851-P: Oral Long-Acting Menin Inhibitor Normalizes Type 2 Diabetes Mellitus (T2DM) in Two Rat Models

Abstract

Menin is a scaffold protein that has been recognized for its role in T2DM as a key regulator of β-cell proliferation. Menin inhibition has previously been shown to improve glycemic control in diabetic mice. Herein, we report the first evidence that BMF-219, an orally bioavailable, selective, irreversible menin inhibitor, restores glycemic control in Zucker Diabetic Fatty (ZDF) Rat and Streptozotocin-induced Rat (STZ) models of T2DM. Rats were treated daily with BMF-219, vehicle, or pioglitazone for 16 days. BMF-2was well tolerated throughout the conduct of the study. BMF-2treatment resulted in a significant 50% reduction in fasting and non-fasting blood glucose levels, reduced serum insulin and c-peptide levels (p<0.05) , and reduced HOMA-IR (p<0.001) after two weeks of treatment in ZDF rats. BMF-2decreased glucose levels at all timepoints during an oral glucose tolerance test at Day 15 (AUC reduction of 54%, p<0.001) and at Day 29 (AUC reduction of 40%, p<0.05, ∼2 weeks after the last dose) in the ZDF model, indicating prolonged glycemic control. Strikingly, BMF-219, but not pioglitazone, reduced blood glucose levels during an OGTT in STZ animals (AUC reduction of 41%, p<0.05, see figure) . Significant reductions in blood lipemic levels (p<0.01) and body weight were observed in both models. Collectively, our data indicate the novel and marked potential of BMF-2as an oral, long-acting treatment for T2DM. Disclosure T. Butler: Employee; Biomea Fusion Inc. W. Li: None. B. Law: Stock/Shareholder; Biomea Fusion Inc., Mirum Pharmaceuticals. T. Archer: Employee; Biomea Fusion. T. Kinoshita: None. P. Somanath: Employee; Biomea Fusion, Inc. Stock/Shareholder; Biomea Fusion, Inc.