Longitudinal change in FEV 1 in adults with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor in France: a prospective observational study

Without cystic fibrosis transmembrane conductance regulator (CFTR) modulators, cystic fibrosis is associated with an accelerated decline in percent predicted FEV 1 (ppFEV 1 ) of approximately 1·a clinically meaningful level per year.

Although treatment with elexacaftor-tezacaftor-ivacaftor (ETI) initially increases ppFEV 1, little is known about its subsequent effect on ppFEV 1 decline. Recent analyses of the extension phases of the Phase 3 ETI pivotal studies found no evidence of ppFEV 1 decline over 4 years in patients aged 12 years and older who were treated with ETI.

The objective of this study was to examine the decline in ppFEV 1 in a large, real-world cohort of adults with cystic fibrosis. Data from adults (aged ≥18 years) with cystic fibrosis and at least one F508del CFTR variant who initiated treatment with ETI between Dec 24, 2019, and Dec 23, 2023, at 31 cystic fibrosis centres included in the French prospective national observational ETI study in adults were analysed over 3 years.

Eligible participants were those with at least three measures of ppFEV 1 taken within 3 months following ETI initiation and the end of follow-up. The reference ppFEV 1 was the highest ppFEV 1 reached during the first 3 months of ETI treatment, after which subsequent decline in ppFEV 1 was analysed by use of a linear mixed-effects model with random effects to estimate each participant's variation from the population mean.

Data from 2321 adults with cystic fibrosis were included in this analysis. 1262 (54·4%) participants were male and 1059 (45·6%) were female.

Median age was 29·2 years (IQR 23·1-36·7) and the pre-ETI initiation ppFEV 1 was 59·7% (IQR 39·8-79·1). Within the first 3 months following ETI initiation, ppFEV 1 increased by a median of 14·5 percentage points (IQR 7·9-22·7).

The subsequent mean decline in ppFEV 1 was 0·70% (9a clinically meaningful level CI 0·57-0·83) per year. Importantly, the decline in ppFEV 1 was heterogeneous, with 1583 (68·2%) of 2321 participants showing no or limited decline (less than or equal to 1·a clinically meaningful level per year).

The remaining 738 (31·8%) participants showed a decline of greater than 1·a clinically meaningful level per year, with 342 (46·3%) of these participants having a decline of greater than 3·0% per year. In multivariable analyses, the decline in ppFEV 1 was greater in participants with a higher ppFEV 1 at 3 months after ETI initiation.

Treatment with oral azithromycin at 1 year after ETI initiation was associated with a lower risk of having a decline greater than 1·a clinically meaningful level per year (relative risk 0·78 [9a clinically meaningful level CI 0·68-0·90]; p <0·01), as was treatment with inhaled antibiotics (0·81 [0·70-0·94]; p <0·01).

These results suggest that approximately a third of adults with cystic fibrosis who are treated with ETI had a persistent decline in ppFEV 1 .

These data emphasise the importance of regular ppFEV 1 monitoring and highlight the need to improve current therapeutic strategies to prevent ppFEV 1 decline. Proposed strategies could include use of newer CFTR modulators to restore CFTR function more effectively, as well as mucoactive, anti-infective, and anti-inflammatory therapies.