Ivacaftor

Impact of novel CFTR modulator on sinonasal quality of life in adult patients with cystic fibrosis

Jennifer E. Douglas, MD1 , Alyssa M. Civantos, BA1 , Tran B. Locke, MD2 , Auddie M. Sweis, MD3, Denis Hadjiliadis, MD4, Gina Hong, MD, MHS4, Daniel J. Dorgan, MD4, Michael A. Kohanski, MD, PhD1, James N. Palmer, MD1 and Nithin D. Adappa, MD1

Introduction

Cystic fibrosis (CF) is a genetic condition caused by an abnormality in the cystic fibrosis transmembrane con- ductance regulator (CFTR) causing recurrent pulmonary infections, pancreatic insufficiency, and, from an otolaryn- gology perspective, chronic rhinosinusitis (CRS).1 Symp- toms are recalcitrant to medical therapies, and over 20% of CF patients require endoscopic sinus surgery (ESS) to address sinonasal complaints. Sinus complaints can exac- erbate lower pulmonary issues, and studies have demon- strated improved pulmonary outcomes with successful treatment of sinonasal symptoms.2,3
CFTR modulators function by enhancing production and function of CFTR, and represent a significant advance- ment in CF treatment.4,5 A novel combination highly- effective CFTR modulator elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was approved in October 2019 for patients 12 years old with at least one F508del mutation, which represents over 85% of all CF patients. Limited data shows improved sinonasal outcomes with both ELX/TEZ/IVA and historic non-highly active CFTR modulators (eg, tezacaftor or lumacaftor [LUM] in combination with ivacaftor for DF508 homozygotes).6,7 The aim of this study was to eval- uate the effect of ELX/TEZ/IVA on sinonasal quality of life (QoL) as measured by the 22-item Sino-Nasal Outcome Test (SNOT-22) questionnaire8 in a cohort of CF adults at the University of Pennsylvania. We hypothesized that ini- tiation of ELX/TEZ/IVA would improve SNOT-22 scores, indicating enhanced sinonasal QoL.

Key Words:
cystic fibrosis; CFTR modulator; elexacafior; tezacafior; iva- cafior; chronic rhinosinusitis; sinus surgery; SNOT-22

Materials and Methods:

Patients and methods

This study was approved by the University of Pennsyl- vania Institutional Review Board. A retrospective review of patients in the adult CF program on ELX/TEZ/IVA was performed. Patients were included if they had at least one F508del mutation, were followed in the Department of Otorhinolaryngology, and completed the SNOT-22 questionnaire pre and post-initiation of ELX/TEZ/IVA.
Demographic data and medical history were reviewed. SNOT-22 scores were collected during routine follow- up prior to and at a single time point post-initiation of ELX/TEZ/IVA. All patients on CFTR modulators be- fore ELX/TEZ/IVA were DF508 homozygotes on either TEZ/IVA or LUM/IVA. Scores were stratified into 5 sub- score domains: rhinologic, extra-rhinologic, ear/face, psy- chologic, and sleep. The primary endpoint was change in SNOT-22, which was analyzed using a two-tailed paired t test.

Results

Of 231 adult CF patients on ELX/TEZ/IVA as of April 2020, 25 met inclusion criteria. Patients were excluded based on lack of ongoing rhinologic care (n 176) and post-treatment SNOT-22 (n 30). Demographics and baseline characteristics are shown in Table 1. No patients underwent ESS during the study. Mean follow-up duration was 146 days (range 7 to 301 days).
Average pre-treatment SNOT-22 was 34.4, which im- proved to 24.30 post-treatment. Two-tailed paired t test showed significance (average mean change [∆] –10.18 points; 95% confidence interval [CI] –16.78 to –3.57; p 0.004) (Table 2). Three sub-scores showed significant im- provement: rhinologic (∆ –4.10; 95% CI, –6.81 to –1.38; p 0.005), extra-rhinologic (∆ –3.72; 95% CI, –5.29 to –2.16; p < 0.0001), and ear/face (∆ –2.20; 95% CI, –3.85 to –0.55; p 0.01). When subjects were stratified by prior modulator use, there was no significant difference in pre-treatment SNOT- 22 (∆ –0.75; 95% CI, –15.24 to 13.74; p 0.91). Among modulator-naïve patients (n 15), there was significant improvement in SNOT-22 (∆ –11.30; 95% CI, –21.45 to –1.15; p 0.03). Among patients previously on a non-highly active CFTR modulator (n 10), SNOT-22 change trended toward significance (∆ –8.50; 95% CI, –17.39 to 0.39; p 0.06). When stratified by transplant status, there was no significant difference in pre-treatment SNOT-22 (∆ 4.25; 95% CI, –11.58 to 20.08; p 0.46). Among patients with- out a history of lung transplant (n 21), there was signifi- cant improvement in SNOT-22 (∆ –8.71; 95% CI, –16.05 to –1.37; p = 0.02). This was not true for patients with a history of lung transplant (n = 4; ∆ –17.88; 95% CI, –41.41 to 5.67; p = 0.09). Discussion Here we show the novel combination highly-effective CFTR modulator ELX/TEZ/IVA results in significantly im- proved sinonasal symptoms in CF adults. SNOT-22 im- proved 10.2 points, greater than the minimally clinically important difference for the questionnaire,8 and was ob- served at an average follow-up time of five months. This expands on one study reporting benefit of ELX/TEZ/IVA at three months, thus showing both early and durable re- sponse to therapy, with important implications for health- care expenditures.7 Overall, the cohort was representative of the CF popula- tion, with average pre-treatment SNOT-22 of 34.5, consis- tent with a diagnosis of CRS in the CF population.9,10 By stratifying SNOT-22 scores into sub-scores, we highlight ar- eas of greatest improvement (rhinologic, extra-rhinologic, and ear/face). Our data did not show a difference in psycho- logical or sleep symptoms, in contrast to prior publications on ivacaftor.6 CFTR modulator and sinonasal outcomes All patients in our study with a history of ESS were initiated on ELX/TEZ/IVA postoperatively (interval to initiation varied widely: one day to 48 years), making it is interesting to consider how ELX/TEZ/IVA may be used as an alternative, bridge, or adjunct to surgery. In our study, patients on a historic non-highly active CFTR modulator or with a history of lung transplant did not have significant improvement in SNOT-22. It is possi- ble these interventions had already improved SNOT-22. However, the difference approached significance, making this more likely attributable to lack of power and type II error. Limitations of our study include its small sample size, short follow-up period for one patient, and retrospective design, which excluded patients lacking ongoing rhino- logic care. The reasons these patients did not seek care or were lost to follow-up is unclear, but could include mild symptomatology, severe acute respiratory syndrome- coronavirus-2 (SARS-CoV-2) concerns, and the burden of healthcare visits in this complex population. Furthermore, this selected for patients with more severe sinus disease who may not be representative of the CF population as a whole. In summary, the novel highly-effective CFTR modula- tor ELX/TEZ/IVA leads to significantly improved sinonasal QoL in CF adults as measured by the SNOT-22 question- naire. Future studies must focus on school-aged children yet to be approved for the therapy, as well as including objective measures of CRS (eg, endoscopic grading, Lund- Mackay scores) and increasing follow-up duration to better assess ongoing sinonasal symptomatology. References 1. Ratjen F, Döring G. Cystic fibrosis. Lancet. 2003;361:681-689. https://doi.org/10.1016/S0140- 6736(03)12567-6. 2. Hamilos DL. Chronic rhinosinusitis in patients with cystic fibrosis. J Allergy Clin Immunol Pract. 2016;4:605-612. https://doi.org/10.1016/j.jaip.2016. 04.013. 3. Holzmann D, Speich R, Kaufmann T, et al. Effects of sinus surgery in patients with cystic fibrosis after lung transplantation: a 10-year experience. Transplan- tation. 2004;77:134-136. https://doi.org/10.1097/01. TP.0000100467.74330.49. 4. 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