Review finds incretin and nutrient-sensing GPCR therapeutic failures in T2D often due to modality, not target biology

Receptor-directed therapeutics, particularly those targeting incretin receptors like GLP-1R and GIPR, have revolutionized type 2 diabetes (T2D) management. Despite strong target biology, many promising drug candidates fail in clinical development. This review addresses the critical gap in understanding why programs arrest, proposing that factors beyond receptor biology—specifically pharmaceutics, modality, and formulation—play a dominant role. Current standards often overlook these aspects, leading to significant attrition rates even for well-validated pathways.

This review established a pharmaceutics-centered framework to evaluate the clinical value of receptor-directed therapeutics for type 2 diabetes. It systematically analyzed 49 programs that reached Phase II, focusing on glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin co-agonism, and selected nutrient-sensing receptors. The framework assessed target biology, modality (e.g., small molecule, peptide), and formulation to identify factors influencing clinical success or program arrest, using disclosed scientific causes.

Among programs with disclosed scientific causes for arrest, modality predominates as the key factor, indicating that the drug's physical form and delivery mechanism are more critical than the target itself. Notably, > two-thirds of program arrests were either unexplained or attributed to portfolio decisions, highlighting a significant lack of transparency in drug development. The review found that deliverability significantly discriminates among mechanisms with comparable target biology, suggesting that even strong receptor targets can fail without effective formulation. However, deliverability cannot overcome a low receptor ceiling, and public records poorly serve insights into these critical pharmaceutical aspects, making it difficult to learn from past failures.