Inside the body with Ecnoglutide

Ecnoglutide is given subcutaneously once weekly. In the phase 1 study in healthy adults (n=64 across single- and multiple-ascending-dose parts), absorption was described as slow, with median time to peak concentration of 12 to 72 hours in the multiple-dose cohorts.[src][src]

The molecule carries a C18 diacid fatty acid on Lys30 via a gamma-Glu-2xAEEA linker; the discovery paper states that acylation was used to extend half-life by promoting albumin binding and resistance to DPP-4. Position 8 carries valine instead of alanine (semaglutide uses the non-natural residue Aib); the authors chose Val8 because it had been reported to favour cAMP signalling and because it allows fully recombinant manufacture from natural amino acids. Steady-state half-life was 124 to 138 hours in healthy adults.[src][src]

In cell assays, ecnoglutide bound the human GLP-1 receptor with about 12-fold higher affinity than semaglutide by surface plasmon resonance (KD 1.45 nM versus 17 nM), induced cAMP with an EC50 of 0.018 nM (semaglutide 0.012 nM), reached a maximal beta-arrestin recruitment of about 60% versus 100% for semaglutide, and induced much less receptor internalisation (EC50 above 10 uM versus 0.093 uM). These are in vitro findings. The authors propose that reduced internalisation prolongs signalling; a clinical advantage over unbiased GLP-1 agonists has not been demonstrated in a randomised head-to-head trial.[src][src]

GLP-1 receptor activation on pancreatic beta cells potentiates glucose-dependent insulin secretion (established GLP-1 biology; in rodents ecnoglutide raised insulin and lowered glucose more than semaglutide, an animal finding). In humans with type 2 diabetes, the phase 2 trial showed HbA1c reductions of 1.81%, 1.90% and 2.39% at the three tested doses versus 0.55% with placebo at week 20. In EECOH-1 at week 24, HbA1c fell 1.96% and 2.43% versus 0.87% with placebo (differences -1.09% and -1.56%). In EECOH-2 at week 32, HbA1c fell 1.91% and 1.89% versus 1.65% with dulaglutide at the comparator dose (non-inferior).[src][src][src][src][src]

Appetite suppression through central GLP-1 receptors is the accepted mechanism of the drug class, but brain activity or food-intake mechanisms were not measured for ecnoglutide in the human trials cited here. In db/db mice and diet-induced obese rats (animal-only data), ecnoglutide produced greater body-weight reduction than semaglutide; this has not been tested head to head in people. In the human SLIMMER trial, the treatment differences versus placebo at week 40 were -9.2%, -11.1% and -13.3% body weight across three doses.[src][src][src]

In SLIMMER, treatment-emergent adverse events occurred in 93% of participants on each ecnoglutide dose versus 84% on placebo; the most common were mild-to-moderate gastrointestinal events. In the phase 1 study, adverse events included decreased appetite, nausea and headache. Slowing of gastric emptying is a recognised GLP-1 class effect (Drucker 2018) but was not specifically reported in the ecnoglutide sources reviewed.[src][src][src]

SLIMMER enrolled 664 adults (BMI at least 28, or at least 24 with a weight-related condition; no diabetes). At week 40, 77%, 84% and 87% of participants on the three doses lost at least 5% of body weight versus 16% on placebo. The sponsor reports, in its approval announcement, a mean 15.4% weight reduction (15.1% placebo-adjusted) at week 48 on the highest dose without a plateau.[src][src]

According to the sponsor's approval announcement, mean liver fat content fell by 53.1% from baseline at week 40 in SLIMMER participants on the highest dose who had baseline liver fat of at least 8%. This figure comes from a company press release rather than the primary paper abstract and should be treated as sponsor-reported.[src]