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

OBJECTIVES

Eloralintide (LY3841136), a novel amylin analog, was evaluated in translational studies to characterize its therapeutic potential for treating obesity.

METHODS

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).

RESULTS

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/m2. 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%).

CONCLUSIONS

Once-weekly dosing with eloralintide, an AMY1R-selective agonist, may offer a promising new therapeutic with favorable gastrointestinal tolerability for the treatment of obesity.