Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).

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). 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). We searched the Cochrane CF Trials Register (28 November 2022), reference lists of relevant articles and online trials registries (3 December 2022). Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations. Two authors independently extracted data, assessed risk of bias and judged evidence certainty (GRADE); we contacted investigators for additional data. 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 (FEV1) % 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; I2 = 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; I2 = 0%; 2 studies, 739 participants); lumacaftor 400 mg (HR 0.61, 95% CI 0.49 to 0.76; I2 = 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 FEV1 % predicted with triple therapy (four studies each across all combinations). The absolute change in FEV1 % 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. 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 FEV1 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 FEV1 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.

Heneghan M ，Southern KW ，Murphy J ，Sinha IP ，Nevitt SJ ... -  《Cochrane Database of Systematic Reviews》

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del).

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 (found in up to 90% of people with CF (pwCF)) is the commonest CF-causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators. 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). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020. Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations. Two authors independently extracted data, assessed risk of bias and evidence quality (GRADE); we contacted investigators for additional data. We included 19 RCTs (2959 participants), lasting between 1 day and 24 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), six dual-therapy RCTs (1840 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and five triple-therapy RCTs (775 participants) (elexacaftor-tezacaftor-ivacaftor or VX-659-tezacaftor-ivacaftor); below we report only the data from elexacaftor-tezacaftor-ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes. Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard design (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 any important 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 with their variety and small number of participants (all F508del/F508del). Dual therapy Investigators reported no deaths (moderate- to high-quality evidence). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low-quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV1) % predicted improved with combination therapies compared to placebo by: 5.21% with once-daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence); 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence); and 6.80% with tezacaftor-ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence). More pwCF reported early transient breathlessness with lumacaftor-ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality 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; high-quality evidence). The tezacaftor-ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftor-ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high-quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV1 (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV1 (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor-ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor-tezacaftor-ivacaftor and placebo or control (moderate-quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol-defined pulmonary exacerbation with elexacaftor-tezacaftor-ivacaftor over 24 weeks (moderate-quality evidence). There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. 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. There is high-quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor-tezacaftor-ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.

Southern KW ，Murphy J ，Sinha IP ，Nevitt SJ ... -  《Cochrane Database of Systematic Reviews》

Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis.

Southern KW ，Patel S ，Sinha IP ，Nevitt SJ ... -  《Cochrane Database of Systematic Reviews》

Macrolide antibiotics (including azithromycin) for cystic fibrosis.

Cystic fibrosis (CF) is a life-limiting genetic condition, affecting over 90,000 people worldwide. CF affects several organs in the body, but airway damage has the most profound impact on quality of life (QoL) and survival. Causes of lower airway infection in people with CF are, most notably, Staphylococcus aureus in the early course of the disease and Pseudomonas aeruginosa at a later stage. Macrolide antibiotics, e.g. azithromycin and clarithromycin, are usually taken orally, have a broad spectrum of action against gram-positive (e.g. S aureus) and some gram-negative bacteria (e.g. Haemophilus influenzae), and may have a modifying role in diseases involving airway infection and inflammation such as CF. They are well-tolerated and relatively inexpensive, but widespread use has resulted in the emergence of resistant bacteria. This is an updated review. To assess the potential effects of macrolide antibiotics on clinical status in terms of benefit and harm in people with CF. If benefit was demonstrated, we aimed to assess the optimal type, dose and duration of macrolide therapy. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals, and abstract books of conference proceedings. We last searched the Group's Cystic Fibrosis Trials Register on 2 November 2022. We last searched the trial registries WHO ICTRP and clinicaltrials.gov on 9 November 2022. We contacted investigators known to work in the field, previous authors and pharmaceutical companies manufacturing macrolide antibiotics for unpublished or follow-up data, where possible. We included randomised controlled trials of macrolide antibiotics in adults and children with CF. We compared them to: placebo; another class of antibiotic; another macrolide antibiotic; or the same macrolide antibiotic at a different dose or type of administration. Two authors independently extracted data and assessed risk of bias. We assessed the certainty of evidence using GRADE. We included 14 studies (1467 participants) lasting 28 days to 36 months. All the studies assessed azithromycin: 11 compared oral azithromycin to placebo (1167 participants); one compared a high dose to a low dose (47 participants); one compared nebulised to oral azithromycin (45 participants); and one looked at weekly versus daily dose (208 participants). Oral azithromycin versus placebo There is a slight improvement in forced expiratory volume (FEV1 % predicted) in one second in the azithromycin group at up to six months compared to placebo (mean difference (MD) 3.97, 95% confidence interval (CI) 1.74 to 6.19; high-certainty evidence), although there is probably no difference at three months, (MD 2.70%, 95% CI -0.12 to 5.52), or 12 months (MD -0.13, 95% CI -4.96 to 4.70). Participants in the azithromycin group are probably at a decreased risk of pulmonary exacerbation with a longer time to exacerbation (hazard ratio (HR) 0.61, 95% CI 0.50 to 0.75; moderate-certainty evidence). Mild side effects were common, but there was no difference between groups (moderate-certainty evidence). There is no difference in hospital admissions at six months (odds ratio (OR) 0.61, 95% CI 0.36 to 1.04; high-certainty evidence), or in new acquisition of P aeruginosa at 12 months (HR 1.00, 95% CI 0.64 to 1.55; moderate-certainty evidence). High-dose versus low-dose azithromycin We are uncertain whether there is any difference in FEV1 % predicted at six months between the two groups (no data available) or in the rate of exacerbations per child per month (MD -0.05 (95% CI -0.20 to 0.10)); very low-certainty evidence for both outcomes. Only children were included in the study and the study did not report on any of our other clinically important outcomes. Nebulised azithromycin versus oral azithromycin We were unable to include any of the data into our analyses and have reported findings directly from the paper; we graded all evidence as being of very low certainty. The authors reported that there was a greater mean change in FEV1 % predicted at one month in the nebulised azithromycin group (P < 0.001). We are uncertain whether there was a change in P aeruginosa count. Weekly azithromycin versus daily azithromycin There is probably a lower mean change in FEV1 % predicted at six months in the weekly group compared to the daily group (MD -0.70, 95% CI -0.95 to -0.45) and probably also a longer period of time until first exacerbation in the weekly group (MD 17.30 days, 95% CI 4.32 days to 30.28 days). Gastrointestinal side effects are probably more common in the weekly group and there is likely no difference in admissions to hospital or QoL. We graded all evidence as moderate certainty. Azithromycin therapy is associated with a small but consistent improvement in respiratory function, a decreased risk of exacerbation and longer time to exacerbation at six months; but evidence for treatment efficacy beyond six months remains limited. Azithromycin appears to have a good safety profile (although a weekly dose was associated with more gastrointestinal side effects, which makes it less acceptable for long-term therapy), with a relatively minimal treatment burden for people with CF, and it is inexpensive. A wider concern may be the emergence of macrolide resistance reported in the most recent study which, combined with the lack of long-term data, means we do not feel that the current evidence is strong enough to support azithromycin therapy for all people with CF. Future research should report over longer time frames using validated tools and consistent reporting, to allow for easier synthesis of data. In particular, future trials should report important adverse events such as hearing impairment or liver disease. More data on the effects of azithromycin given in different ways and reporting on our primary outcomes would benefit decision-making on whether and how to give macrolide antibiotics. Finally, it is important to assess azithromycin therapy for people with CF who are established on the relatively new cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies which correct the underlying molecular defect associated with CF (none of the trials included in the review are relevant to this population).

Southern KW ，Solis-Moya A ，Kurz D ，Smith S ... -  《Cochrane Database of Systematic Reviews》

Vanzacaftor-tezacaftor-deutivacaftor versus elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials.

The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor-tezacaftor-deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor-tezacaftor-deutivacaftor compared with standard of care elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older. In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor-tezacaftor-ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively. Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening. They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period. All participants received matching placebo tablets to maintain the treatment blinding. Randomisation was done using an interactive web-response system and stratified by age, FEV1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103. The primary endpoint for both trials was absolute change in FEV1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor-tezacaftor-deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was -3·0 or higher). Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period. Safety was assessed in all participants who received at least one dose of study drug during the treatment period. These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete. In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=202) or vanzacaftor-tezacaftor-deutivacaftor (n=196). Median age was 31·0 years (IQR 22·6-38·5), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White. In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=289) or vanzacaftor-tezacaftor-deutivacaftor (n=284). Median age was 33·1 years (IQR 24·5-42·2), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White. The absolute change in least squares mean FEV1 % predicted from baseline through week 24 for Trial VX20-121-102 was 0·5 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·3 (0·3) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference of 0·2 percentage points [95% CI -0·7 to 1·1]; p<0·0001), and for Trial VX20-121-103, was 0·2 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·0 (0·2) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference 0·2 percentage points [95% CI -0·5 to 0·9]; p<0·0001). Most adverse events were mild or moderate, with the most common being infective pulmonary exacerbation (133 [28%] of 480 participants in the pooled vanzacaftor-tezacaftor-deutivacaftor group vs 158 [32%] of 491 in the pooled elexacaftor-tezacaftor-ivacaftor group), cough (108 [23%] vs 101 [21%]), COVID-19 (107 [22%] vs 127 [26%]), and nasopharyngitis (102 [21%] vs 95 [19%]). Vanzacaftor-tezacaftor-deutivacaftor is non-inferior to elexacaftor-tezacaftor-ivacaftor in terms of FEV1 % predicted, and is safe and well tolerated. Once daily dosing with vanzacaftor-tezacaftor-deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice daily regimen of the current standard of care. The restoration of CFTR function and the potential variants treated are also considerations that should be compared with currently available CFTR modulators. Vertex Pharmaceuticals.

Keating C ，Yonker LM ，Vermeulen F ，Prais D ，Linnemann RW ，Trimble A ，Kotsimbos T ，Mermis J ，Braun AT ，O'Carroll M ，Sutharsan S ，Ramsey B ，Mall MA ，Taylor-Cousar JL ，McKone EF ，Tullis E ，Floreth T ，Michelson P ，Sosnay PR ，Nair N ，Zahigian R ，Martin H ，Ahluwalia N ，Lam A ，Horsley A ... -  《-》