June 20, 2025 – ABSTRACT – Randomized Phase 1a Single-Ascending Dose Study of ENT-03 in Healthy Obese Subjects and Subjects with Type 2 Diabetes
Authors
Richard S. Larson, G. Alexander Fleming, Michael B. Zemel, Alan C. Moses
Abstract
Introduction and Objective: Although GLP-1 agonists show efficacy treating obesity and T2D, significant side effects and high discontinuation rates occur. Drugs with different mechanisms of actions are needed for mono- and combination therapy. ENT-03 is a subcutaneously administered aminosterol antagonist of PTP1B that acts in the hypothalamus to decrease weight.
Methods: This was a first-in-human, randomized, placebo-controlled Phase 1a study to evaluate the safety, tolerability, and pharmacokinetics and pharmacodynamic profile of single doses of ENT-03 from 3.0 mg to 75 mg in healthy obese subjects (BMI 30-35) and obese subjects with T2D (HbA1c 6.6%-8.5%). Although not powered for statistical significance, clinical efficacy was assessed with exploratory endpoints.
Results: Forty-nine subjects were enrolled and randomized to either ENT-03 or placebo at a 5:2 (active: placebo) ratio. In healthy obese (n=27) and obese subjects with diabetes (n=8), ENT-03 was well-tolerated, with no safety signals, no treatment-emergent adverse events (TEAEs) ≥3, no SAEs and no TEAEs leading to study discontinuation. No vital sign, clinical lab or ECG changes were observed compared to baseline. All TEAEs were reported as mild (grade 1) or moderate (Grade 2), indicating a favorable AE profile. Mild nausea was observed in 4 patients, and 2 patients had moderate vomiting (3 mg dose and 50 mg dose). Four mild injection site reactions were observed and did not require intervention. t1/2 increased as doses increased in each treatment group with mean t1/2 of 72.3 hr (+7.1) at a dose of 75 mg. Of the 10 subjects receiving a single 50 mg dose, 8 lost an average of 0.99 kg on day 8 (p<0.04). All 8 subjects returned to baseline weight on day 14. In obese patients with type 2 diabetes, there was a trend toward decreased insulin, decreased Matsuda index, and decreased HOMA-IR.
Conclusion: ENT-03 with a novel mechanism of action to treat obesity and/or T2D appears safe and well-tolerated in this Phase 1a study.
R.S. Larson: Employee; Metabolics Pharma, Enterin Inc. G. Fleming: Advisory Panel; Abvance Therapeutics. Consultant; AdipoPharm, ADOCIA, Aerami Therapeutics, Biocon. Stock/Shareholder; Diasome Pharmaceuticals. Consultant; Biomea Fusion, Glyscend Therapeutics, Intarcia Therapeutics, Inc, Kriya Therapeutics. Other Relationship; Juvenile Diabetes Research Foundation (JDRF). Consultant; Oramed Pharmaceuticals, Regor Therapeutics, Rhythm Pharmaceuticals, Inc, Rivus Pharmaceuticals Inc, TIXiMED, vTv Therapeutics, Zealand Pharma A/S, Zucara Therapeutics. M.B. Zemel: Consultant; AdipoPharm, Aerami Therapeutics, Diasome Pharmaceuticals, Glyscend Therapeutics, Intercept Pharmaceuticals, Inc, NeuroBo Pharmaceuticals, Inc, Rhythm Pharmaceuticals, Inc, TIXiMED, Zealand Pharma A/S, Enterin. A.C. Moses: Consultant; Vertex Pharmaceuticals Incorporated, Virta Health Corp, Alnylam Pharmaceuticals, Inc. Board Member; diaTribe. Stock/Shareholder; Minutia, Inc. Consultant; Scholar Rock. Advisory Panel; TIXiMED.
