Exocrine pancreatic function and highly effective modulators: A dual center retrospective study

Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators (HEMTs) have significantly improved outcomes in people with cystic fibrosis (CF). Their impact on established pancreatic disease remains uncertain. We aimed to evaluate the effects of HEMTs on exocrine pancreatic function in children with CF.

This retrospective dual-center observational study included children with CF treated with HEMTs for at least 12 months at the CF centers of Naples and Florence, Italy. Patients received elexacaftor/tezacaftor/ivacaftor (ETI) or ivacaftor (IVA). Fecal elastase-1 (FE-1), body mass index (BMI) z-score, sweat chloride, ppFEV1, pancreatic enzyme replacement therapy (PERT) use and history of recurrent acute pancreatitis (RAP) were evaluated at baseline and during follow-up. Patients with EPI were categorized as responders if FE-1 increased by ≥100 μg/g.

A total of 136 children (median age 11 years) were included. At baseline, 116/136 (85.3%) had EPI. Median FE-1 increased from 7.5 μg/g (interquartile range [IQR] 7.5-11) at baseline to 11.9 μg/g (IQR 7.5-21) after 12 months (p < 0.01). An increase in FE-1 was observed in 55/116 patients (47.4%), while a clinically relevant increase (≥ 100 μg/g) occurred in 5 patients at 12 months and in 3 additional patients at 24 months. One patient reached repeated FE-1 values in the pancreatic-sufficient range and discontinued PERT under clinical and nutritional monitoring. Significant improvements were observed in BMI z-score, ppFEV1, and sweat chloride (p < 0.01). Among pancreatic-sufficient patients, none with prior RAP experienced recurrence during follow-up.

Clinically meaningful FE-1 improvement in established EPI appears limited, although a subset of younger patients may show meaningful improvement. HEMTs may also reduce pancreatitis recurrence in pancreatic-sufficient individuals.