Ecnoglutide

1. 01Skin

   A weekly injection is absorbed slowly from under the skin

   Ecnoglutide is injected just under the skin once a week. From there it moves into the blood slowly, so the effect lasts for days instead of hours.

   For experts

   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]

2. 02Bloodstream

   A fatty-acid tail keeps it in the blood for days

   Natural GLP-1 is broken down within about two minutes. Ecnoglutide has a small fat chain attached that lets it hitch a ride on a blood protein called albumin, which slows its removal from the body. This is why one injection a week is enough.

   For experts

   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]

3. 03Pancreas

   It switches on GLP-1 receptors, with a tilt toward the cAMP signal

   Ecnoglutide fits GLP-1 receptors, which work like locks on the surface of cells such as the insulin-making cells of the pancreas. Once switched on, the receptor sends signals inside the cell. In lab tests, ecnoglutide favoured one signal (called cAMP) over another (called beta-arrestin). The company says this may make the effect last longer, but that has not been proven in people.

   For experts

   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]

4. 04Pancreas

   Insulin is released when blood sugar is high, and blood sugar falls

   When GLP-1 receptors on pancreas cells are switched on, the body releases more insulin after meals, mainly when blood sugar is high. In trials in adults with type 2 diabetes, ecnoglutide lowered a long-term blood sugar measure called HbA1c by clearly more than placebo.

   For experts

   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]

5. 05Brain

   Signals in the brain help people feel full sooner

   GLP-1 receptors are also found in parts of the brain that control hunger. Drugs of this kind are thought to work there to reduce appetite. In the obesity trial, people taking ecnoglutide lost much more weight than those on placebo, but the trials did not measure activity in the brain directly.

   For experts

   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]

6. 06Gut

   The gut is where most side effects show up

   GLP-1 drugs also act on the digestive system. In the trials, the most common side effects were stomach and gut problems such as nausea. They were mostly mild to moderate.

   For experts

   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]

7. 07Fat tissue

   Weight comes down over the course of a year

   In a 48-week trial in Chinese adults with overweight or obesity, people on the highest dose lost about 15% of their body weight on average by week 48, according to the company. On placebo, weight stayed about the same at week 40.

   For experts

   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]

8. 08Liver

   Fat stored in the liver also went down

   In the same obesity trial, the company reports that people on the highest dose who started with a lot of fat in their liver had about half as much after 40 weeks.

   For experts

   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]

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