Tezacaftor 50mg / Ivacaftor 75mg tablets

Background Cystic fibrosis is a life-limiting genetic condition that affects over 9000 people in England. Cystic fibrosis is usually diagnosed through newborn screening and causes symptoms throughout the body, including the lungs and digestive system. Around 90% of individuals with cystic fibrosis have at least one copy of the F508del mutation on the cystic fibrosis transmembrane conductance regulator gene. Objectives To appraise the clinical effectiveness and cost-effectiveness of elexacaftor–tezacaftor–ivacaftor, tezacaftor–ivacaftor and lumacaftor–ivacaftor within their expected marketing authorisations for treating people with cystic fibrosis and at least one F508del mutation, compared with each other and with established clinical management before these treatments. Methods A de novo systematic literature review (search date February 2023) was conducted searching electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), bibliographies of relevant systematic literature reviews, clinical trial registers, recent conferences and evidence provided by Vertex Pharmaceuticals (Boston, MA, USA). Data on the following outcomes were summarised: acute change in per cent predicted forced expiratory volume in 1 second (change in weight-for-age z-score; and change in pulmonary exacerbation frequency requiring intravenous antibiotics. Network meta-analyses were conducted where head-to-head data were not available. Data from clinical trials and real-world evidence were examined to assess long-term effectiveness. A patient-level simulation model was developed to assess the cost-effectiveness of the three modulator treatments. The model employed a lifetime horizon and was developed from the perspective of the National Health Service. Results Data from 19 primary studies and 7 open-label extension studies were prioritised in the systematic literature review. Elexacaftor/tezacaftor/ivacaftor was associated with a statistically significant increase in predicted forced expiratory volume in 1 second and weight-for-age z-score and a reduction in pulmonary exacerbations compared with established clinical management, lumacaftor/ivacaftor and tezacaftor/ivacaftor, and also led to a reduction in the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management, although the magnitude of this decrease was uncertain. Lumacaftor/ivacaftor and tezacaftor/ivacaftor were also associated with a statistically significant increase in predicted forced expiratory volume in 1 second and reduction in pulmonary exacerbations relative to established clinical management, but with a smaller effect size than elexacaftor/tezacaftor/ivacaftor. There was some evidence that tezacaftor/ivacaftor reduced the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management, but little evidence that lumacaftor/ivacaftor reduced the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management. The incremental cost-effectiveness ratios from the economic analysis were confidential. However, for all genotypes studied the incremental cost-effectiveness ratios were above what would be considered cost-effective based on the National Institute for Health and Care Excellence threshold of £20,000–30,000 per quality-adjusted life-year gained. Conclusions Despite the improved clinical benefits observed, none of the cystic fibrosis transmembrane conductance regulator gene modulators assessed would be considered cost-effective based on the National Institute for Health and Care Excellence threshold of £20,000–30,000 per quality-adjusted life-year gained. This is largely driven by the high acquisition costs of cystic fibrosis transmembrane conductance regulator gene modulator treatments. Study registration This study is registered as PROSPERO CRD42023399583. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135829) and is published in full in Health Technology Assessment; Vol. 29, No. 19. See the NIHR Funding and Awards website for further award information.

Abstract licence: CC BY 4.0

BackgroundElexacaftor/tezacaftor/ivacaftor (ETI) has transformed clinical outcomes in people with cystic fibrosis (PwCF), but its impact on airway and systemic inflammation is less well defined.MethodsWe systematically searched PubMed, Embase and CENTRAL (January 1, 2019-September 30, 2025) for full-text human studies of pwCF treated with ETI that reported at least one inflammatory biomarker before and after ETI initiation. Because of heterogeneity in study design, sample type, biomarker panels and assays, we did not perform a meta-analysis but instead conducted a structured narrative synthesis, grouping biomarkers by compartment (systemic vs airway); when reported, we also recorded associations between biomarker changes and clinical outcomes.ResultsThirty-two observational studies (8-272 participants) met inclusion criteria; 25 evaluated systemic and 10 airway biomarkers, with follow-up up to 30 months. ETI was associated with substantial reductions in sputum neutrophil elastase, IL-1β and IL-8, and in systemic C-reactive protein, other acute-phase reactants, circulating neutrophils and selected Th17-related cytokines, indicating an overall reduction in inflammatory burden, although residual inflammation relative to healthy controls was common. Th1-associated markers and immune-cell activation phenotypes showed heterogeneous changes, while Th2/eosinophilic markers showed less consistent modulation with ETI. Just over half of studies examined biomarker-outcome relationships; in these, reductions in neutrophil-associated markers, CRP, fibrinogen and selected cytokines were often associated with improvements in ppFEV1 or other clinical measures.ConclusionETI is associated with substantial but incomplete reductions in airway and systemic inflammation in pwCF, with the most consistent effects in neutrophil and acute-phase pathways and more variable changes across other immune markers. Persistent low-grade inflammation in many cohorts suggests that adjunctive anti-inflammatory strategies may still be relevant and that further longitudinal studies are needed to link residual biomarker abnormalities with long-term clinical and structural outcomes.

Abstract licence: CC BY