Orkambi (lumacaftor/ivacaftor) / Vertex - LARVOL DELTA

Post-marketing safety profile of lumacaftor/ivacaftor in cystic fibrosis treatment: a pharmacovigilance analysis based on FAERS. (PubMed, Front Med (Lausanne)) - "Our findings underscore the importance of continuous post-marketing surveillance and the need for updated drug label to reflect associated risks, particularly those related to psychiatric symptoms and long-term adverse effects. Personalized treatment strategies based on patient characteristics, including sex, are recommended to optimize safety during LUM/IVA therapy."

Adverse events • Journal • P4 data • CNS Disorders • Cystic Fibrosis • Depression • Genetic Disorders • Hypoglycemia • Immunology • Psychiatry • Pulmonary Disease • Respiratory Diseases • Suicidal Ideation • ROR1

Drugs Associated with Pediatric Cataracts: A Real-World Pharmacovigilance Study. (PubMed, Children (Basel)) - "Difluprednate showed the highest pharmacovigilance signal (ROR: 963.67; 95% CI: 316.27-2936.31; n = 4). Notably, CFTR modulators exhibited striking signals: ivacaftor (ROR: 30.75; 95% CI: 18.06-52.37; n = 14), elexacaftor-ivacaftor-tezacaftor (ROR: 15.58; 95% CI: 9.86-24.63; n = 19), and ivacaftor-lumacaftor (ROR: 13.2; 95% CI: 7.9-22.07; n = 15). This study provides a comprehensive large-scale pharmacovigilance profile of drug-induced pediatric cataracts, identifying agents with high-risk pharmacovigilance signals and underscoring the need for proactive ocular monitoring. These findings can inform clinical decision making and prevention strategies and guide future mechanistic research."

Adverse events • Journal • Real-world evidence • Cataract • Cystic Fibrosis • Genetic Disorders • Immunology • Oncology • Ophthalmology • Pediatrics • Pulmonary Disease • Respiratory Diseases • CFTR

Modulate-CF: Cystic Fibrosis Transmembrane Regulator (CFTR) Biomarker Study to Evaluate the Rescue of Mutant CFTR in Patients With Cystic Fibrosis Treated With CFTR-modulators (clinicaltrials.gov) - P=N/A | N=500 | Recruiting | Sponsor: Charite University, Berlin, Germany | N=200 ➔ 500

Biomarker • Enrollment change • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Global Research Status and Trends in Quality of Life in Children With Cystic Fibrosis From 1985 to 2025: A 40-Year Bibliometric Analysis. (PubMed, Pediatr Pulmonol) - "The present study offers a global overview to researchers into quality of life in children with cystic fibrosis and also to healthcare professionals in clinical practice. It gives insights for future research on the topic and also shows existing gaps that could guide future studies in the field."

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

Gut-lung microbial dynamics with lumacaftor/ivacaftor in children with cystic fibrosis: a prospective multicenter study. (PubMed, Pediatr Res) - "In 116 children aged 2-11, lumacaftor/ivacaftor reshaped gut and lung microbiota and reduced fecal calprotectin over 12 months. First pediatric multicenter study integrating bacterial and fungal profiling of stool and sputum with gut-lung network analyses; identifies two distinct lung microbiome response profiles. Baseline gut and lung composition predicted the response profile with approximately 81% accuracy. Highlights a 3-month interaction peak and baseline profiling as practical markers to guide monitoring and microbiome-informed precision care."

Clinical • Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pediatrics • Pulmonary Disease • Respiratory Diseases

CFTR Modulator Therapy and Glycemic Control: A Meta-Analysis. (PubMed, Pediatrics) - "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."

Journal • Retrospective data • Cystic Fibrosis • Diabetes • Genetic Disorders • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases

Personalized Theratyping Trial (clinicaltrials.gov) - P1 | N=20 | Recruiting | Sponsor: George Solomon | Trial completion date: Sep 2026 ➔ Sep 2027 | Trial primary completion date: Jan 2026 ➔ Jan 2027

Trial completion date • Trial primary completion date • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Greenness, Whiteness, and Blueness Assessment With a Novel and Fully Validated HPLC Method for Simultaneous Analysis of Lumacaftor and Ivacaftor in Sweat. (PubMed, Int J Anal Chem) - "The AGREE score of the method was calculated as 0.72, the BAGI score as 87.5, and the RGB 12 algorithm as 88.3. As a result, the method was presented to researchers as a sustainable, green, and efficient method."

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

Improvement of Cystic Fibrosis-Associated Liver Disease in Adults on Long-Term Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulators. (PubMed, Life (Basel)) - "Patients received lumacaftor/ivacaftor and/or elexacaftor/tezacaftor/ivacaftor for a median of 43 months (range, 15-123) until last assessment (T2). In conclusion, adults with CF receiving long-term CFTR modulators, showed improvement of liver disease assessed by ultrasonography and transient elastography. At the last assessment, half of the patients no longer met the criteria for CFLD."

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

Clinical management and outcomes of hepatobiliary disease in the cystic fibrosis transmembrane conductance regulator modulator era. (PubMed, Curr Opin Gastroenterol) - "To better understand the possible benefit of CFTR modulator therapies on hepatobiliary health, additionally larger, longer-term, multicenter studies with sub-group phenotyping are necessary. Until then, providers should watch for liver-related adverse events, and be cognizant on how CFTR modulators may impact areas of clinical care for individuals with CF."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Hepatology • Immunology • Liver Cirrhosis • Pulmonary Disease • Respiratory Diseases • Solid Organ Transplantation • Transplantation • CFTR

Case Report: Pitfalls in CF screening - targeted variant analysis can cause misleading results and therapy recommendations. (PubMed, Front Genet) - "Despite early Orkambi therapy, her response was suboptimal, with high sweat chloride levels and recurrent respiratory infections...Upon switching to elexacaftor/tezacaftor/ivacaftor (ETI), sweat chloride levels significantly improved...This case highlights the necessity of comprehensive genetic analysis in patients with unexpected therapy responses. When CFTR modulator therapy does not yield the expected improvements, re-sequencing should be considered to optimize precision medicine approaches for CF."

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

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