Metabolics Pharma, a clinical-stage biopharmaceutical company based in Doylestown, Pennsylvania, has reported encouraging results from its first-in-human Phase 1a clinical trial of ENT-03, a novel drug candidate for treating obesity and type 2 diabetes. The study, presented at the American Diabetes Association 85th Scientific Sessions on June 22, 2025, demonstrated that ENT-03 was safe and well tolerated at all evaluated doses while showing positive efficacy trends.
Novel Mechanism of Action
ENT-03 represents a unique approach to metabolic disease treatment as a centrally acting aminosterol with Protein Tyrosine Phosphatase 1B (PTP1B) inhibitory activity. The compound works by acting on brain circuits that regulate energy and metabolism, leading to glucose normalization, improved insulin sensitivity, and weight loss. This central nervous system approach distinguishes ENT-03 from traditional peripheral metabolic therapies.
Preclinical studies have shown that ENT-03 is effective as a monotherapy and demonstrates additive effects when combined with GLP-1 agonists in animal models. Notably, the compound has shown durable weight loss and glucose and insulin normalization that persist after therapy cessation, suggesting potential long-term benefits.
Phase 1a Trial Design and Results
The Phase 1a clinical trial was designed as a single ascending dose study that evaluated seven dose cohorts of ENT-03 in healthy obese subjects and obese subjects with type 2 diabetes. The drug was administered subcutaneously at six different doses, with the primary endpoint focused on safety, tolerability, and pharmacokinetic data.
Secondary endpoints included assessments of fasting blood glucose, fasting insulin, lipid levels, and changes in body weight measured at seven days post-administration. The study results showed that ENT-03 was very well tolerated across all dose levels, with efficacy endpoints demonstrating trends toward weight loss at higher doses for both obese and obese patients with type 2 diabetes, accompanied by improvements in insulin sensitivity.
Clinical Significance and Future Development
"Our first-in-human study has demonstrated that ENT-03 is safe and very well tolerated and showed positive trends in both weight loss and insulin sensitivity that are consistent with what we have seen in preclinical in vivo studies," said Richard Larson, M.D., Ph.D., Chief Executive Officer and Chief Medical Officer of Metabolics Pharma.
The positive safety profile and encouraging efficacy trends observed in this Phase 1a trial support the advancement of ENT-03 into the next phase of clinical development. Metabolics Pharma is planning a Phase 1b study to evaluate optimal dosing regimens, which the company expects to initiate in the second half of 2025.
Company Focus on Metabolic Diseases
Metabolics Pharma specializes in developing novel therapies for metabolic diseases, including obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH). The company's lead compound, ENT-03, represents a differentiated approach to treating metabolic disorders by targeting insulin sensitivity through brain-mediated mechanisms rather than traditional peripheral pathways.
