Long-term effectiveness of dual CFTR modulator treatment of cystic fibrosis

Background Although short-term efficacy of lumacaftor/ivacaftor and tezacaftor/ivacaftor is clearly established in clinical trials, data on long-term effectiveness is limited. This registry-based cohort study assessed real-world longitudinal outcomes of F508del-homozygous people with cystic fibrosis (pwCF) ⩾12 years, up to 3 years after the introduction of dual cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Methods Annual data (2010–2019) were retrieved from the Dutch Cystic Fibrosis Registry. Longitudinal trends of per cent predicted forced expiratory volume in 1 s (FEV₁ % pred) decline, body mass index (BMI), BMI Z-score and intravenous antibiotic treatment duration before and after CFTR modulator initiation were assessed with linear and negative binomial mixed models. Results We included 401 participants (41.9% female, baseline age 24.5 years (IQR 18.0–31.5 years), baseline mean±SD FEV₁ 70.5±23.4% pred). FEV₁ decline improved from −1.36% pred per year to −0.48% pred per year after modulator initiation (change: 0.88% pred, 95% CI: 0.35–1.39%, p=0.001). This change was even 1.40% pred per year (95% CI: −0.0001–2.82%, p=0.050) higher in participants with baseline FEV₁ <40% pred. In adults, annual BMI trend was not altered (change: 0.10 kg·m^{−2·year−1}, 95% CI:−0.01–0.21, p=0.079). Annual BMI Z-score in children reversed from −0.08 per year before modulator treatment to 0.06 per year afterwards (change: 0.14 per year, 95% CI: 0.06–0.22, p<0.001). Intravenous antibiotic treatment duration showed a three-fold reduction in the first year after modulator initiation (incidence rate ratios (IRR): 0.28, 95% CI: 0.19–0.40, p<0.001), but the annual trend did not change in the subsequent years (IRR: 1.19, 95% CI: 0.94–1.50, p=0.153). Conclusion Long-term effectiveness of dual CFTR modulator therapies on FEV₁ decline, BMI and intravenous antibiotic treatment duration is less pronounced in a real-world setting than in clinical trials and varies considerably between pwCF and different baseline FEV₁ levels.