FRI605 Inhibition Of Intestinal SGLT1 With Mizagliflozin For The Treatment Of Post-bariatric Hypoglycemia

Disclosure: H.M. Lawler: Grant Recipient; Self; Vogenx, Inc. T.L. McLaughlin: Advisory Board Member; Self; January AI. Grant Recipient; Self; Eli Lilly & Company, Merck, Vogenx, Inc. Stock Owner; Self; January AI, Eiger BioPharmaceuticals. S. Shakeri: None. E.F. Stortz: None. A. Gupta: None. V. Singh: None. N. Turk: None. S. Walker: Employee; Self; Vogenx, Inc. Stock Owner; Self; Vogenx, Inc. B. Cheatham: Employee; Self; Vogenx, Inc. Stock Owner; Self; Vogenx, Inc. W. Wilkison: Employee; Self; Vogenx, Inc. Stock Owner; Self; Vogenx, Inc. Post-bariatric hypoglycemia (PBH) is a dangerous condition for which there is no approved medical therapy. Mizagliflozin (Miza) is a novel, first-in-class, orally administered selective sodium glucose transporter 1 (SGLT1) inhibitor. Miza is minimally absorbed with effects limited to the gastrointestinal lumen, where SGLT1 is primarily expressed. This clinical study (NCT05541939) was a randomized, sequential crossover single dose study to determine the effect of Miza on safety, tolerability and postprandial glucose and insulin in patients with PBH after a mixed meal tolerance test (MMTT). Nine patients (8 female and 1 male, 30-69 years old) were randomized to one of two treatment arms. All patients received a baseline MMTT. Treatment Arm A received a 2.5 and 5.0 mg Miza capsule at sequential visits. Treatment Arm B received a 2.5 mg Miza liquid formulation and 10.0 mg Miza capsule at sequential visits. Miza was administered 20 min prior to MMTT administration. Pharmacodynamic (PD) samples were taken at times 0-180 min, and glucose and insulin PD profiles determined. The primary endpoints were safety and change in glucose nadir from baseline. Secondary endpoints included change from baseline peak plasma glucose and insulin. Glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) were examined as exploratory endpoints in a subset of patients. Miza was well-tolerated with no SAEs. Adverse events were Grade 1 to 2, including treatment related events (nausea [4], headache [2], abdominal bloating [3], lack of satiety [2], diarrhea [2], dizziness [1], and taste disorder [1]). Glucose nadir change from baseline increased at all doses of Miza (6.2, 4.0, 31.5, and 17.5 mg/dL for 2.5, 5.0, 10.0 mg capsules and 2.5 mg liquid formulation, respectively). The mean glucose nadir change from baseline for all capsule doses was 12.6 ± 22.5 mg/dL (p = 0.045). Peak glucose change from baseline was decreased for all doses of Miza (−6.2, −37, −48, and −26 mg/dL for 2.5, 5.0, 10.0 mg capsules and 2.5 mg liquid formulation, respectively). The mean peak glucose change from baseline for all capsules was −29 ± 36.4 mg/dL (p = 0.027). Peak insulin change from baseline was decreased at all doses of Miza (−143, −180, −174, and −71 uU/ml for 2.5, 5.0, 10.0 mg capsules and 2.5 mg liquid formulation, respectively). The mean peak insulin change from baseline for all capsules was −165 ± 237 uU/ml (p = 0.012). Miza had no significant effect on circulating GLP-1. All Miza treatments showed decreased peak GIP levels and AUC(0-3h) compared to baseline. These data are consistent with previous studies showing excellent safety and tolerability. Improvements in glucose nadir and reductions in both peak glucose and insulin were observed, supportive of further development of Miza as an orally administered treatment for PBH. Presentation: Friday, June 16, 2023