WS05.03 A phase 3b study of the effects of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on glucose tolerance in people with cystic fibrosis (CF) and abnormal glucose metabolism

Objectives: We assessed the impact of ELX/TEZ/IVA treatment on glucose tolerance in people with CF and either impaired glucose tolerance (IGT) or CF-related diabetes (CFRD) over a 48-week period. Methods: VX19-445-117 (NCT04599465) was a Phase 3b, single-arm, open-label study of ELX/TEZ/IVA in people with CF aged ≥12 years heterozygous for F508del and a minimal function mutation and who had abnormal glucose tolerance as determined by oral glucose tolerance testing (OGTT), with either IGT or CFRD at screening. Primary endpoint was change in 2-hour OGTT blood glucose levels from baseline to the average of Week 36 and Week 48. Secondary endpoints were proportion of participants with improved dysglycemia categorization at Week 48 (defined as change from CFRD at baseline to IGT or normal glucose tolerance or change from IGT at baseline to normal glucose tolerance), and safety and tolerability. Results: Sixty-nine participants enrolled and received ≥1 dose of ELX/TEZ/IVA (mean [SD] age 25.1 [9.5] years; BMI 20.54 [2.60]; 2-hour OGTT blood glucose 217.6 [73.1] mg/dL); 29 participants had IGT and 40 had CFRD at screening. Three participants discontinued treatment (commercial drug availability [n = 2]; physician decision [n = 1]). Mean change from baseline in 2-hour OGTT blood glucose at the average of Week 36 and Week 48 was –35.0 mg/dL (95% CI: –49.2, –20.7; P < 0.0001). Overall, 37.7% of participants (95% CI: 24.8, 52.1) had improved dysglycemia categorization at Week 48; 35.5% of participants had normal glucose tolerance at Week 48 compared to 13.0% at baseline. Safety and tolerability were generally consistent with established safety profile of ELX/TEZ/IVA. Conclusion: In this largest trial to date of a CFTR modulator in people with CF and abnormal glucose metabolism, ELX/TEZ/IVA treatment led to clinically meaningful benefits in blood glucose regulation with statistically significant within-group decreases in blood glucose levels and improved dysglycemia categorization.