Cystic fibrosis (CF) care has advanced rapidly, yet diagnosis and inclusion in patient registries remain severely limited in low- and middle-income countries (LMICs). Barriers include restricted newborn screening, limited availability of sweat chloride testing, and underrepresentation of non-European CFTR variants in standard panels. Sparse registries further impede epidemiological insight and resource planning. Also, access to comprehensive CF care remains a major challenge in LMICs, where limitations in basic therapies, including pancreatic enzyme replacement, airway clearance strategies, and infection control, continue to result in markedly reduced life expectancy. Within this context, access to CFTR modulators (CFTRm) represents an additional and critical barrier, constrained by prohibitive costs, restricted variant eligibility, and few tiered pricing mechanisms. Patient-derived intestinal organoids (PDIOs) offer a versatile platform to help address some of these gaps. PDIOs enable functional diagnosis, genotype-phenotype characterization, and renewable material for comprehensive CFTR sequencing and drug testing, including for rare variants. While implementation in LMICs is challenging, targeted mentorship, collaborative screening pipelines, and sustained funding could expand access. Integrating PDIOs into CF care could help bridge some global disparities, but success will require coordinated scientific, clinical, and policy efforts.

Abstract Background The consequences of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein dysfunction or absence begin during fetal development, with pancreatic, intestinal, hepatobiliary, and reproductive manifestations evident at birth. The advent of CFTR modulator therapies (CFTR modulator)—most notably elexacaftor/tezacaftor/ivacaftor (ETI), approved for children and adults with CF who carry responsive variants, and the recently approved vanzacaftor/tezacaftor/deutivacaftor (VTD), currently indicated for older pediatric and adult populations—has transformed long‐term health outcomes and substantially increased the number of pregnancies among individuals with CF. As maternal use of CFTR modulator during pregnancy has become more common, early observational studies and case series suggest potential fetal benefit for fetuses affected by CF, particularly with respect to inspissated meconium obstructing the terminal ileum, potentially reducing the need for postnatal surgical intervention. Methods To synthesize current evidence regarding maternal, fetal, and neonatal outcomes following prenatal CFTR modulator exposure; describe the rationale and early experience with intentional prenatal therapy for affected fetuses; and outline practical counseling and monitoring strategies. Evidence was drawn from clinical pregnancy cohorts, pharmacokinetic studies, case series treating fetal meconium ileus, mechanistic fetal and animal models, and expert consensus documents, including the PRenatal MOdulator Treatment to PrEvent CF ComplicaTions (PROTECT) Workshop summary. Both maternal‐ and fetal‐indication uses of CFTR modulator were evaluated. Results Continuation of ETI during pregnancy has been associated with stabilization of maternal pulmonary function and nutritional status and has not been linked to an increased risk of congenital anomalies, preterm delivery, or miscarriage in available observational cohorts. Both ETI and VTD cross the placenta and achieve fetal drug exposure at concentrations expected to be pharmacologically active. Case series in fetuses with CF describe improvement or resolution of prenatal bowel abnormalities indicative of evolving meconium ileus, with suggestive evidence of preservation of exocrine pancreatic function and the male reproductive tract in limited cases. Cataracts have rarely been reported, are typically small and not visually significant, and have not been consistently observed across cohorts. Prenatal exposure may result in falsely negative newborn screening results. However, the optimal timing and duration of prenatal modulator initiation for fetal benefit, fetal pharmacokinetics and pharmacodynamics, and long‐term neurodevelopmental outcomes remain uncertain. Conclusion Prenatal CFTR modulator therapy shows promise as the first fetal therapy for CF. While continuation for maternal CF is supported by available evidence (although not label‐approved), fetal‐indication use remains investigational. Robust counseling, interdisciplinary coordination, and structured monitoring are essential, alongside ongoing research to define therapeutic windows, safety, and long‐term outcomes.

Sweat chloride concentrations are elevated in people with cystic fibrosis due to the absence or dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial cell membrane ion channel. For many people with cystic fibrosis with responsive variants and drug access, treatment with CFTR modulators increases CFTR function, reduces sweat chloride concentrations, and improves lung health and quality of life. In clinical trials, average sweat chloride reduction is correlated with clinical efficacy across different modulators and study populations. Thus, for people with cystic fibrosis, larger reductions and lower absolute sweat chloride concentrations are often presumed to indicate greater clinical response and better prognosis. However, although true at the population level, at the individual level, a relationship between sweat chloride and clinical outcomes has not been definitively shown. This Personal View highlights how sweat chloride quantification informs our understanding of CFTR modulator therapeutic response while cautioning its ability to fully predict individual clinical response.

RATIONALE:Elexacaftor/tezacaftor/ivacaftor, a CF transmembrane conductance regulator (CFTR) modulator, stabilizes and restores F508del-CFTR function, which is the most common CFTR variant. In multiple clinical and real-world studies, elexacaftor/tezacaftor/ivacaftor was shown to be safe and highly effective in people with CF carrying at least one F508del-CFTR (∼80% of people with CF). OBJECTIVES:To characterize the response of rare, non-F508del CFTR variants to elexacaftor/tezacaftor/ivacaftor in vitro, and in clinical and real-world studies. METHODS:We engineered Fischer rat thyroid (FRT) cells each of which express 1 of 620 rare exonic CFTR variants present in public databases and evaluated their in vitro response to elexacaftor/tezacaftor/ivacaftor. We evaluated efficacy and safety of elexacaftor/tezacaftor/ivacaftor in a 24-week randomized, placebo-controlled, Phase 3 trial (445-124) in participants with 1 of 18 rare variants and no F508del and in a real-world study (CFD-016) in people carrying 82 rare variants and no F508del. MEASUREMENTS AND MAIN RESULTS:In FRT cells, 518 of 620 (84%) rare variants responded to elexacaftor/tezacaftor/ivacaftor. In 445-124, mean improvements were seen in the primary endpoint of percent predicted FEV1 (9.2 percentage points [95% CI: 7.2, 11.3; P < .0001]), and secondary endpoints of sweat chloride (-28.3 mmol/L [95% CI: -32.1, -24.5 mmol/L; P < .0001]) and CFQ-R RD (19.5 points [95% CI: 15.5, 23.5; P < .0001]). In CFD-016, improvements in lung function were seen after treatment initiation. CONCLUSIONS:In vitro, clinical, and real-world data support elexacaftor/tezacaftor/ivacaftor treatment in people carrying a range of CFTR variants and no F508del. The response of 84% of rare CFTR variants that produce protein to protein-stabilizing therapy suggests variants in many regions of the protein causes disease via protein destabilization.

OBJECTIVE:We assessed incidence of liver cirrhosis, risk factors for developing cirrhosis, and if there is an association between hormonal contraception (HC) use and liver cirrhosis among reproductive-aged females with cystic fibrosis (CF). STUDY DESIGN:Between January 2021 and April 2022, we recruited reproductive-aged females with CF to complete a questionnaire. We linked their responses to the Cystic Fibrosis Foundation Patient Registry (CFFPR) to examine potential risk factors for incident liver cirrhosis and its association with time-varying HC using survival analysis. RESULTS:Among 551 persons with CFFPR survey and registry data, 8 had cirrhosis at first available registry report and 3 were excluded for other reasons. Of the 540 remaining participants, 250 (46.3%) were F508 homozygous, 437 (80.9%) were using modulators, and 28 (5.2%) had new onset cirrhosis. Genotype and modulator use were not associated with cirrhosis incidence (adjusted hazard ratios (aHR) 0.57 with 95% confidence interval (CI) 0.15-2.22 and 0.86 with CI 0.24-3.11, respectively). Over all 5146 years of reporting including a median of 12 years per person, 64.9% of years involved reported non-HC, 23.6% combined HC, and 11.5% progestin-only HC. HC use was not associated with cirrhosis incidence (aHR 0.68 with CI 0.25-1.86 for combined HC and 0.57 with CI 0.13-2.49 for progestin-only HC). CONCLUSION:In our observational cohort, the incidence of cirrhosis was 5.2%. HC use is not associated with liver cirrhosis. Future research should explore the risk factors in CF for developing liver cirrhosis and its relation with HC use. IMPLICATIONS:In females with cystic fibrosis, hormonal contraception is not associated with liver cirrhosis.

RATIONALE:Inflammation is a hallmark of cystic fibrosis (CF) and associated with bronchiectasis and lung disease progression. The effects of elexacaftor/tezacaftor/ivacaftor (ETI), a CF transmembrane conductance regulator modulator therapy, on inflammation remain incompletely understood. OBJECTIVES:Investigate 2-year changes in airway and systemic inflammation in adolescents and adults with CF clinically prescribed ETI and the relationships between inflammatory changes and clinical outcomes. METHODS:PROMISE is a prospective, multicenter, observational study in people with CF aged ≥12 years. Assessments of sputum and blood inflammatory markers occurred before and through 24-30 months of ETI therapy in participants who enrolled in the PROMISE-Inflammation substudy. Changes in inflammation were tested with mixed-effects models. Relationships between inflammatory markers and clinical outcomes were examined using Spearman correlations. RESULTS:The study cohort comprised 223 participants. ETI was associated with sustained reductions in sputum neutrophil elastase activity, calprotectin, IL-1β, and IL-8, increases in sputum IL-6 through 24/30 months of therapy, and reductions in circulating high-sensitivity CRP (hsCRP) through 12/18 months of therapy. Sputum NE activity reductions correlated with percent predicted forced expiratory volume in 1 second (ppFEV1) and respiratory symptom score improvements at 24/30 months post-ETI. Sputum IL-6 increases correlated with ppFEV1 improvements. Serum hsCRP reductions were associated with ppFEV1 and respiratory symptoms improvements at 12/18 months post-ETI, and circulating calprotectin reductions were associated with respiratory symptom improvements. CONCLUSIONS:Airway and systemic inflammation decreases through 2.5 years of ETI therapy in adolescents and adults with CF. Reductions in inflammation correlate with clinical improvements. These changes in inflammation represent a disease-modifying benefit of this transformative therapy. CLINICAL TRIALS REGISTRATION:NCT04038047.

BACKGROUND:Cystic fibrosis (CF) transmembrane conductance regulator modulators improve lung function, however, effects on cough frequency, physical activity, and sleep have not been assessed in clinical studies. METHODS:After a 12-week, phase 4 pilot feasibility study, we conducted a 13-week, phase 3b, open-label study in participants with CF aged ≥12 years previously naïve to elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) to assess the effects of ELX/TEZ/IVA on cough frequency, physical activity, and sleep using wearable cough monitors and actigraphy sensors (VX-445-126). RESULTS:In study VX-445-126 (N = 81), participants treated with ELX/TEZ/IVA experienced a 91.7% reduction in cough frequency (cough events per day) (95% CI, 89.2% to 93.6%; 241.3 coughs per day at baseline to 20.3 coughs per day) from baseline at the average of week 8 through week 12 (primary endpoint). Total steps per day (secondary endpoint) increased by 638 (95% CI, 298 to 977) at the average of week 8 through week 12. Time spent above sedentary physical activity per day, time spent on moderate-to-vigorous physical activity per day, and total mean activity count per day all increased from baseline at the average of week 8 through week 12 (other efficacy endpoints). While no changes in sleep activity patterns were observed in actigraphy data, patient-reported measures of sleep quality improved (other efficacy endpoints). ELX/TEZ/IVA was generally safe and well-tolerated. CONCLUSIONS:ELX/TEZ/IVA treatment led to a > 90% reduction in daily cough frequency, with sustained improvements in physical activity and better perceptions of sleep quality.

Cystic fibrosis (CF) is an autosomal recessive disease caused by variants in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Delivery of a functional CFTR transgene to airway epithelial cells (AEC) offers the potential to provide durable restoration of normal CFTR function. Adeno-associated virus (AAV) vectors are the leading platform for the delivery of in vivo gene therapy; however, wild-type AAV vectors exhibit a limited capacity to transduce airway cells and evade pre-existing human neutralizing antibodies (NAb). We therefore employed a directed evolution platform to invent a novel AAV capsid (A101) with the capacity to efficiently transduce AECs, including in the presence of NAbs, following aerosolized administration to nonhuman primates (NHP). We then engineered 4D-710, a gene therapy comprising the A101 vector and a CFTR transgene with a partial deletion in the regulatory domain (CFTRΔR) to facilitate vector packaging. 4D-710 exhibited efficient transduction of human bronchial epithelial (HBE) cell air-liquid interface (ALI) cultures in vitro and robust functional activity in CF HBE ALI cultures. Aerosolized administration of 4D-710 to NHPs was well tolerated and resulted in dose-dependent transgene expression and increased CFTR protein in diverse AEC types compared with vehicle controls. No significant differences in CFTRΔR mRNA levels were observed in lung samples from NHPs with pre-existing serum anticapsid NAbs compared with NAb-negative NHPs. These findings demonstrate the tolerability and feasibility of A101-mediated transgene delivery and expression in primate airways. A clinical trial evaluating aerosol delivery of 4D-710 in adults with CF (NCT05248230) is underway.

We reviewed the contemporary use of cystic fibrosis transmembrane conductance regulator modulator therapy (CFTRm) during pregnancy, including animal data and published human cases involving unaffected pregnant CF (heterozygote) carriers with a prenatal diagnosis of fetal cystic fibrosis (CF). In pregnant individuals with CF, continuation of CFTRm is associated with preserved maternal pulmonary function comparable to nonpregnant peers and favorable obstetrical outcomes. CFTRm crosses the placenta readily, appears at low levels in breastmilk, and concerns for cataracts from animal models have not been translated clinically. Among 20 reported fetal cases treated prenatally with CFTRm in unaffected carrier individuals, ultrasound findings of meconium ileus (MI) resolved in approximately two-thirds of cases. Several reports describe preserved or borderline exocrine pancreatic function and lower-than-expected sweat chloride levels. Nonresolution of MI was more common when therapy began later in gestation or in the presence of complications such as meconium peritonitis. MI was diagnosed at a mean gestational age of 24 weeks, while treatment began at 31 weeks, reflecting delays in both diagnosis and insurance coverage. The CF Foundation PROTECT Workshop identified key knowledge gaps, including optimal timing of prenatal diagnosis and therapy, fetal pharmacokinetics, neurodevelopmental safety, minimal effective dosing, and prevention of postnatal withdrawal.

OBJECTIVES:Evaluate if early therapeutic initiation may begin ameliorating olfactory dysfunction in addition to chronic rhinosinusitis in young children with cystic fibrosis. METHODS:Participants ≤ 10 years were enrolled across six U.S. cystic fibrosis centers (May 2023-December 2024). Data were collected at baseline and one year following therapeutic initiation. Mixed-effects models were adjusted for age, sex, and nasal steroid use. MEASUREMENTS:Sinus magnetic resonance imaging analysis included sinus volume, sinus opacification, olfactory bulb volume, olfactory cleft opacification, Lund-Mackay, and CRS-MRI scores. Psychophysical olfactory testing and quality of life assessments included the Pediatric Smell Wheel, Brief Questionnaire of Olfactory Disorders, EuroQol-5-Dimensions-Youth, and Sinonasal-5.Main Results: 31 participants (mean age 4.8 years) enrolled, 27 initiated treatment, and 26 completed follow-up (mean treatment duration 1.0 years). Following therapy, three olfactory measures improved: odor identification scores increased by 1.3 points (p = 0.03), olfactory bulb volume increased by 7.4mm3 (p = 0.02), and olfactory cleft opacification decreased by 14.4% (p = 0.004). Sinus opacification, Lund-Mackay, and CRS-MRI scores improved by 25.5% (p = 0.001), 5.0 points (p = 0.002) and 7.0 points (p = 0.005), respectively. Quality of life scores remained at near-normal levels. CONCLUSIONS:Children receiving therapy demonstrated improvements in olfactory function, olfactory structure, and sinonasal opacification. Predominantly stable, near-normal quality of life metrics preliminarily suggest symptom-based instruments alone may be insufficient to identify sinonasal disease and treatment response at this age.

BACKGROUND:Chronic rhinosinusitis (CRS) and olfactory dysfunction (OD) are highly prevalent among people with cystic fibrosis (PwCF) and negatively impact quality of life. The 40-item Smell Identification Test (SIT) is widely used to assess psychophysical olfaction, but a CF-specific minimal clinically important difference (MCID) has not been established. This study aimed to determine the SIT MCID in PwCF treated with elexacaftor/tezacaftor/ivacaftor (ETI) and/or endoscopic sinus surgery (ESS). METHODS:Data from three prospective, multi-institutional observational studies were pooled. Participants were ≥12 years old with confirmed CF and CRS who completed SIT at baseline and ≥1 follow-up (3, 6, 9, 12, or 24 months). Distribution-based MCIDs were calculated using four methods: standard error of measurement (SEM), minimal detectable change (MDC = 1.96 × SEM), 0.5 × baseline standard deviation (SD), and 0.5 × SD of change scores (ΔSD). RESULTS:A total of 122 participants were enrolled (mean age 32.9 years, 54% female). Of these, 99 contributed follow-up SIT scores (79 ETI, 20 ESS). SIT scores remained stable with ETI, with a small but statistically significant decline at 6 months (-1.4, p = 0.02). ESS was associated with mean gains of 3.1-4.5 points at early follow-up, though these did not reach significance. Pooled distribution-based MCID estimates ranged from 2 to 4 points, with an overall threshold of 3.1 (95% CI: 2.1-4.1). CONCLUSIONS:This CF-specific SIT threshold provides a clinically interpretable cut-off for assessing olfaction. These findings establish a foundation for future work and highlight the importance of developing disease-specific MCIDs to guide clinical care and research.

RATIONALE:Elexacaftor-tezacaftor-ivacaftor (ETI) broadly improves outcomes in cystic fibrosis (CF). Cystic fibrosis transmembrane conductance regulator (CFTR) correction by ETI is incomplete, and patients with established disease continue to experience infection. We hypothesized that CFTR restoration by ETI would modify T cell memory, providing a basis for improved infectious outcomes after treatment. OBJECTIVES:To evaluate ETI modification of lymphocyte signatures using transcriptomics and metabolomics, in blood samples taken from adults with CF (awCF). METHODS AND MAIN RESULTS:Circulating CD3 + T cells from awCF (n = 18) before and after ETI initiation were evaluated by CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by sequencing). Single cell data profiled multiple T cell populations, including naive, memory, and effector states, with the most extensive changes occurring in CD4 + T populations. Simultaneous plasma metabolomic measurements were analyzed in association with CD4 + T cell metabolic gene signatures. The relationships between clinical outcomes, cell-specific gene expression and metabolomics were evaluated using generalized linear mixed models. The effect of reduced CFTR in lymphocytes was evaluated in vitro utilizing CRISPR/Cas9-mediated CFTR knockdown in primary human lymphocyte cultures, as well in splenocytes harvested from CFTR knockout mice. CONCLUSIONS:We reveal that altered metabolism occurs within the CD4 + T memory compartment following CFTR modulation, identifying multiple previously unrecognized changes in memory functions. Memory T cell metabolic switches are highly related to reduction in hospitalizations after treatment. Adaptive immune memory in awCF after modulator therapy is highly associated with improved outcomes from CF pulmonary infections, with variation seen in individuals experiencing lesser benefit after modulators.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have transformed the management of cystic fibrosis; however, substantial interindividual variability in clinical response persists, even among people with identical CFTR genotypes. This variability challenges clinicians, regulators, and researchers in defining treatment success and optimising long-term outcomes. We synthesise evidence from clinical trials, real-world cohorts, and mechanistic studies to examine the contributors to heterogeneity in response to CFTR modulators, with a focus on triple therapy (elexacaftor-tezacaftor-ivacaftor). Treatment response varies across lung function, pulmonary exacerbations, sweat chloride, nutritional status, and quality of life, and is influenced by different factors, including disease stage, CFTR genotype and complex alleles, pharmacokinetic variability, adherence, side-effects, environmental exposures, and host modifiers. No single metric adequately captures individual response. Binary classifications of responder and non-responder are therefore overly reductive. A multidimensional and longitudinal approach integrating clinical outcomes with biomarkers and selected functional assessments is required to maximise benefit and guide future therapeutic strategies.

BACKGROUND:Cystic fibrosis (CF) is a genetic condition that can cause multisystem damage that progresses into life-threatening complications. Sex differences in CF-related outcomes have been reported such that females with CF experience increased morbidity and mortality earlier in the disease course compared to males. The mechanisms that contribute to these sex differences in clinical outcomes, however, have yet to be fully elucidated. Since CF is known to have cardiac sequelae, and sex differences in CVD also exist in the general population, the present investigation sought to comprehensively evaluate vascular health in males and females with CF to gain insight into these sex disparities. METHODS:Twenty-two individuals with CF (12 male and 10 female) participated in this cross-sectional study. Aortic stiffness was assessed using pulse wave analysis (PWA), and central arterial stiffness was determined by carotid to femoral pulse wave velocity (cfPWV). Conduit vessel endothelial function was evaluated using the flow-mediated dilation (FMD) test, and microvascular endothelial function was determined using laser Doppler imaging following cutaneous reactive hyperemia, local thermal heating, and iontophoresis with acetylcholine. RESULTS:Females were significantly (p = 0.035) younger compared to males. Controlling for age, PWA was significantly (p < 0.001; Cohen's d = -1.990) higher in females (24.1 ± 7.5%) compared to males (7.2 ± 9.2%) while cfPWV was similar (p = 0.756; Cohen's d = 0.693) between groups. FMD (p = 0.547; Cohen's d = 0.208), post-occlusive reactive hyperemia (p = 0.721; Cohen's d = 0.568), and local thermal heating responses (p = 0.100; Cohen's d = -0.392) were all similar between males and females with CF. Although a significant (p < 0.001) increase in cutaneous perfusion in response to acetylcholine was observed in both groups, the peak response to acetylcholine iontophoresis was significantly (p = 0.002; Cohen's d = -1.384) higher in females compared to males. CONCLUSIONS:Overall findings indicate that sex differences in vascular health are observed in people with CF and demonstrate that the CF pathophysiology may impact vascular beds differently dependent on sex.

RATIONALE:In an 8-week, active-controlled, phase 3 study (445-104), elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in participants ≥ 12 years of age with cystic fibrosis (CF) and F508del-gating (F/G) or F508del-residual function (F/RF) genotypes, conferring additional clinical benefits relative to IVA and TEZ/IVA. Participants who completed this 8-week parent study continued to an open-label extension. OBJECTIVE:To assess the long-term safety and efficacy of ELX/TEZ/IVA in adolescents and adults with CF and F/G or F/RF genotypes. METHODS:This 2-part (Part A [96 weeks] and Part B [48 weeks]) phase 3 open-label extension study enrolled adolescents and adults age ≥ 12 years with CF and F/G or F/RF genotypes who completed study 445-104. Primary endpoint (Part A and Part B) was safety and tolerability. Secondary endpoints (Part A only) included absolute changes in percent predicted FEV1 (ppFEV1), sweat chloride concentration, CF Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI). RESULTS:A total of 251 participants received ≥ 1 dose of ELX/TEZ/IVA in Part A; 217 (86.5%) completed treatment. In Part A, 96.0% of participants had ≥ 1 adverse event (AE), which for most were mild (32.3%) or moderate (55.0%) in severity. Thirteen participants (5.2%) discontinued due to treatment-emergent AEs. Participants who received ELX/TEZ/IVA in the parent study maintained improvements in ppFEV1, sweat chloride concentration, CFQ-R respiratory domain score, and BMI while participants who received IVA or TEZ/IVA (active controls) in parent study had similar improvements after transitioning to ELX/TEZ/IVA. Eighty-four participants (33.5%) entered Part B, 96.4% of whom discontinued due to commercial drug availability. In Part B, 62 participants (73.8%) had ≥ 1 AE, which for most were mild or moderate in severity and none of which led to discontinuation. CONCLUSIONS:ELX/TEZ/IVA remained generally safe and well-tolerated with no new safety findings. Improvements in lung function, CFTR function, respiratory symptoms, and nutritional status after starting ELX/TEZ/IVA were maintained through 96 weeks of follow-up. These results demonstrate the safety and durable efficacy of ELX/TEZ/IVA in adolescents and adults with F/G or F/RF genotypes.

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, 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. 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 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%]). Interpretation 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. Funding Vertex Pharmaceuticals.

BackgroundChronic rhinosinusitis (CRS) and olfactory dysfunction (OD) are prevalent disease complications in people with cystic fibrosis. These understudied comorbidities significantly impact quality of life. The impact of highly effective modulator therapy (HEMT) in young children with cystic fibrosis (YCwCF) on these disease complications is unknown. This proposed study aims to characterise CRS and OD in YCwCF and assess the efficacy of HEMT in improving sinus and olfactory health in this young age group.MethodsThis six-centre, prospective, observational study will enrol 80 YCwCF aged 2–8 years. Patients are divided into two groups: those receiving HEMT and those not on HEMT based on clinical indication. Both groups undergo sinus magnetic resonance imaging, psychophysical olfactory tests, and complete patient- or parent-reported quality of life surveys over 2 years. Outcomes will be compared before and after initiation of HEMT and between groups. Ethical approval has been obtained for all sites, and this study has been registered on ClinicalTrials.gov (NCT06191640).ResultsEnrolment began in April 2023. 21 participants have been enrolled as of October 2023 with ongoing enrolment at all sites.ConclusionThis investigation is expected to provide critical insights into the potential benefits of early HEMT initiation in managing CRS and OD in YCwCF. It will assist in developing targeted interventions and contribute to the understanding of HEMT's role in altering the disease course in this demographic.

Nearly all males with cystic fibrosis (MwCF) are infertile and, thus, require the use of assisted reproductive technology (ART) to have biologic children. This study aims to describe the fertility and family-building knowledge, experiences, and care utilization of this population and to compare these findings to the general United States (US) population. We conducted an anonymous cross-sectional study of self-reported survey data compared to data from the 2017–2019 US National Survey for Family Growth (NSFG). We recruited MwCF age 15 years and older at seven US cystic fibrosis (CF) centers. A total of 532 MwCF (mean age 35.3 ± 11.6 years) completed the survey. 83