Impact of elexacaftor/tezacaftor/ivacaftor on gastrointestinal outcomes, inflammation, exocrine pancreatic function and fat malabsorption: Report of PROMISE pediatric substudy

Background CFTR mutations likely contribute to inflammation, dysmotility and dysbiosis in the CF intestine. While CFTR modulators such as Elexacaftor/Tezacaftor/Ivacaftor (ETI) have shown pulmonary benefit, their efficacy on gastrointestinal (GI) outcomes is less clear. The PROMISE pediatric sub-study examines GI symptoms and fecal biomarkers in children with CF 6 to <12 years of age who recently initiated ETI. Methods Patient-Reported Outcome Measures (PROMs) from 3 validated GI symptom questionnaires (PAGI-SYM, PAC-SYM, PAC-QOL) and a stool-specific questionnaire (SSQ) were obtained. Stool samples were collected for biomarker analysis. We report on changes from baseline in PROMs, fecal calprotectin, elastase and steatocrit after ETI initiation. Estimated change and 95 % confidence interval (CI) were obtained from linear regression with adjustment for prior modulator use and sex at birth. Results There was no significant change from baseline in GI symptoms based on PROMs at 12 months. For fecal calprotectin, the proportion of participants with values in the normal range (≤80μg/g) increased from 22 % at baseline to 30 % at 1 month and 40 % at 6 months. There were no statistically significant changes in the proportions of those with fecal elastase in the normal range (>200μg/g), nor in the severe insufficiency range (<100μg/g). Conclusions As fecal calprotectin is a marker of intestinal inflammation, the increase in the proportion of patients with normal calprotectin at 6 months suggests that use of ETI potentially led to amelioration of intestinal inflammation. There was little change in exocrine pancreatic function after 6 months or GI symptoms after 12 months of treatment.