Prediction of Real-World Long-Term Outcomes of People with CF Homozygous for the F508del Mutation Treated with CFTR Modulators

Abstract

The clinical response to cystic fibrosis transmembrane conductance regulator (CFTR) modulators is variable within people with cystic fibrosis (pwCF) homozygous for the F508del mutation. The prediction of clinical effect in individual patients would be useful to target therapy to those who would benefit from it. A multicenter observational cohort study was conducted including 97 pwCF (F508del/F508del), who started lumacaftor/ivacaftor (LUM/IVA) treatment before June 2018. In order to assess the associations of individual in vivo and in vitro biomarkers with clinical outcomes, we collected clinical data regarding sex, age, and sweat chloride concentration (SwCl) at baseline and after six months of LUM/IVA; the percent predicted forced expiratory volume in 1 s (ppFEV1) and the number of pulmonary exacerbations (PEx) during the three years before up to three years after modulator initiation; and the forskolin-induced swelling (FIS) responses to LUM/IVA, quantified in intestinal organoids. On a group level, the results showed an acute change in ppFEV1 after LUM/IVA initiation (2.34%, 95% CI 0.85–3.82, p = 0.003), but no significant change in annual ppFEV1 decline in the three years after LUM/IVA compared to the three years before (change: 0.11% per year, 95%CI: −1.94–2.19, p = 0.913). Neither of these two outcomes was associated with any of the candidate predictors on an individual level. The median number of pulmonary exacerbations (PEx) per patient year did not significantly change in the three years after LUM/IVA compared to the years before (median: 0.33/patient year, IQR: 0–0.67 before vs. median: 0/patient year, IQR: 0–0.67 after p = 0. 268). The PEx rate after modulator initiation was associated with the PEx rate before (IRR: 2.26, 95%CI: 1.67–3.08, p < 0.001), with sex (males vs. females IRR: 0.36, 95%CI: 0.21–0.63, p = 0.001) and with sweat chloride concentration (SwCl) at baseline (IRR: 0.96, 95%CI: 0.94–0.98, p = 0.001). The change in SwCl was also significant (−22.9 mmol/L (95%CI: −27.1–−18.8, p < 0.001) and was associated with SwCl at baseline (−0.64, 95%CI: −0.90–−0.37, p < 0.001) and with sex (males vs. females 8.32, 95%CI: 1.82–14.82, p = 0.013). In conclusion, ppFEV1 decline after CFTR modulator initiation remains difficult to predict in individual patients in a real-world setting, with limited effectiveness for double CFTR modulator therapies. The PEx rate prior to CFTR modulator treatment initiation, sex and SwCl at baseline could be potential predictors of long-term PEx rate and of changes in SwCl after modulator initiation.

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

“…Most studies reported a moderate change from baseline ppFEV1 [13,14] and a moderate change in ppFEV1 decline after one [16,17] or two years [18] of follow-up. The discrepancy with a different recently published study that focused on predictors of long-term clinical outcomes using encounter-based ppFEV1 measurements [19] might be explained by the inclusion of annual best ppFEV1 measurements in the NCFR. Annual best measurements may provide a better estimation of long-term trends, as this reduces the impact of measurement variability over time compared to multiple repeated measurements.…”

“…Nevertheless, similar differences were reported in the PROGRESS trial, showing an increasing BMI trend in treated pwCF and matched registry controls, whereas BMI Z-score and weight-for-age trend improved after LUM/IVA initiation compared to a decline in matched registry controls [6]. Moreover, LUM/IVA and TEZ/IVA might induce a short-term improvement of pulmonary exacerbations [13,14] and reduce the use of IV antibiotics in the first year after treatment initiation in pwCF above 12 years of age, but this improvement was not sustained in the subsequent years [18,19]. This could indicate that the benefit of dual CFTR modulators on severe pulmonary exacerbations diminishes on the long-term, but it could also be related to a decreasing long-term adherence to modulators or to a reduced prescription or adherence to other co-medication such as dornase alpha, hypertonic saline and inhaled antibiotics in a real-life setting, The contrast between short-and long-term changes in this study also illustrates that traditional short-term clinical endpoints such as ppFEV1 might not always be the best measures to capture treatment benefits.…”

“…Real-world studies with a long-term follow-up are therefore important to provide additional post-approval data of the impact and sustainability of treatments on the entire heterogeneous population [12]. So far, seven studies have been published that assessed the effectiveness of LUM/IVA in a real-world setting [13][14][15][16][17][18][19]. Most of these studies were conducted in small populations, examining different subgroups and outcomes with a follow-up period of one year after LUM/IVA initiation and a limited observation period, not exceeding 845 patient-years.…”

Newly Discovered Cutting-Edge Triple Combination Cystic Fibrosis Therapy: A Systematic Review

“…Elexacaftor is a CFTR corrector that operates at a different binding location on the CFTR protein than tezacaftor to improve the CFTR protein's functioning at the cell surface [ 15 ]. When administered as a combination, Trikafta enhances the function of the Phe508del mutant CFTR protein on the cell surface, resulting in greater chloride ion transport and amelioration of symptoms [ 9 , 16 , 17 ].…”

“…In patients homozygous for Phe508del mutations, elexacaftor-tezacaftor-ivacaftor revealed no serious adverse events and no consequences that led to cessation when compared to tezacaftor-ivacaftor. Both experimental groups experienced similar adverse effects, which were mostly resolved by the end of the four-week study [ 17 , 25 ].…”