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. 2025 May;29(19):1–111. doi: 10.3310/CPLD8546

Ivacaftor-tezacaftor-elexacaftor, tezacaftor-ivacaftor and lumacaftor-ivacaftor for treating cystic fibrosis: a systematic review and economic evaluation.

Steven J Edwards, Benjamin G Farrar, Kate Ennis, Nicole Downes, Victoria Wakefield, Isaac Mackenzie, Archie Walters, Tracey Jhita
PMCID: PMC12127894  PMID: 40418577

Abstract

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.

Plain language summary

This project reviewed the medical benefits, risks and costs of three treatments for cystic fibrosis: elexacaftor/tezacaftor/ivacaftor, lumacaftor/ivacaftor and tezacaftor/ivacaftor. They correct the underlying cause of cystic fibrosis in people who have a specific faulty version of the cystic fibrosis transmembrane conductance regulator gene called F508del. A thorough search of medical journals and other relevant publications was undertaken to identify evidence on how well each treatment works. People treated with elexacaftor/tezacaftor/ivacaftor had large increases in lung function and other markers of overall health than people not treated with this medication, and this was expected to make them live longer. People treated with lumacaftor/ivacaftor and tezacaftor/ivacaftor also had increases in lung function, but this was not as large an improvement as with elexacaftor/tezacaftor/ivacaftor. These treatments have only been widely available in the United Kingdom since 2019 (lumacaftor/ivacaftor and tezacaftor/ivacaftor) or 2021 (elexacaftor/tezacaftor/ivacaftor), and so there is still uncertainty about their long-term effectiveness. This project also assessed whether these treatments are likely to be considered good value for money for the National Health Service. The analysis found that based on the current prices of these treatments, they are unlikely to be considered good value for money for the National Health Service. In summary, lumacaftor/ivacaftor and tezacaftor/ivacaftor appear to be effective, and elexacaftor/tezacaftor/ivacaftor appears to be very effective, at improving the health of people with cystic fibrosis, but they are also very expensive.

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