Impact of Elexacaftor/Tezacaftor/Ivacaftor on Glucose Tolerance and Abnormal Glucose Metabolism: A Phase 3b, Open-Label Clinical Trial

Rationale: Abnormal glucose metabolism is a common complication in people with cystic fibrosis (CF), and those with impaired glucose tolerance (IGT) or CF-related diabetes (CFRD) have increased disease burden. Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is safe and effective for people with CF aged ≥2 years with ELX/TEZ/IVA-responsive CFTR mutations; however, efficacy on glycemic control has not been studied. Objectives: To evaluate the impact of ELX/TEZ/IVA on glucose tolerance in people with CF who have IGT or CFRD. Methods: This phase 3b, open-label study, ELX/TEZ/IVA was administered for 48weeks to participants aged ≥12 years, heterozygous for F508del and a minimal function CFTR mutation, and with either IGT or CFRD. Measurements and Main Results: Sixty-nine participants received ELX/TEZ/IVA. The primary endpoint was change in blood glucose levels following 2-hour oral glucose tolerance test (OGTT) from baseline to the average of Week36 and Week48; participants had a mean change of -35.0 mg/dL (95%CI:-49.2,-20.7;P<0.0001) (-1.9 mmol/L [95%CI: 2.7, 1.2]). Secondary endpoints were the proportion of participants with improvement in dysglycemia categorization (CFRD, IGT, normal glucose tolerance) at Week48 and safety. Among participants with abnormal glucose tolerance at baseline, 37.7% (95%CI:24.8,52.1) had improvements in dysglycemia categorization at Week48. Overall, 35.5% of participants had normal glucose tolerance at Week48 compared to 13.0% at baseline. Safety was consistent with the established safety profile of ELX/TEZ/IVA. Conclusions: ELX/TEZ/IVA treatment led to clinically meaningful improvements in blood glucose regulation with significant within-group decreases in blood glucose levels following OGTT and improved dysglycemia categorization in people with CF with early IGT or CFRD. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT04599465.