Identification of early changes in multiple biomarkers following CFTR modulator initiation in patients with cystic fibrosis.

Background
There are currently no early parameters that allow prediction of long-term responses to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator treatment on an individual level.
Objectives
To identify early parameters measured within 7 to 14 days after initiation of treatment with a CFTR modulator to assess CFTR modulator efficacy.
Study Design
Prospective observational study of patients diagnosed with CF who begin elexacaftor/tezacaftor/ivacaftor (ETI) therapy at 3 CF clinics in Switzerland (Geneva, Lausanne, Lucerne).
Methods
Standardized measurements were taken within 2 months prior to and 7 to 14 days after starting CFTR modulator treatment.Results
ETI treatment was started on 47 patients [median age: 12 years] of whom 12 (26%) were switching from lumacaftor/ivacaftor (n = 8) or tezacaftor/ivacaftor (n = 4) to ETI. A significant early treatment effect was observed for BMI z-score (p < 0.001) and inflammatory parameters (white blood cells (p = 0.006), neutrophils (p = 0.006), immunoglobulin G (p = 0.012), and fecal calprotectin (p = 0.002)). In CFTR functional assays, sweat chloride concentration and nasal potential difference testing [Δlow-chloride+isoproterenol, Sermet score, and Wilschanski index] improved significantly (all p < 0.001). Improvement was also observed in lung function (FVC, FEV1, MMEF25-75, LCI2.5%) (all p < 0.001). No changes were found for blood pressure, SpO2, respiratory rate, erythrocyte sedimentation rate, C-reactive protein, and fecal elastase.
Conclusion
This study identified clinical, biologic, and functional parameters showing treatment effect early after initiation of CFTR modulator therapy. These parameters may serve as potential predictors of long-term responses to CFTR modulator treatment.Early signs of treatment response after 7 to 14 days in patients with cystic fibrosis starting new CFTR modulator therapyCystic Fibrosis (CF) is a genetic disease that mainly affects the lungs and other organs. A newer group of medications, known as CFTR modulators, has significantly improved treatment options for people with CF. One of the most effective combinations is elexacaftor, tezacaftor, and ivacaftor (ETI). However, not all patients respond equally well to this treatment, and the reasons for these differences are still not fully understood. In addition, ETI is only approved for certain genetic variants, meaning that about 10% of people with CF cannot currently receive it—despite research suggesting that many of them could benefit. Identifying early on who is likely to respond well to ETI could help avoid unnecessary side effects and healthcare costs for those unlikely to benefit. In our study, we aimed to identify early signs that could predict whether a patient will respond positively to ETI therapy. We followed 47 patients with CF (median age: 12 years) at three hospitals in Switzerland. We measured various health indicators - such as weight, markers of inflammation, CFTR function tests, and lung function - just before starting ETI and again 7 to 14 days after treatment began. Even within this short period, we observed improvements in body weight, blood and gut inflammation, lung function, and CFTR function (based on sweat chloride levels and nasal potential difference tests). These early improvements could help predict long-term benefits of CFTR modulator treatment. Our ongoing research is investigating whether these early indicators can reliably support doctors in making more personalized treatment decisions for people with CF.