Elexacaftor-Tezacaftor-Ivacaftor Treatment Reduces Abdominal Symptoms in Cystic Fibrosis-Early results Obtained With the CF-Specific CFAbd-Score

Abstract

Background: The novel and highly effective CFTR modulator combination of elexacaftor-tezacaftor-ivacaftor (ETI) has been shown to improve lung function and body weight in people with Cystic Fibrosis (pwCF) carrying a F508del mutation. However, the impact of these modulators on gastrointestinal (GI) symptoms is relatively unknown. Therefore, the CFAbd-Score was developed and validated following FDA recommendations for development of a PROM including focus groups, multidisciplinary CF specialists, people with CF and their families. The aim of this study was to assess effects of ETI on GI symptoms using the CFAbd-Score.Methods: Gastrointestinal symptoms were prospectively assessed in pwCF using the CFAbd-Score before and up to 26 weeks during therapy. The CFAbd-Score was also administered to a healthy control (HC) group. The one-sided questionnaire includes 28 items grouped in five domains. Data analysis included calculation of scores with a weighting tool, developed according to FDA recommendations.Results: A total of 107 pwCF attended in four CF centres in Germany and four centres in the UK completed the CFAbd-Score on at least two occasions. Results were compared to those obtained from the questionnaire of 45 HCs. Despite differences in demographics, age and proportion of pancreatic insufficiency between German and UK patients, analyses based on linear mixed-effects models at week 24 of ETI therapy revealed that estimated marginal means (EMMs) of total CFAbd-Scores significantly reduced (mean ± SE: 14.9 ± 1.2→10.6 ± 1.4; p < 0.01). Also EMMs of all five domains significantly declined (“pain” 16.3 ± 1.6→10.2 ± 2.3, “GERD” 15.8 ± 1.8→8.2 ± 1.9, “disorders of bowel movement” 20.9 ± 1.5→16.0 ± 1.7, “disorders of appetite” 7.9 ± 1.1→2.6 ± 1.1 and “quality of life impairment” 10.1 ± 1.92→3.9 ± 1.9). However, during 24 weeks, CF participants’ symptoms mostly still did not reach the reference levels of HCs.Discussion: Using the CFAbd-Score, the first PROM specifically developed for assessment of CF-related abdominal symptoms, we demonstrate comprehensive improvements in GI symptoms after initiation of the highly effective modulator therapy ETI.

Need to study simplification of gastrointestinal medication regimen in cystic fibrosis in the era of highly effective modulators

“…Improvement of other GI symptoms with use of ETI has recently been reported. 7 Previous surveys in both the United States and Europe have identified simplification of medical regimen to a top priority among PwCF. 8,9 A randomized, controlled trial is underway to evaluate short-term differences in lung function between cohorts of PwCF on ETI that continue or discontinue inhaled hypertonic saline or dornase alfa.…”

“…11 Persistent, untreated or undertreated GERD can increase the risk of Barrett's esophagus and esophageal adenocarcinoma. 12 With the possibility of HEMT improving symptoms of GERD, 7 ongoing need for ASM must be reassessed.…”

“…Improvement of fecal elastase levels and malabsorption with ETI has only been reported anecdotally in PwCF ≥12 years of age, however, large scale reports have not yet been published. Improvement of other GI symptoms with use of ETI has recently been reported 7 …”

“…Persistent, untreated or undertreated GERD can increase the risk of Barrett's esophagus and esophageal adenocarcinoma 12 . With the possibility of HEMT improving symptoms of GERD, 7 ongoing need for ASM must be reassessed. Especially due to recent reports linking PPIs to several negative health consequences with long‐term use in the general population, 13,14 including increased risk of bacterial pneumonia, 15 Clostridium difficile infection, 15,16 bone health concerns including osteopenia and osteoperosis, 15,17 and risk of worsening kidney disease, although this remains a controversy 14,18 .…”

Triterapia con moduladores de la proteína de conductancia de transmembrana en fibrosis quística

“…Recientemente fue publicado un estudio multicéntrico europeo realizado en ocho centros distribuidos en Alemania y Reino Unido que midió la respuesta de los síntomas digestivos a la triterapia con un cuestionario específico para este fin en pacientes con FQ de 12 o más años. Los pacientes de Alemania lograron un mejor control de síntomas que los del Reino Unido, diferencias que fueron atribuidas al tipo de alimentación de cada país, a la mayor edad y por ende mayor proporción de insuficiencia pancreática en los pacientes del Reino unido 19 .…”