Peripheral lung effect of elexacaftor/tezacaftor/ivacaftor in adult cystic fibrosis

Dimitri Stylemans a,∗, Chantal Darquenne b, Daniël Schuermans a, Sylvia Verbanck a,1, Eef Vanderhelsta,1

a b s t r a c t

Despite being an important patient group, adult cystic fibrosis patients with an FEV1 below 40%predicted have been excluded from clinical trials with elexacaftor/tezacaftor/ivacaftor. We conducted a real-life 3 months follow-up study in 14 adult CF patients (median FEV1 34%predicted) demonstrating significant treatment effects in terms of FEV1 (an increase of 12%predicted at 4 weeks, remaining stable thereafter).
Corresponding decreases in lung clearance index LCI (by 31%predicted, down from baseline 247%predicted) and ventilation heterogeneity in the acinar compartment (Sacin) (by 411%predicted, down from baseline 798%predicted) suggest a distinct peripheral lung effect. One patient had intermittent treatment interruptions because of drug-induced liver injury. Our real-life data confirm that treatment with elexa- caftor/tezacaftor/ivacaftor is effective in severely obstructive patients, and this is the first study to show time evolution of ventilation distribution improvement, pointing to the peripheral lung as the main site of treatment effect.

1. Introduction

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly re- duced symptoms and improved forced expiratory volume in one second (FEV1) in randomized controlled trials (RCTs) in both Phe508del homozygous (F/F) [1] and Phe508del heterozygous pa- tients with a minimal function mutation (F/MF) [2]. Patients with an FEV1 below 40%predicted were deliberately excluded from these RCTs. A mono-centric Irish study in 14 adult CF patients with FEV1 below 40%predicted demonstrated an increase of 10.6%predicted in FEV1 at four weeks along with a reduction in pulmonary ex- acerbation rate during a 5 month follow-up [3]. A more recent French multicentric study in 245 CF patients with a median FEV1 of 29%predicted [IQR: 24-34], showed a FEV1 increase of 15.1%pre- dicted in conjunction with reductions in exacerbations, long-term oxygen need and lung transplantation [4]. On the other side of the spectrum, where mild CF patients may well have FEV1 within nor- mal limits, it was suggested that the use of a ventilation distri- bution test could be useful to monitor CFTR modifying treatment since the lung clearance index (LCI) was shown to be associated with CFTR function [5]. The evolution of LCI in patients treated with ELX/TEZ/IVA has not been documented yet. The goal of this study was to quantify the effect of ELX/TEZ/IVA treatment on LCI, and on proximal and peripheral components of ventilation distri- bution, in addition to its effects on standard lung function indices and pulmonary exacerbations, also including patients previously excluded from clinical trials.

2. Materials and methods

We conducted a real-life follow-up study (BUN 143201940879) using the data from the UZ Brussel adult CF center database from December 2019 to November 2020. Adult CF patients with F/F or F/MF genotype treated with ELX/TEZ/IVA in an open la- bel extension trial (VX19-445-115) or in a medical need treat- ment program (high symptom burden and FEV1 below 30%pre- dicted for F/F patients and below 40%predicted for F/MF pa- tients at screening) were included, provided they could be mea- sured on the same multiple breath washout (MBW) equipment throughout the study period. Monthly exacerbation rate and need for oral or intravenous antibiotics in the year prior to baseline and in the 3 months follow-up period was documented; pul- monary exacerbations were defined based on the criteria of Bil- ton et al. [6]. Blood tests, complete pulmonary function (MasterScreenPFT,SentrySuite2.19,Mettawa,IL,USA) and nitrogen MBW with 1L tidal volume (EasyPro,Wbreath3.55,NDDMedizintechnick, Switzerland) were performed on the day of treatment initiation, after 2 weeks, 4 weeks and monthly thereafter up to 3 months. From the expired N2 concentration washout curve, LCI and alveolar mixing efficiency (AME) were computed; from N2 phaseIII slopes, Sacin and Scond were determined [7,8]. The Friedman test was used to detect differences in outcome measures across the dif- ferent follow-up visits; potential associations were explored using Spearman rank correlation (MedCalc v18,Ostend,Belgium).

3. Results

Fourteen patients met the inclusion criteria: 11 patients re- ceived treatment in the medical need program and 3 patients were treated in the open label extension trial. Median age was 36 years, the majority had F/F genotype (64%), where all patients suffered pancreatic insufficiency and half of the cohort had cystic-fibrosis- related-diabetes. Baseline median FEV1 was low (34%predicted; Table 1). In the 13 out of 14 patients who performed MBW testing, baseline LCI was abnormal (IQR (LCI): 13.2-22.2), with a median LCI of 16 corresponding to a z-score of 9.0. Median monthly exac- erbation rate in the previous year was 0.33 (IQR:0.17-0.50) and the monthly exacerbation rate with need for intravenous antibiotics of 0.25 (IQR:0.08-0.33).
Significant improvements in FEV1 were observed up until four weeks of treatment (Fig. 1, Table 1), with FEV1 remaining stable thereafter; for the entire group this corresponded to a median FEV1 increase by 12%predicted (IQR: 8%predicted; 18%predicted). A similar response, with asymptote beyond 2-4 weeks, was seen for indices of ventilation distribution (Fig. 1B-D). Median LCI de- creased by 31%predicted (IQR: -48%predicted; -23%predicted) from 247%predicted at baseline. Acinar ventilation heterogeneity (Sacin) decreased significantly (by 411%predicted, down from baseline 798%predicted) and predictably this was paralleled by a significant AME increase [8]. Taken together with the other statistically sig- nificant improvements for RV/TLC ratio (p<0.001), FVC (p<0.001) and VA (p<0.001) (Table 1) occurring within a month, these col- lude to indicate marked improvements in peripheral lung function. There were associations between improvements and baseline con- dition (2 last columns in Table 1), which was most consistent for RV, showing a greater reduction in patients with a greater baseline RV (highly significant both in absolute value and in %predicted). Treatment was generally well tolerated, although 1 patient suf- fered from a biopsy-proven drug-induced liver injury and had to interrupt treatment (single asterisk in Fig. 1). No rash was observed and patients did not report an increase in dyspnoea or cough. Exacerbation rate decreased from 0.33 to 0.07 per month in the three-month follow-up. One patient suffered an infectious exacer- bation after 2 months of treatment, with complete recovery at 3 months (double asterisk in Fig. 1). 4. Discussion This real-life study, which also included patients not eligible for clinical trials because of their low baseline FEV1, showed im- provements in lung function in line with those previously re- ported in clinical trials and in two recent observational studies with ELX/TEZ/IVA [1–4]. The majority of the benefit was already present at 2-4 weeks after treatment onset and prolonging the follow-up period did not alter these results. Evolution of ventila- tion inhomogeneity shows a particular beneficial effect in the pe- ripheral lung. Our findings can be related to results in patients with low base- line FEV1, from a recent French real-life study [4] and from a clini- cal trial subgroup analysis [2], showing FEV1 increases of the order of 15%predicted after 4-12 weeks of ELX/TEZ/IVA treatment. Our median FEV1 increase is slightly lower, and in fact very sim- ilar to that obtained in another recent real-life monocentric study with patients showing a similar exacerbation rate decrease to ours [3]. In our study, we believe this could be partly explained by the high proportion of F/F patients who were on compulsory treatment with another CFTR modulator (lumacaftor/ivacaftor) prior to initi- ation of ELX/TEZ/IVA, thus potentially limiting room for improve- ment. Previous studies including LCI measurement to evaluate treat- ment effect of CFTR modifiers have shown LCI decreases varying between 0.5 to 1.0 units (down from typical baseline LCI values of 9.5 to 11) with different CFTR modulators [9–11]. Inasmuch as LCI changes from very different study populations can be compared, the relative effect of ELX/TEZ/IVA on LCI, with the median LCI de- creasing by 2.0 units down from 16.0 (Table 1), appears to exceed that observed in the aforementioned studies. While LCI is a mea- sure of overall ventilation heterogeneity, Sacin, which interrogates the peripheral lung, markedly decreased after only two weeks of treatment. Taken together with the fact that Scond (as a marker for conductive ventilation inhomogeneity) did not improve at all, the dominant impact of treatment with ELX/TEZ/IVA appears to be in the acinar lung zone. In this context where peripheral im- provements can be expected, one could consider just using LCI in combination with AME, without the need for cumbersome phaseIII slope analysis, since AME has been shown to be a surrogate mea- sure of Sacin [8]. Besides inherently accounting for potential FRC change following treatment, LCI and AME are also simple to com- pute, making them more accessible for future studies. The limitation to our study is small cohort size, which is in- trinsic to the prevalence of the study population. In the future, the impact of ELX/TEZ/IVA on LCI will likely be monitored in larger patient groups, where for instance the capability of LCI to predict pulmonary exacerbations [12] could also be examined. 5. Conclusion We can conclude that marked effects on FEV1 and pulmonary exacerbations could be obtained in real life under treatment with ELX/TEZ/IVA, even in severely obstructive patients. Additional mea- surement of ventilation heterogeneity indicated a marked thera- peutic effect in the acinar lung zone. References [1] Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and safety of the elex- acaftor plus tezacaftor plus ivacaftor combination regimen in people with cys- tic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet 2019;394(10212):1940–8. [2] Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor-tezacaftor-iva- caftor for cystic fibrosis with a single Phe508del Allele. N Engl J Med 2019;381(19):1809–19. 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