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 (FEV(1) % 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 FEV(1) 70.5±23.4% pred). FEV(1) 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 FEV(1) <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 FEV(1) 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 FEV(1) levels.