Bamadutide

The paradigm of one drug against multiple targets, known as unimolecular polypharmacology, offers the potential to improve efficacy while overcoming some adverse events associated with the treatment. This approach is best exemplified by targeting two or three class B1 G protein-coupled receptors, namely, glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR) and glucose-dependent insulinotropic polypeptide receptor for treatment of type 2 diabetes and obesity. Some of the dual and triple agonists have already shown initial successes in clinical trials, although the molecular mechanisms underlying their multiplexed pharmacology remain elusive. In this study we employed structure-based site-directed mutagenesis together with pharmacological assays to compare agonist efficacy across two key signaling pathways, cAMP accumulation and ERK1/2 phosphorylation (pERK1/2). Three dual agonists (peptide 15, MEDI0382 and SAR425899) and one triple agonist (peptide 20) were evaluated at GLP-1R and GCGR, relative to the native peptidic ligands (GLP-1 and glucagon). Our results reveal the existence of residue networks crucial for unimolecular agonist-mediated receptor activation and their distinct signaling patterns, which might be useful to the rational design of biased drug leads.

To gain further insights into the efficacy of SAR425899, a dual glucagon‐like peptide‐1/glucagon receptor agonist, by providing direct comparison with the glucagon‐like peptide‐1 receptor agonist, liraglutide, in terms of key outcomes of glucose metabolism.

Seventy overweight to obese subjects with type 2 diabetes (T2D) were randomized to receive once‐daily subcutaneous administrations of SAR425899 (0.12, 0.16 or 0.20 mg), liraglutide (1.80 mg) or placebo for 26 weeks. Mixed meal tolerance tests were conducted at baseline (BSL) and at the end of treatment (EOT). Metabolic indices of insulin action and secretion were assessed via Homeostasis Model Assessment (HOMA2) and oral minimal model (OMM) methods.

From BSL to EOT (median [25th, 75th] percentile), HOMA2 quantified a significant improvement in basal insulin action in liraglutide (35% [21%, 74%]), while secretion enhanced both in SAR425899 (125% [63%, 228%]) and liraglutide (73% [43%, 147%]). OMM quantified, both in SAR425899 and liraglutide, a significant improvement in insulin sensitivity (203% [58%, 440%] and 36% [21%, 197%]), basal beta‐cell responsiveness (67% [34%, 112%] and 40% [16%, 59%]), and above‐basal beta‐cell responsiveness (139% [64%, 261%] and 69% [−15%, 120%]). A significant delay in glucose absorption was highlighted in SAR425899 (37% [52%,18%]).

SAR425899 and liraglutide improved postprandial glucose control in overweight to obese subjects with T2D. A significantly higher enhancement in beta‐cell function was shown by SAR425899 than liraglutide.