Lumacaftor 75mg / Ivacaftor 94mg granules sachets

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

ContextCystic fibrosis-related diabetes significantly impacts health outcomes of people with cystic fibrosis (CF). Understanding the effects of CF transmembrane conductance regulator modulator (CFTRm) therapy on glycemic control is crucial for improving overall health in CF.ObjectiveTo evaluate the impact of CFTRm therapy on glycemic control in people with CF.Data sourcesA comprehensive literature search was conducted from January 1, 2011, to September 19, 2024, in PubMed, Embase, and Cochrane Central Register of Controlled Trials.Study selectionEligible studies included interventional trials comparing CFTRm therapy to no treatment or placebo and observational studies reporting glycemic outcomes-assessed by oral glucose tolerance test or continuous glucose monitoring-pretherapy and on therapy or between treated individuals and controls.Data extractionTwo authors independently extracted data with full adherence to the Cochrane Handbook.ResultsElexacaftor/tezacaftor/ivacaftor therapy (ETI) significantly improved 120-minute glucose levels (mean difference, -24.30 mg/dL; 95% CI, -44.82 to -3.96) and lowered hemoglobin A1c (HbA1c) levels (mean difference, -0.44%; 95% CI, -0.75 to -0.13). Regression analyses showed that earlier ETI therapy initiation was associated with lower HbA1c values (P = .03). In contrast, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and ivacaftor monotherapy were not associated with significant changes in any assessed outcomes.LimitationsOur analyses may underestimate the endocrine effects of CFTRm therapies, as most included papers assessed pre- and on-therapy outcomes in the same patients, potentially overlooking the gradual deterioration of glycemic control.ConclusionsETI therapy significantly improves glycemic control in CF, particularly when initiated at a young age. Further research is needed to confirm and detail these findings.

Abstract licence: CC BY-NC-ND