Eloralintide (LY3841136), a novel amylin receptor agonist for the treatment of obesity: From discovery to clinical proof of concept

Eloralintide (LY3841136), a novel amylin analog, was evaluated in translational studies to characterize its therapeutic potential for treating obesity. In vitro assays were performed in cell lines selectively expressing rat or human amylin 1 receptor (AMY1R), amylin 3 receptor (AMY3R), or calcitonin receptor (CTR). In vivo studies were conducted in rats and monkeys. A phase 1, randomized, placebo-controlled, participant/investigator-blinded trial evaluated the safety and tolerability of single-ascending eloralintide doses (0.04–12 mg) in healthy participants (NCT05295940). In vitro, eloralintide preferentially activated human AMY1R (12-fold > CTR, 11-fold > AMY3R), while in rats, both AMY1R and AMY3R were activated more potently than CTR. Eloralintide induced significantly less conditioned taste avoidance in lean rats than cagrilintide, a non-selective amylin receptor agonist (p<0.05). Eloralintide dose dependently reduced food intake and lowered body weight, primarily through fat mass loss, in diet-induced obese rats. Eloralintide demonstrated favorable pharmacokinetics in both rats and monkeys. In the phase 1 trial, 48 healthy participants had a mean body mass index of 27.5 kg/m 2 . Nine participants in the eloralintide cohorts reported 16 adverse events, with most being mild (n=15/16). Two participants reported 4 gastrointestinal events, including one moderate vomiting event. The pharmacokinetic profile of eloralintide supports once-weekly dosing. In eloralintide cohorts receiving single doses of 4 or 12 mg, week-4 mean percent change from baseline in body weight was -2.5% (p<0.01) and -4.4% (p<0.001), respectively, vs placebo (+0.6%). (+0.6%). Once-weekly dosing with eloralintide, an AMY1R-selective agonist, may offer a promising new therapeutic with favorable gastrointestinal tolerability for the treatment of obesity. • Eloralintide selectively activates human AMY1R compared to human AMY3R and CTR. • Eloralintide induces weight loss mainly through fat mass reduction in rodent models. • Eloralintide’s PK profile in animal models and humans supports once-weekly dosing. • Eloralintide is well tolerated in humans and reduces weight after a single dose. • Eloralintide may offer a new and effective therapeutic option for people with obesity.