PMID- 37983082
OWN - NLM
STAT- MEDLINE
DCOM- 20231127
LR  - 20231201
IS  - 1469-493X (Electronic)
IS  - 1361-6137 (Linking)
VI  - 11
IP  - 11
DP  - 2023 Nov 20
TI  - Corrector therapies (with or without potentiators) for people with cystic 
      fibrosis with class II CFTR gene variants (most commonly F508del).
PG  - CD010966
LID - 10.1002/14651858.CD010966.pub4 [doi]
LID - CD010966
AB  - BACKGROUND: Cystic fibrosis (CF) is a common life-shortening genetic condition 
      caused by a variant in the cystic fibrosis transmembrane conductance regulator 
      (CFTR) protein. A class II CFTR variant F508del is the commonest CF-causing 
      variant (found in up to 90% of people with CF (pwCF)). The F508del variant lacks 
      meaningful CFTR function - faulty protein is degraded before reaching the cell 
      membrane, where it needs to be to effect transepithelial salt transport. 
      Corrective therapy could benefit many pwCF. This review evaluates single 
      correctors (monotherapy) and any combination of correctors (most commonly 
      lumacaftor, tezacaftor, elexacaftor, VX-659, VX-440 or VX-152) and a potentiator 
      (e.g. ivacaftor) (dual and triple therapies). OBJECTIVES: To evaluate the effects 
      of CFTR correctors (with or without potentiators) on clinically important 
      benefits and harms in pwCF of any age with class II CFTR mutations (most commonly 
      F508del). SEARCH METHODS: We searched the Cochrane CF Trials Register (28 
      November 2022), reference lists of relevant articles and online trials registries 
      (3 December 2022). SELECTION CRITERIA: Randomised controlled trials (RCTs) 
      (parallel design) comparing CFTR correctors to control in pwCF with class II 
      mutations. DATA COLLECTION AND ANALYSIS: Two authors independently extracted 
      data, assessed risk of bias and judged evidence certainty (GRADE); we contacted 
      investigators for additional data. MAIN RESULTS: We included 34 RCTs (4781 
      participants), lasting between 1 day and 48 weeks; an extension of two 
      lumacaftor-ivacaftor studies provided additional 96-week safety data (1029 
      participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, 
      lumacaftor, cavosonstat and FDL169), 16 dual-therapy RCTs (2627 participants) 
      (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and 11 triple-therapy RCTs (1804 
      participants) (elexacaftor-tezacaftor-ivacaftor/deutivacaftor; 
      VX-659-tezacaftor-ivacaftor/deutivacaftor; VX-440-tezacaftor-ivacaftor; 
      VX-152-tezacaftor-ivacaftor). Participants in 21 RCTs had the genotype 
      F508del/F508del, in seven RCTs they had F508del/minimal function (MF), in one RCT 
      F508del/gating genotypes, in one RCT either F508del/F508del genotypes or 
      F508del/residual function genotypes, in one RCT either F508del/gating or 
      F508del/residual function genotypes, and in three RCTs either F508del/F508del 
      genotypes or F508del/MF genotypes. Risk of bias judgements varied across 
      different comparisons. Results from 16 RCTs may not be applicable to all pwCF due 
      to age limits (e.g. adults only) or non-standard designs (converting from 
      monotherapy to combination therapy). Monotherapy Investigators reported no deaths 
      or clinically relevant improvements in quality of life (QoL). There was 
      insufficient evidence to determine effects on lung function. No 
      placebo-controlled monotherapy RCT demonstrated differences in mild, moderate or 
      severe adverse effects (AEs); the clinical relevance of these events is difficult 
      to assess due to their variety and few participants (all F508del/F508del). Dual 
      therapy In a tezacaftor-ivacaftor group there was one death (deemed unrelated to 
      the study drug). QoL scores (respiratory domain) favoured both 
      lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all 
      time points (moderate-certainty evidence). At six months, relative change in 
      forced expiratory volume in one second (FEV(1)) % predicted improved with all 
      dual combination therapies compared to placebo (high- to moderate-certainty 
      evidence). More pwCF reported early transient breathlessness with 
      lumacaftor-ivacaftor (odds ratio (OR) 2.05, 99% confidence interval (CI) 1.10 to 
      3.83; I(2) = 0%; 2 studies, 739 participants; high-certainty evidence). Over 120 
      weeks (initial study period and follow-up), systolic blood pressure rose by 5.1 
      mmHg and diastolic blood pressure by 4.1 mmHg with twice-daily 400 mg 
      lumacaftor-ivacaftor (80 participants). The tezacaftor-ivacaftor RCTs did not 
      report these adverse effects. Pulmonary exacerbation rates decreased in pwCF 
      receiving additional therapies to ivacaftor compared to placebo (all 
      moderate-certainty evidence): lumacaftor 600 mg (hazard ratio (HR) 0.70, 95% CI 
      0.57 to 0.87; I(2) = 0%; 2 studies, 739 participants); lumacaftor 400 mg (HR 
      0.61, 95% CI 0.49 to 0.76; I(2) = 0%; 2 studies, 740 participants); and 
      tezacaftor (HR 0.64, 95% CI 0.46 to 0.89; 1 study, 506 participants). Triple 
      therapy No study reported any deaths (high-certainty evidence). All other 
      evidence was low- to moderate-certainty. QoL respiratory domain scores probably 
      improved with triple therapy compared to control at six months (six studies). 
      There was probably a greater relative and absolute change in FEV(1) % predicted 
      with triple therapy (four studies each across all combinations). The absolute 
      change in FEV(1) % predicted was probably greater for F508del/MF participants 
      taking elexacaftor-tezacaftor-ivacaftor compared to placebo (mean difference 
      14.30, 95% CI 12.76 to 15.84; 1 study, 403 participants; moderate-certainty 
      evidence), with similar results for other drug combinations and genotypes. There 
      was little or no difference in adverse events between triple therapy and control 
      (10 studies). No study reported time to next pulmonary exacerbation, but fewer 
      F508del/F508del participants experienced a pulmonary exacerbation with 
      elexacaftor-tezacaftor-ivacaftor at four weeks (OR 0.17, 99% CI 0.06 to 0.45; 1 
      study, 175 participants) and 24 weeks (OR 0.29, 95% CI 0.14 to 0.60; 1 study, 405 
      participants); similar results were seen across other triple therapy and genotype 
      combinations. AUTHORS' CONCLUSIONS: There is insufficient evidence of clinically 
      important effects from corrector monotherapy in pwCF with F508del/F508del. 
      Additional data in this review reduced the evidence for efficacy of dual therapy; 
      these agents can no longer be considered as standard therapy. Their use may be 
      appropriate in exceptional circumstances (e.g. if triple therapy is not tolerated 
      or due to age). Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) 
      result in similar small improvements in QoL and respiratory function with lower 
      pulmonary exacerbation rates. While the effect sizes for QoL and FEV(1) still 
      favour treatment, they have reduced compared to our previous findings. 
      Lumacaftor-ivacaftor was associated with an increase in early transient shortness 
      of breath and longer-term increases in blood pressure (not observed for 
      tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although 
      data are lacking in children under 12 years. In this population, 
      lumacaftor-ivacaftor had an important impact on respiratory function with no 
      apparent immediate safety concerns, but this should be balanced against the blood 
      pressure increase and shortness of breath seen in longer-term adult data when 
      considering lumacaftor-ivacaftor. Data from triple therapy trials demonstrate 
      improvements in several key outcomes, including FEV(1) and QoL. There is probably 
      little or no difference in adverse events for triple therapy 
      (elexacaftor-tezacaftor-ivacaftor/deutivacaftor; 
      VX-659-tezacaftor-ivacaftor/deutivacaftor; VX-440-tezacaftor-ivacaftor; 
      VX-152-tezacaftor-ivacaftor) in pwCF with one or two F508del variants aged 12 
      years or older (moderate-certainty evidence). Further RCTs are required in 
      children under 12 years and those with more severe lung disease.
CI  - Copyright (c) 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
FAU - Heneghan, Matthew
AU  - Heneghan M
AD  - Department of Women's and Children's Health, University of Liverpool, Liverpool, 
      UK.
FAU - Southern, Kevin W
AU  - Southern KW
AD  - Department of Women's and Children's Health, University of Liverpool, Liverpool, 
      UK.
FAU - Murphy, Jared
AU  - Murphy J
AD  - Leighton Hospital, Crewe, UK.
FAU - Sinha, Ian P
AU  - Sinha IP
AD  - Department of Women's and Children's Health, University of Liverpool, Liverpool, 
      UK.
FAU - Nevitt, Sarah J
AU  - Nevitt SJ
AD  - Department of Health Data Science, University of Liverpool, Liverpool, UK.
AD  - Centre for Reviews and Dissemination, University of York, York, UK.
LA  - eng
SI  - ClinicalTrials.gov/NCT01225211
SI  - ClinicalTrials.gov/NCT00865904
SI  - ClinicalTrials.gov/NCT03029455
SI  - ClinicalTrials.gov/NCT03224351
SI  - ClinicalTrials.gov/NCT03559062
SI  - ClinicalTrials.gov/NCT01746784
SI  - ClinicalTrials.gov/NCT03093714
SI  - ClinicalTrials.gov/NCT03227471
SI  - ClinicalTrials.gov/NCT00004428
SI  - ClinicalTrials.gov/NCT03525444
SI  - ClinicalTrials.gov/NCT01931839
SI  - ClinicalTrials.gov/NCT02514473
SI  - ClinicalTrials.gov/NCT00590538
SI  - ClinicalTrials.gov/NCT04105972
SI  - ClinicalTrials.gov/NCT01807923
SI  - ClinicalTrials.gov/NCT01807949
SI  - ClinicalTrials.gov/NCT00016744
SI  - ClinicalTrials.gov/NCT01897233
SI  - ClinicalTrials.gov/NCT00742092
SI  - ClinicalTrials.gov/NCT00945347
SI  - ClinicalTrials.gov/NCT01899105
SI  - ClinicalTrials.gov/NCT03447262
SI  - ClinicalTrials.gov/NCT03525574
SI  - ClinicalTrials.gov/NCT03537651
SI  - ClinicalTrials.gov/NCT03601637
SI  - ClinicalTrials.gov/NCT03633526
SI  - ClinicalTrials.gov/NCT03691779
SI  - ClinicalTrials.gov/NCT04043806
SI  - ClinicalTrials.gov/NCT04058366
SI  - ClinicalTrials.gov/NCT04183790
SI  - ClinicalTrials.gov/NCT04235140
SI  - ClinicalTrials.gov/NCT04362761
SI  - ClinicalTrials.gov/NCT04537793
SI  - ClinicalTrials.gov/NCT04545515
SI  - ClinicalTrials.gov/NCT02392234
SI  - ClinicalTrials.gov/NCT03045523
SI  - ClinicalTrials.gov/NCT05033080
SI  - ClinicalTrials.gov/NCT05076149
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PT  - Systematic Review
DEP - 20231120
PL  - England
TA  - Cochrane Database Syst Rev
JT  - The Cochrane database of systematic reviews
JID - 100909747
RN  - EGP8L81APK (lumacaftor)
RN  - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
RN  - 1Y740ILL1Z (ivacaftor)
RN  - 9A4381183B (VX)
RN  - 0 (Aminophenols)
RN  - 0 (CFTR protein, human)
SB  - IM
UOF - Cochrane Database Syst Rev. 2020 Dec 17;12:CD010966. PMID: 33331662
MH  - Adult
MH  - Child
MH  - Humans
MH  - *Cystic Fibrosis/drug therapy/genetics
MH  - Cystic Fibrosis Transmembrane Conductance Regulator/genetics
MH  - Aminophenols/adverse effects
MH  - Dyspnea/drug therapy
MH  - Mutation
PMC - PMC10659105
COIS- Matthew Heneghan declares no potential conflict of interest. Professor Kevin 
      Southern declares no potential conflict of interest. Dr Jared Murphy declares no 
      potential conflict of interest. Dr Ian Sinha is in receipt of a NIHR HTA grant 
      for paediatric asthma and is a member of the NICE asthma committee; however, 
      neither of these are related to cystic fibrosis or this review and thus do not 
      constitute a potential conflict of interest. Dr Sarah J Nevitt declares no 
      potential conflict of interest.
EDAT- 2023/11/20 13:43
MHDA- 2023/11/27 12:43
PMCR- 2024/11/20
CRDT- 2023/11/20 12:03
PHST- 2024/11/20 00:00 [pmc-release]
PHST- 2023/11/27 12:43 [medline]
PHST- 2023/11/20 13:43 [pubmed]
PHST- 2023/11/20 12:03 [entrez]
AID - CD010966.pub4 [pii]
AID - 10.1002/14651858.CD010966.pub4 [doi]
PST - epublish
SO  - Cochrane Database Syst Rev. 2023 Nov 20;11(11):CD010966. doi: 
      10.1002/14651858.CD010966.pub4.