2858-LB: Icovamenib, a Menin Inhibitor, Improves Endogenous Insulin Secretion in Type 1 Diabetes: Results from the COVALENT-112 Study

Introduction and Objective: Loss of functional pancreatic beta-cell mass in T1D leads to progressive decline in endogenous insulin secretion. Therapies restoring or improving beta-cell function remain a major unmet need. Icovamenib is an oral small-molecule menin inhibitor that modulates pathways involved in insulin secretion. COVALENT-112 evaluated the effect of icovamenib on insulin secretion in T1D. Methods: COVALENT-112 is a Phase 2, randomized, multicenter study evaluating icovamenib in adults with T1D. Participants were enrolled into 2 cohorts based on time since diagnosis and baseline endogenous insulin secretion. Cohort-1: participants diagnosed ≤3 years with measurable C-peptide during MMTT. Cohort-2: participants diagnosed >3 to ≤15 years with minimal C-peptide. Participants received 100mg or 200mg icovamenib once-daily for 12 weeks. Endogenous insulin secretion was assessed by MMTT and C-peptide AUC was calculated. Results: Thirty-seven participants were enrolled; only those receiving ≥80% of planned dosing were included in the analysis per protocol. In Cohort-1 (N=11), participants receiving 100mg (N=6) showed C-peptide AUC −7% from baseline at Week 12 and −31% at Week 52. Participants receiving 200mg (N=5) showed +56% C-peptide AUC at Week 12 and −7% from baseline at Week 52. In Cohort-2 (N=9), C-peptide AUC remained stable during dosing; participants receiving 100mg (N=5) showed −29% at Week 52, while those receiving 200mg (N=4) showed −3% at Week 52. Icovamenib was generally well tolerated with no serious treatment-emergent adverse events. Two participants in Cohort-2 receiving 200mg discontinued treatment due to elevated liver enzymes. All other safety events were mild or moderate. Conclusion: Icovamenib treatment in individuals with T1D appeared to slow the decline in endogenous insulin secretion observed in natural history studies, with a dose-response trend. Despite the small sample size, these findings suggest menin inhibition may enhance residual beta-cell function. Disclosure J.P. Frias: Employee; Ended; Biomea Fusion.