Daniel A. Briere, Hongchang Qu, Katherine Lansu, Minxia M. He, Julie S. Moyers, Tamer Coşkun, Annie Long, Dawn Allen, Libbey S. O’Farrell, Breanna Bowen, Edward Pratt, Beth Tidemann‐Miller, Lai Tham, Hilda Ibriga, Jorge Alsina‐Fernandez, Kieren J. Mather, Axel Haupt, Shobha Bhattachar
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.