Orkambi (lumacaftor/ivacaftor) / Vertex - LARVOL DELTA

Impact of Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapies on Liver Transplant Outcomes. (PubMed, Gastro Hep Adv) - "Food and Drug Administration (FDA) approval of CFTR modulators: ivacaftor (January 31, 2012; single therapy), ivacaftor-lumacaftor (July 2, 2015; dual therapy), and ivacaftor-tezacaftor-elexacaftor (October 21, 2019; triple therapy). There were no significant differences in post-LT survival pre- and post-FDA approval of single, dual, or triple CFTR therapy. These findings suggest that CFTR modulators may mitigate CFrLD complications and delay the need for waitlisting as physicians await the patient's response to therapy and reassess the need for LT."

Journal • Cystic Fibrosis • Genetic Disorders • Hepatology • Immunology • Pulmonary Disease • Respiratory Diseases • Transplantation • CFTR

Cystic fibrosis-related diabetes in the era of modern treatment using CFTR modulators in pediatric patients-a systematic review. (PubMed, Front Pediatr) - "While early findings suggest CFTR modulators may offer metabolic benefits and potentially delay or reduce the need for insulin therapy in children CFRD, current evidence is limited. Larger, pediatric-focused clinical trials with standardized glycemic outcomes are essential to determine the long-term efficacy and safety of CFTRm in managing or preventing CFRD."

Journal • Review • Cystic Fibrosis • Diabetes • Genetic Disorders • Immunology • Metabolic Disorders • Pediatrics • Pulmonary Disease • Respiratory Diseases • CFTR

The cost-effectiveness of cystic fibrosis transmembrane conductance regulator modulators: A systematic review of economic evaluations. (PubMed, Br J Clin Pharmacol) - "This systematic review examined cost-effectiveness studies of four CFTR modulators: ivacaftor (IVA), lumacaftor-ivacaftor (LUM-IVA), tezacaftor-ivacaftor (TEZ-IVA) and elexacaftor-tezacaftor-ivacaftor (ELX-TEZ-IVA). CFTR modulators provide substantial health benefits but pose significant financial challenges. Future research should broaden economic evaluations, consider societal impacts and explore strategies to improve affordability and access."

HEOR • Journal • Review • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Rare Diseases • Respiratory Diseases • CFTR

Estimating the Long-Term Impact of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Treatments on the Annual Decline of Percent-Predicted Forced Expiratory Volume in One Second (ppFEV1) Compared to Established Clinical Management... (ISPOR-EU 2025) - "Modelling long-term ppFEV1 changes following CFTR modulators remains challenging. Future modelling may prefer to use the directly observed rate/shape of ppFEV1, or as a calibration, as longer follow-up data emerges."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • CFTR

A Systematic Review (SR) and Network Meta-Analysis (NMA) of Cystic Fibrosis Transmembrane Conductance Receptor (CFTR) Modulator Therapies and Established Clinical Management (ECM) Using Percent Predicted Forced Expiratory Volume in One Second... (ISPOR-EU 2025) - "OBJECTIVES: This research aimed to assess the effectiveness of elexacafor/tezacaftor/ivacaftor (ELX/TEZ/IVA), lumacaftor/ivacaftor (LUM/IVA) and tezacaftor/ivacaftor (TEZ/IVA) compared to each other and ECM. An SR was conducted to identify relevant studies assessing the acute effects of CFTR modulators on ppFEV1... CFTR modulators lead to acute improvements in ppFEV1 for people with CF. The magnitude of this improvement is considerably larger for ELX/TEZ/IVA. While there is a strong evidence base for the acute improvements, modelling long-term changes in ppFEV1 decline following CFTR modulator therapy remains challenging."

Retrospective data • Review • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Therapeutic Drug Monitoring of Elexacaftor, Tezacaftor, and Ivacaftor: An Overview of Bioanalytical Methods. (PubMed, Ther Drug Monit) - "Although CFTR modulators meet many of the established criteria for therapeutic drug monitoring, critical gaps persist, particularly regarding exposure-response relationships and optimal sampling strategies. Addressing these issues will be essential to establish therapeutic drug monitoring as a reliable tool for personalizing CFTR modulator therapy in patients with cystic fibrosis."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR

Modeling CF patient-specific responses to modulators using human induced pluripotent stem cells (NACFC 2025) - "Cultures were treated with VX-809/VX-770 or VX-445/VX-661/VX-770 for 48 hours, and CFTR functional rescue was assessed using an apical chloride conductance assay. iPSC-derived lung models offer a renewable, patient-specific platform for theratyping in CF. While fetal lung progenitors provided strong responses, making them useful for early-stage modulator screening, mature airway models captured patient-specific cellular diversity, which may contribute to variable modulator responses. By enabling genetically matched comparisons and capturing inter-individual variability, these models represent a promising tool for optimizing treatment strategies in CF (Figure 1)."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Pivotal Potential: Predictors of pancreatic function restoration in children with CF on CFTR modulators (NACFC 2025) - "IVA: Ivacaftor ETI: Elexacaftor/tezacaftor/ivacaftor LUM/IVA: Lumacaftor/ivacaftor TEZ/IVA: tezacaftor/ivacaftor VTD: vanzacaftor/tezacaftor/deutivacaftor Findings from this pilot study highlighted younger age at CFTRm initiation and CFTRm exposure history as potential predictors of pancreatic function restoration. Findings from this pilot study highlighted younger age at CFTRm initiation and CFTRm exposure history as potential predictors of pancreatic function restoration. These results support the development of a personalized approach to CF-related care and may inform future guidelines regarding PERT withdrawal. Ongoing research is warranted to further elucidate the safety and long-term outcomes associated with PERT discontinuation in this emerging cohort of individuals with CF who have achieved PS."

Clinical • Cystic Fibrosis • Diabetes • Gastrointestinal Disorder • Genetic Disorders • Hepatology • Immunology • Metabolic Disorders • Pediatrics • Respiratory Diseases • Short Bowel Syndrome • CFTR

Elexacaftor/tezacaftor/ivacaftor reduces bronchial dilatations in adolescents with CF (NACFC 2025) - "Two hundred and eight had not previously been treated with CFTR modulators and 112 had previously received Lumacaftor-Ivacaftor. These data point to improvements in bronchial dilatation in awCF treated with ETI."

Cystic Fibrosis • Genetic Disorders • Immunology • Pediatrics • Respiratory Diseases • CXCL8 • ELANE • IL1B • IL6 • TNFA

Long term causal effects of ivacaftor on airway microbiology and lung function outcomes in people with CF: An emulation of target trials with the U.S. CF Foundation Patient Registry data (NACFC 2025) - "The per-protocol analysis censored individuals who deviated from their initial treatment, and a third approach further censored those who started other modulators (lumacaftor/ivacaftor or tezacaftor/ivacaftor). Our findings demonstrate a robust long-term clinical benefit over a 7-year period of ivacaftor across both clinical and microbiological outcomes, particularly among younger patients and those with gating mutations. These results provide real-world support for sustained ivacaftor use in eligible CF populations."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Maximizing benefits with early CFTR modulator treatment: Lower sweat chloride is associated with improved clinical outcomes in children aged 6 to 11 years (NACFC 2025) - " Data from elexacaftor/tezacaftor/ivacaftor (ETI) and vanzacaftor/ tezacaftor/deutivacaftor (VTD) Phase 3 clinical trials in pwCF with F508del/ minimal function mutation (F/MF) and F508del/F508del (F/F) genotypes were assessed to determine the relationship between SwCl concentrations achieved through Week 24 and age (≥18yrs, 12-17yrs, and 6–11yrs). In addition, data from lumacaftor/ivacaftor, tezacaftor/ivacaftor, ETI, and VTD Phase 3 clinical trials and open-label extension studies in children with CF aged 6-11yrs with F/MF and F/F genotypes were pooled to assess the relationship between SwCl concentrations on CFTRm and clinical outcomes in this age group... YOGA-CF is currently recruiting to time and target highlighting the desire of the CF community (patients and CF teams) to engage with real world remote clinical trials and the importance of identifying non-pharmacological strategies to improve outcomes. Final recruitment data available for NACFC 2025."

Clinical • Clinical data • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Sweat sodium: chloride ratio differs in people with CF by CFTR modulator treatment status (NACFC 2025) - "We compared sweat sodium: chloride ratios in pwCF pre- and post-treatment with lumacaftor/ivacaftor (LUM/IVA), tezacaftor/ivacaftor (TEZ/IVA), ivacaftor (IVA), or elexacaftor/tezacaftor/ivacaftor (ETI). Sweat sodium: chloride ratios increased following treatment with moderately effective (LUM/IVA and TEZ/IVA) and, to a greater degree, highly effective modulators (IVA and ETI). Sweat sodium: chloride ratios normalized in some pwCF despite having sweat chloride values that remained elevated, suggesting that sweat sodium relative to chloride may serve as an additional biomarker of CFTR function and predictor of sufficient CFTR response for symptom improvement."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Medication adherence to cystic fibrosis transmembrane conductance regulator (CFTR) modulators: Analysis on the French CF population from 2012-2020 (NACFC 2025) - "Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, ivacaftor and lumacaftor/ivacaftor, were introduced in France in 2012 and 2015, respectively, and have transformed the treatment landscape... Patients on CFTR modulators showed optimal implementation with declining persistence over time, potentially affecting long-term treatment outcomes. This finding underscores the importance of real-world data in understanding medication adherence to CFTR modulators and improving long-term treatment outcomes."

Adherence • Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Mitochondrial Fragmentation Induced by the CFTR Modulators Lumacaftor and Ivacaftor in Immortalized Cystic Fibrosis Cell Lines. (PubMed, Cells) - "These results highlight a previously unrecognized role for CFTR modulators in shaping mitochondrial morphology. A better understanding of these effects may reveal novel mechanisms underlying the regulation of mitochondrial structure and function."

Journal • Preclinical • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR • CISD1

Effect of elexacaftor-tezacaftor-ivacaftor on bronchial dilatations in adolescents with cystic fibrosis: a multicentre prospective observational study. (PubMed, Lancet Respir Med) - P=N/A | "Bronchial dilatations can reverse in adolescents with cystic fibrosis treated with ETI. The correlation with reduced airway inflammation provides insight into the effect of ETI on cystic fibrosis lung disease."

Journal • Observational data • Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Pediatrics • Pulmonary Disease • Respiratory Diseases • ABCF2 • CRP • CXCL8 • ELANE • IL1B • IL6 • TNFA

Impact of birth order on report of behavioral side effects with elexacaftor/tezacaftor/ivacaftor in people with CF age 2-5 years old (NACFC 2025) - "The most common previous CFTR modulator prior to ETI was lumacaftor/ivacaftor at 52.4% in the first-born group and 53.2% in the not first-born group (p = 0.95), however 38.1% of first-born and 36.2% of not first-born (p = 0.88) subjects were modulator naïve. This study found a statistically significant difference in behavioral/mental health/sleep side effects with ETI use in PwCF ages 2–5 years old who were first-born children versus not first-born children. First-time parents may be more likely to report behavioral/mental health/sleep side effects. Preemptive guidance on normal toddler development and behavior may be helpful for some parents of children starting ETI."

Adverse events • Cough • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Pediatrics • Respiratory Diseases • CFTR

Bone mineral density in young children with CF pre- and post-elexacaftor/tezacaftor/ivacaftor – The BEGIN Study (NACFC 2025) - "Thirty-five percent reported previously taking lumacaftor/ ivacaftor; all Part B participants (n = 24) were initiated on ETI. These results are some of the very first to be presented on bone outcomes in young children with CF using robust pediatric reference data. Prior to ETI initiation, children demonstrated greater than average height, BMI, TBLH-BMD, and LS-BMD. BMD tended to decrease over the course of the study, but it remains unclear to what extent this decrease represents natural history."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Musculoskeletal Diseases • Orthopedics • Pediatrics • Respiratory Diseases

GRIP STRENGTH, PHYSICAL ACTIVITY LEVELS, AND BODY COMPOSITION IN THE MODULATOR ERA: INSIGHTS FROM PAEDIATRIC CYSTIC FIBROSIS (UEGW 2025) - "Out of these, 66 patients were receiving CFTR modulator therapy (39 LUM/IVA, 27 ETI)... GSS, HGS and FEV1 showed weak correlation and may be useful in assessing aspects of functional and physical performance in children with CF. In contrast, body composition and BMI showed no correlation with these performance measures."

Cystic Fibrosis • Genetic Disorders • Immunology • Pediatrics • Respiratory Diseases

Identification of early changes in multiple biomarkers following CFTR modulator initiation in patients with cystic fibrosis. (PubMed, Ther Adv Respir Dis) - "This study identified clinical, biologic, and functional parameters showing treatment effect early after initiation of CFTR modulator therapy. These parameters may serve as potential predictors of long-term responses to CFTR modulator treatment."

Biomarker • Journal • Observational data • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR • CRP

The impact of vanzacaftor/tezacaftor/deutivacaftor on parent and child perceived psychosocial functioning in people with cystic fibrosis: a single center experience (NACFC 2025) - "Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective modulator therapy (HEMT) for children with cystic fibrosis (CwCF)...Prior to VTD, 31 (94%) CwCF were prescribed ETI, 1 LUM/IVA, and 1 was not on CFTR modulator therapy... Baseline PSC data showed 97% of scores in normal range with only one score considered elevated. The highest scoring questions highlight common trends in behavioral adverse events, correlating with concerns raised by the CF community. The increased scores for sleep indicate poor sleep quality and difficulties with sleep onset and maintenance among CwCF."

Clinical • CNS Disorders • Cystic Fibrosis • Genetic Disorders • Immunology • Pediatrics • Psychiatry • Respiratory Diseases • Sleep Disorder

Hepatic function improvement in children with cystic fibrosis following elexacaftor/tezacaftor/ivacaftor therapy: a case series (NACFC 2025) - "Notably, one pediatric study found that ETI did not replicate the hepatic biomarker improvements seen with lumacaftor/ivacaftor [4]. ETI was associated with favorable hepatic outcomes in pediatric PwCF, including those with preexisting CFLD, particularly with close monitoring and dose adjustment. While limited by small sample size and observational design, these findings challenge assumptions of universal hepatotoxicity and highlight the potential hepatic benefit of ETIs. Discordance between hepatic and pulmonary responses emphasizes the need for individualized, organ-specific monitoring and suggests that dose modification may be a viable alternative to discontinuation of ETI therapy."

Clinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Failure • Pediatrics • Respiratory Diseases

The effects of CFTR modulator therapy on glycemic control: evidence from a meta-analysis (NACFC 2025) - " Elexacaftor/tezacaftor/ivacaftor therapy (ETI) significantly improved 120-minute glucose levels (MD, −1.35 mmol/L; 95% CI, −2.49 to −0.22) and lowered hemoglobin A1c (HbA1c) levels (MD, −0.44%; 95% which near-road air pollution is associated with changes in lung function after initiating a highly effective modulator...In contrast, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and ivacaftor monotherapy were not associated with significant changes in any assessed outcomes. ETI therapy significantly improves glycemic control in CF, particularly when initiated at a young age. Further research is needed to confirm and detail these findings."

Retrospective data • Cystic Fibrosis • Diabetes • Genetic Disorders • Immunology • Metabolic Disorders • Respiratory Diseases • CFTR

Therapeutic transgenes need optimization - Dissecting factors that affect CFTR super exon performance (NACFC 2025) - "In primary hBEs, we have observed functional rescue similar to lumacaftor/ivacaftor in a heterozygous F508del cells and continued optimization is in progress... In summary, we demonstrated robust rescue of CFTR using the SE approach and show that optimizing SE sequence elements is critical for efficient expression, splicing, stability, and function of the SE. Our ongoing work is focused on understanding SE expression, and optimizing constructs for CFTR. Deletion of almost all of intron 1 did not affect CFTR expression or function."

CFTR

Making CF-MAGIC (CFTR ModulAtor PharmacoGenomICs): creation of a genomics-based clinical decision support program to improve time to initiation and optimization of CFTR modulator therapies (NACFC 2025) - " When compared to historical CFTRm approvals and expansions, CF-MAGIC correctly identified all PwCF with eligible mutations for CFTRm, capturing one PwCF eligible for elexacaftor/tezacaftor/ivacaftor (ETI) that was missed when SmartReport and other manual methods were previously utilized...At the time of implementation of the proactive report, CF-MAGIC identified three PwCF who were eligible for ETI but had not been noted by the clinical team; one patient who had a missed dose adjustment on lumacaftor/ivacaftor; three patients receiving the improper dosage form based on age; and eleven patients who are on the cusp of a dose adjustment based on weight...With the label expansion of ETI and approval of vanzacaftor/tezacaftor/deutivacaftor at the end of December 2024, our center ran a report of eligible mutations for the new expansions and approvals three days after the approval was announced... Early initiation of modulator therapy is critical, but multiple logistical..."

Biomarker • Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Pediatrics • Respiratory Diseases

Application of the CF-ABLE score as a prognostic tool in rare genotypes and marker of therapeutic response (NACFC 2025) - "Background: Highly effective modulator therapies (HEMT) such as elexacaftor/tezacaftor/ivacaftor (ETI) are approved for the majority of people with cystic fibrosis (PwCF)...Score reductions following ETI commencement were greater than those observed following commencement of ivacaftor, lumacaftor/ivacaftor or tezacaftor/ivacaftor (p < 0.001), with this effect sustained at 2 years of follow-up... The CF-ABLE score identifies durable therapeutic response to HEMT in eligible PwCF early in treatment and can be used to justify drug reimbursement by virtue of its close relationship with future clinical outcome. The score may also have a role as a composite endpoint for interventional studies involving HEMT-ineligible PwCF with rare mutations."

Bronchiectasis • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • CFTR