At the 2025 European Respiratory Society (ERS) International Congress taking place in Amsterdam, the Netherlands, from 27 September to 1 October, researchers from Canada’s Dalhousie University and the University of Toronto have presented findings from a comprehensive registry-based analysis examining the long-term clinical and microbiological impacts of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy in cystic fibrosis (CF) patients. The study, spanning data from 2019 to 2023 across Canadian and US CF registries, examined the long-term clinical and microbial impacts of CFTR modulator therapy to better inform patient monitoring strategies, infection risk stratification and treatment optimisation in the era of disease-modifying CF therapy.
The retrospective cohort analysis focused on patients with more than 12 months of continuous modulator use, evaluating lung function changes and trends in key respiratory pathogens including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, the Burkholderia species and nontuberculous mycobacteria (NTM). Findings demonstrated the expected clinical benefits, with sustained improvements in lung function metrics consistent with previous clinical trial data. However, the microbiological landscape proved more complex than anticipated. While overall infection rates showed some positive trends, the analysis revealed a notable rise in reported NTM detections among non-hospitalised adults receiving CFTR therapy – a 300% relative increase between 2019 and 2023 – though absolute numbers remained relatively small (22 vs 88 cases, respectively).
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The temporal analysis highlighted concerning trends in specific patient subgroups. Adults with Burkholderia cepacia complex colonisation showed variable responses, with some experiencing sustained clinical benefits while others demonstrated persistent infection-related complications despite improved CFTR function. Similarly, the relationship between modulator therapy and Pseudomonas aeruginosa clearance proved inconsistent across age groups, with adult patients showing more favourable microbiological outcomes and lowering of hospitalisation rates compared to paediatric patients. Perhaps most intriguingly, the study identified potential signals suggesting that microbial adaptation may persist despite clinical gains. The research team noted that while forced expiratory volume in one second (FEV₁) improvements remained durable across the observation period, certain pathogen-specific trends raised questions about long-term infection risk stratification.
The implications of the study extend beyond individual patient management to the broader CF care strategy. As modulator therapy becomes lifelong treatment for an increasing numbers of patients, understanding the evolution of airway microbiology becomes critical for preventing long-term complications and optimising infection surveillance protocols. The registry data suggests that current microbiological monitoring frameworks may need adaptation and findings underscore the complexity of CFTR restoration’s impact on the CF airway ecosystem. While improved mucus clearance and reduced infection burden represent clear therapeutic benefits, the data suggests that some pathogens may persist or emerge through mechanisms independent of CFTR dysfunction. This necessitates continued vigilance in infection prevention and management, even as patients experience unprecedented clinical improvements.
From a competitive landscape perspective, these results highlight the need for comprehensive long-term safety and efficacy monitoring as newer CFTR modulators become standard of care. GlobalData’s CF market forecast estimates that CFTR modulators accounted for 87.5% of CF treatment sales in 2024 across the 7MM (Canada, the 5EU [France, Germany, Italy, the Netherlands and Spain] and the US) and are projected to maintain a dominant market share until 2034. This dominance, driven by the clinical success of Vertex’s portfolio including the recent launch of Alyftrek in Canada, the 5EU and the US, creates both opportunities and challenges for emerging competitors. Future therapies will need to demonstrate not only functional improvements but also favourable long-term microbiological profiles. As the integration of registry-based surveillance into clinical development programmes becomes more prevalent, understanding real-world microbiological outcomes will guide evidence-based prescribing decisions.
The study’s longitudinal design provides valuable insights into the natural history of CF in the modulator era, informing both clinical practice and regulatory oversight. However, despite the $16.0 billion projected CF market across the 7MM by 2034, significant barriers remain. Specifically, the limited pipeline diversity, with ~45% of agents still targeting CFTR mechanisms as per GlobalData’s drugs database, underscores both the validation of this therapeutic approach and the critical need for breakthrough innovations in mutation-agnostic treatments, chronic infection management and high treatment burden solutions. As the CF patient population ages and treatment duration extends, registry-based analyses will prove instrumental in tracking pathogen-specific trends and long-term disease evolution, ultimately supporting the development of more personalised and cost-effective therapeutic strategies in an increasingly outcomes-driven CF landscape.
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