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<h2>Summary</h2><h3>Background</h3> The development of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (correctors and potentiators) emerged as a promising approach, aiming to restore CFTR protein function. A lack of head-to-head trials comparing CFTR modulators leaves uncertainty about the optimal treatment. We aimed to evaluate the comparative efficacy and safety of CFTR modulators for people with cystic fibrosis who have a phe508del mutation. <h3>Methods</h3> We conducted an extensive literature search for both published and unpublished randomized controlled trials in databases such as PubMed, EMBASE, Scopus, Ovid, Cochrane Central Register of Controlled Trials, and international trial registers from inception until May 21, 2025. We included studies that used any CFTR modulators (monotherapy or combination) for the treatment of children and adults with a confirmed diagnosis of cystic fibrosis with phe508del CFTR mutation. Two reviewers independently and in duplicate performed study selection, data extraction, and quality assessment. Our primary outcomes were efficacy (change in percent predicted forced expiratory volume (ppFEV₁), sweat chloride) and safety (frequency of serious adverse events). We performed a random effect bayesian network meta-analysis for each outcome using the gemtc and BUGSnet package in R. The confidence in the network meta-analysis framework was utilized to determine the certainty of evidence. The study protocol was registered with Prospective Register of Systematic Reviews (CRD42024505081). <h3>Findings</h3> Of the 3473 studies identified through our literature search, 29 studies involving 6450 patients examining 34 treatment combinations were included. For adults treated over 4–8 weeks, vanzacaftor 10 mg-tezacaftor 100 mg-deutivacaftor 150 mg combination therapy had a significant improvement over placebo in improving ppFEV₁ (MD: 15.9; 95% CrI: 7.2–24.2 [high certainty]) with a SUCRA of 92% suggesting the highest probability of effectiveness. Moreover, the vanzacaftor 20 mg-tezacaftor 100 mg-deutivacaftor 150 mg showed a significant reduction in sweat chloride levels (MD: −49.3 mmol/L; 95% CrI: −67.2 to −31.7 [high certainty]) and improved the CFQ-R scores (MD: 39; 95% CrI: 21.2–56.9; [high certainty]) when compared to placebo after 4–8 weeks of treatment. Our findings also highlighted that the triple combination therapies of vanzacaftor 20 mg-tezacaftor 100 mg-deutivacaftor 250 mg and elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg provided clinically meaningful improvements across all measured outcomes in adults treated for more than 8 weeks. Confidence in the estimates ranged from high to low, and safety analyses were limited by the low serious adverse event rates. <h3>Interpretation</h3> Our findings indicate that vanzacaftor-tezacaftor-deutivacaftor and elexacaftor-tezacaftor-deutivacaftor emerged as the most effective treatment options in adults. However, these results should be interpreted cautiously due to limited data and the low quality of existing evidence. <h3>Funding</h3> None.

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The triple combinations of CFTR modulators, elexacaftor-tezacaftor-ivacaftor and more recently vanzacaftor-tezacaftor-deutivacaftor, have transformed the clinical course of cystic fibrosis (CF). These drug combinations were identified for their ability to restore CFTR function in F508del epithelial cells, and their efficacy has been shown in large randomized clinical trials involving people with CF with at least one F508del variant. Approximately 20 % of pwCF worldwide have no F508del variant however. Recent data show that CFTR modulator triple combinations may be effective in a large subset of pwCF with non-F508del, often rare, CFTR variants. The purpose of this review is to explore the various strategies that may contribute to the identification of all patients with modulator-responsive CFTR variants in order to expand access to these transformative therapies.

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Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride and bicarbonate channel localized on the plasma membrane of epithelial cells. Over the last three decades, high-throughput screening assays have been extensively employed in identifying drugs that target specific defects arising from CFTR mutations. The two main categories of such compounds are potentiators, which enhance CFTR gating by increasing the channel’s open probability, and correctors, which improve CFTR protein folding and trafficking to the plasma membrane. In addition to these, other investigational molecules include amplifiers and stabilizers, which enhance the levels and the stability of CFTR on the cell surface, and read-through agents that promote the insertion of correct amino acids at premature termination codons. Currently, four CFTR modulators are clinically approved: the potentiator ivacaftor (VX-770), either as monotherapy or in combination with the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Among these, the triple combination VX-445/VX-661/VX-770 (marketed as Trikafta® in the US and Kaftrio® in Europe) has emerged as the most effective CFTR modulator therapy to date, demonstrating significant clinical benefits in phase III trials for patients with at least one F508del CFTR allele. Despite these advancements, the mechanisms of action and binding sites of these modulators on CFTR have only recently begun to be elucidated. A deeper understanding of these mechanisms could provide essential insights for developing more potent and effective modulators, particularly in combination therapies. This narrative review delves into the mechanism of action, binding sites, and combinatorial effects of approved and investigational CFTR modulators, highlighting ongoing efforts to broaden therapeutic options for individuals with CF.

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Objective: This analysis aimed to provide a mechanistic understanding and an evaluation of the clinical relevance of pharmacokinetic drug-drug interactions (DDIs) associated with drugs approved by the Food and Drug Administration in 2024. Methods: , and clinical data. Results: As objects, 11 drugs were identified as clinical substrates. Of these, 7 drugs were substrates of CYP3A, 3 of CYP2C9, one of CYP1A2, and one of CYP2C8, including the sensitive substrates vanzacaftor (CYP3A) and vorasidenib (CYP1A2). As precipitants, 6 drugs (acoramidis, cefepime/enmetazobactam, givinostat, lazertinib, mavorixafor, and resmetirom) were clinical inhibitors of CYP enzymes (2C8, 2C9, 2D6, 2E1, and 3A), with mavorixafor being a CYP2D6 strong inhibitor. Two drugs (elafibranor and tovorafenib) showed weak induction of CYP3A. Regarding transporter data, 3 drugs were substrates of transporters, including seladelpar (BCRP and OAT3), sulopenem (OAT3), and vadadustat (OAT1/3), and 8 drugs (arimoclomol, danicopan, givinostat, lazertinib, mavorixafor, resmetirom, vadadustat, and vazacaftor/tezacaftor/deutivacaftor) were inhibitors of transporters. All clinical DDIs with AUC changes ≥ 2-fold triggered labeling recommendations. Several DDIs with an AUC change <2 also had labeling recommendations, pertaining most often to the concomitant use of drugs with a narrow therapeutic index. Conclusions: Mechanistic DDI insights from newly approved therapies can be extrapolated to inform the management of commonly co-administered drugs, supporting a safer and more effective use of new drug products in the context of polypharmacy.

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Background 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.Methods 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, FEV 1 % 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 FEV 1 % 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 -30 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.Findings 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 310 years (IQR 226-385), 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 331 years (IQR 245-422), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White.The absolute change in least squares mean FEV 1 % predicted from baseline through week 24 for Trial VX20-121-102 was 05 (SE 03) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 03 (03) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference of 02 percentage points [95% CI -07 to 11]; p<00001), and for Trial VX20-121-103, was 02 (SE 03) percentage points in the vanzacaftortezacaftor-deutivacaftor group versus 00 (02) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least

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BACKGROUND: In phase 2 trials in people with cystic fibrosis aged 18 years and older, vanzacaftor-tezacaftor-deutivacaftor has been shown to be a safe and effective, once-daily cystic fibrosis transmembrane conductance regulator (CFTR) modulator. Restoring normal CFTR function early in life has the potential to prevent manifestations of cystic fibrosis. We aimed to evaluate the safety, tolerability, efficacy, and pharmacokinetics of vanzacaftor-tezacaftor-deutivacaftor in children with cystic fibrosis aged 6-11 years. METHODS: % predicted of 60% or higher, and stable cystic fibrosis as determined by investigators. Before study treatment, participants were either on stable elexacaftor-tezacaftor-ivacaftor for at least 28 days before screening or received the combination for a 4-week run-in period. Participants then received vanzacaftor-tezacaftor-deutivacaftor (<40 kg bodyweight: vanzacaftor 12 mg, tezacaftor 60 mg, and deutivacaftor 150 mg orally as three fixed-dose combination tablets once daily; ≥40 kg bodyweight: vanzacaftor 20 mg, tezacaftor 100 mg, and deutivacaftor 250 mg orally as two fixed-dose combination tablets once daily (manufactured by Patheon Pharmaceuticals, Cincinnati, OH, USA) from day 1 for 24 weeks. The primary endpoint was safety and tolerability, as measured by adverse events, vital signs, clinical laboratory values, electrocardiograms, and pulse oximetry. Endpoints were analysed in all participants who received at least one dose of vanzacaftor-tezacaftor-deutivacaftor. This trial is registered with ClinicalTrials.gov, NCT05422222, and evaluation of the 6-11-year-old cohort is complete. FINDINGS: Between Feb 6 and May 18, 2023, 83 children were screened, of whom five were not eligible, and 78 children aged 6-11 years received at least one dose of vanzacaftor-tezacaftor-deutivacaftor. Median age was 9·3 years (IQR 7·6-10·4), 34 (44%) of 78 participants were female, 44 (56%) were male, 71 (91%) were White, one (1%) was Black or African American, and one (1%) was of multiple races. The analysis for these data was completed on Dec 15, 2023. Median exposure of participants to vanzacaftor-tezacaftor-deutivacaftor was 168 days (IQR 166-170). 75 (96%) of 78 participants had adverse events, all of which were mild or moderate; the most common events were generally consistent with cystic fibrosis manifestations, including, cough (36 [46%]), pyrexia (16 [21%]), headache (14 [18%]), infective pulmonary exacerbation of cystic fibrosis (13 [17%]), and oropharyngeal pain (13 [17%]). Serious adverse events occurred in six (8%) participants (two had infective pulmonary exacerbation, one of whom also had failure to thrive; one participant each had adenovirus infection, constipation, pulmonary function test decreased, and cough), and one (1%) participant discontinued due to adverse events of cough and fatigue that were considered possibly related to study drug. INTERPRETATION: % predicted from elexacaftor-tezacaftor-ivacaftor baseline with further improved CFTR function. Improvements in CFTR function compared with baseline elexacaftor-tezacaftor-ivacaftor values demonstrate the potential opportunity to restore normal physiology early and prevent development or progression of cystic fibrosis. Nearly all participants had sweat chloride below the diagnostic threshold for cytstic fibrosis (<60 mmol/L) and more than half had normal levels (<30 mmol/L). Additional long-term data in children with cystic fibrosis are being collected in an open-label extension study to demonstrate clinical benefits and safety. These findings will inform health-care providers and people with cystic fibrosis regarding the benefits of early initiation of CFTR modulators. FUNDING: Vertex Pharmaceuticals.

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Background: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Modulator therapies have the ability to improve CFTR function in CF patients, but despite the clear evidence of benefits regarding CFTR modulator therapy, including improved lung function, the reduced rate of exacerbations, and an overall improved quality of life, studies focusing on the reduction rates of P. aeruginosa infections during modulator therapy expressed the need for future research on this topic. Objective: This study aimed to evaluate the impact of CFTR modulator therapies on the prevalence, density, and persistence of P. aeruginosa infection in CF patients and to explore the mechanisms involved. Methods: A systematic literature review was performed by searching five major databases (PubMed, Cochrane Library, Scopus, Google Scholar, and Web of Science), and 21 relevant articles investigating the link between CFTR therapy and P. aeruginosa infections were selected following the PRISMA guidelines. Results: The data indicated that Ivacaftor and the combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) can reduce total bacterial load and markers of systemic inflammation. However, clonal lines of P. aeruginosa persist in most cases, and complete eradication is rare, mainly due to biofilm formation and antimicrobial resistance. Conclusions: Although CFTR-modulating therapies help to improve clinical condition and reduce inflammation, they do not consistently lead to the elimination of P. aeruginosa.

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