual function CFTR variant, JOURNAL OF CYSTIC FIBROSIS, Vol: 21, Pages: 675-683, ISSN: 1569-1993

Journal article

Murphy R, Coates M, Thrane S, Sabnis A, Harrison J, Schelenz S, Edwards A, Vorup-Jensen T, Davies Jet al., 2022, Synergistic activity of repurposed peptide drug glatiramer acetate with tobramycin against cystic fibrosis Pseudomonas aeruginosa, Microbiology Spectrum, Vol: 10, ISSN: 2165-0497

Pseudomonas aeruginosa is the most common pathogen infecting the lungs of people with cystic fibrosis (CF), causing both acute and chronic infections. Intrinsic and acquired antibiotic resistance, coupled with the physical barriers resulting from desiccated CF sputum, allow P. aeruginosa to colonize and persist in spite of antibiotic treatment. As well as the specific difficulties in eradicating P. aeruginosa from CF lungs, P. aeruginosa is also subject to the wider, global issue of antimicrobial resistance. Glatiramer acetate (GA) is a peptide drug, used in the treatment of multiple sclerosis (MS), which has been shown to have moderate antipseudomonal activity. Other antimicrobial peptides (AMPs) have been shown to be antibiotic resistance breakers, potentiating the activities of antibiotics when given in combination, restoring and/or enhancing antibiotic efficacy. Growth, viability, MIC determinations, and synergy analysis showed that GA improved the efficacy of tobramycin (TOB) against reference strains of P. aeruginosa, reducing TOB MICs and synergizing with the aminoglycoside. This was also the case for clinical strains from people with CF. GA significantly reduced the MIC50 of TOB for viable cells from 1.69 mg/L (95% confidence interval [CI], 0.26 to 8.97) to 0.62 mg/L (95% CI, 0.15 to 3.94; P = 0.002) and the MIC90 for viable cells from 7.00 mg/L (95% CI, 1.18 to 26.50) to 2.20 mg/L (95% CI, 0.99 to 15.03; P = 0.001), compared to results with TOB only. Investigation of mechanisms of GA activity showed that GA resulted in significant disruption of outer membranes, depolarization of cytoplasmic membranes, and permeabilization of P. aeruginosa and was the only agent tested (including cationic AMPs) to significantly affect all three mechanisms.

Journal article

Dobra R, Bentley S, Edmondson C, Ovens M, Saunders C, Short C, Wilson G, Davies JC, Bush Aet al., 2022, Going the Extra Mile: Why Clinical Research in Cystic Fibrosis Must Include Children, CHILDREN-BASEL, Vol: 9

Journal article

King JA, Nichols A-L, Bentley S, Carr SB, Davies JCet al., 2022, An Update on CFTR Modulators as New Therapies for Cystic Fibrosis., Paediatr Drugs, Vol: 24, Pages: 321-333

Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug-drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.

Journal article

Davies J, Horsley A, Brightling C, Djukanovic R, Heaney LG, Hussell T, Marciniak SJ, McGarvey L, Porter JC, Wilkinson T, Ho L-Pet al., 2022, Early-phase clinical trials in a pandemic: learning from the response to COVID-19, The Lancet Respiratory Medicine, Vol: 10, Pages: 625-627, ISSN: 2213-2600

Journal article

Balfour-Lynn IM, Puckey M, Simmonds NJ, Davies JCet al., 2022, Revisiting a diagnosis of cystic fibrosis - Uncertainties and considerations, PAEDIATRIC RESPIRATORY REVIEWS, Vol: 42, Pages: 29-34, ISSN: 1526-0542

Journal article

Dixon E, Dick K, Ollosson S, Jones D, Mattock H, Bentley S, Saunders C, Matthews J, Dobra B, King J, Edmondson C, Davies JCet al., 2022, Telemedicine and cystic fibrosis: Do we still need face-to-face clinics?, PAEDIATRIC RESPIRATORY REVIEWS, Vol: 42, Pages: 23-28, ISSN: 1526-0542

Journal article

King J, Nichols A, Bentley S, Carr S, Davies Jet al., 2022, An update on CFTR modulators as new therapies for Cystic Fibrosis, Paediatric Drugs, Vol: 24, Pages: 321-333, ISSN: 1174-5878

Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug–drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.

Journal article

Robinson PD, Jensen R, Seeto RA, Stanojevic S, Saunders C, Short C, Davies JC, Ratjen Fet al., 2022, Impact of cross-sensitivity error correction on representative nitrogen-based multiple breath washout data from clinical trials., J Cyst Fibros, Vol: 21, Pages: e204-e207

Journal article

Irving S, Bayfield K, Davies JC, Bush Aet al., 2022, Curvilinearity provides additional information to lung clearance index only in a minority of children with early cystic fibrosis lung disease, ERJ Open Research, Vol: 8, ISSN: 2312-0541

Curvilinearity, as calculated from multiple-breath washout, is abnormal in a small number of children with cystic fibrosis when other tests are still normal https://bit.ly/3p9QAV4.

Journal article

Davies J, Goss C, Fajac I, Jain R, Seibold W, Gupta A, Hsu M-C, Sutharsan S, Mall Met al., 2022, Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis: BALANCE–CF™ 1 – a randomised, Phase II study, European Respiratory Journal, Vol: 59, ISSN: 0903-1936

Background: Inhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated preclinical efficacy and safety already demonstrated in humans.Objective: We present results from BALANCE-CF™ 1, a Phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF.Results: Initially, 28 randomised subjects (n=14 each BI 1265162 200 µg BID, placebo BID) were assessed at an interim futility analysis. Compared with placebo, numerical changes of –0.8% (95%CI –6.6, 4.9) in ppFEV1 and +2.1 units (95%CI –2.4, 6.5) in LCI were observed in the active group, meeting a predefined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV1, 200 µg BID dose versus placebo) were not supportive of relevant clinical effect. LCI change was also not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in CFQ-R Respiratory Domain was observed in the 200 µg BID dose group versus placebo. BI 1265162 up to 200 µg BID was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers.Conclusion: BI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated.

Journal article

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

Request URL: http://wlsprd.imperial.ac.uk:80/respub/WEB-INF/jsp/search-html.jsp Request URI: /respub/WEB-INF/jsp/search-html.jsp Query String: respub-action=search.html&id=00303343&limit=30&person=true