Real‐life efficacy and safety of elexacaftor/tezacaftor/ivacaftor on severe cystic fibrosis lung disease patients

Abstract

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane conductance regulator modulator, which has shown efficacy in CF patients (≥6 years) with ≥1 Phe508del mutation and a minimal function mutation. In October 2019, ETI became available on compassionate use basis for Dutch CF patients with severe lung disease. Our objective was to investigate safety and efficacy of ETI in this patient group in a real‐life setting. A multicenter longitudinal observational study was conducted to examine changes in FEV 1 , BMI, and adverse events at initiation and 1, 3, 6, and 12 months after starting ETI. The number of exacerbations was recorded in the 12 months before and the 12 months after ETI treatment. Patients eligible for compassionate use had a FEV 1 <40% predicted. Wilcoxon signed‐rank test analyzed changes over time. Twenty subjects were included and followed up for up to 12 months after starting ETI. Treatment was well tolerated with mild side effects reported, namely, rash (15%) and stomach ache (20%) with 80% resolving within 1 month. Mean absolute increase of FEV 1 was 11.8/13.7% ( p ≤ .001) and BMI was 0.49/1.87 kg/m 2 ( p < .001–0.02) after 1/12 months, respectively. In comparison to the number of exacerbations pretrial, there was a marked reduction in exacerbations after initiation. Our findings show long‐term effects of treatment with ETI in patients with severe CF lung disease in a real‐life setting. Treatment with ETI is associated with increased lung function and BMI, less exacerbations, and only mild side effects.

Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor—Ivacaftor

“…The phase 3 trials reported a mean absolute increase in ppFEV1 of 14 points after 24 weeks of therapy with ELX/TEZ/IVA in pwCF with one p.Phe508del allele and a ppFEV1 of 40%–90% at baseline ( Middleton et al, 2019 ). A similar absolute increase in the ppFEV1 of 15% was observed in French, Dutch, and Belgian CF patients with advanced pulmonary disease (ppFEV1< 40% at baseline) ( Burgel et al, 2021 ; Kos et al, 2022 ; Stylemans et al, 2022 ). In a real-world, postapproval setting ELX/TEZ/IVA did not only significantly improve spirometry but also the lung clearance index as a measure of ventilation homogeneity ( Graeber et al, 2022b ; Stylemans et al, 2022 ).…”

Use of CFTR modulators in special populations, part 2: Severe lung disease

“…There were no major safety concerns for pwCF and severe lung disease reported with use of IVA, TEZ/IVA, or ELE/TEZ/IVA 10–29 . Popowicz et al did note a transient yet significant decline in pulmonary function soon after initiation of full‐dose LUM/IVA that persisted for 24 hours; however, at 1 month, lung function returned to baseline for all pwCF 16 .…”

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

“…Overall, most therapeutic benefits were observed within 2–4 weeks after the start of ETI therapy and particularly beneficial effects were observed in peripheral zones of the lungs [ 52 ]. Another prospective, real-life study was performed by Kos and collaborators in a follow-up of 12 months [ 53 ]. Changes in ppFEV 1 , BMI, frequency of pulmonary exacerbations, and adverse effects were assessed in 20 PwCF carrying at least one copy of F508del-CFTR and advanced lung disease.…”

“…Compared to baseline values, there were significant improvements at 12 months of ETI therapy in ppFEV 1 (mean increase of 13.7%), BMI (mean increase of 1.87 kg/m 2 ), CFQ-R score (mean increase of 32.3 points), and frequency of exacerbations (mean of 2.89 vs. 0.19, before and after ETI, respectively). Despite 55% of participants experiencing at least one therapy-related adverse event, these were mild to moderate in severity and no discontinuation of ETI therapy was required [ 53 ].…”