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

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

  • Mol Metab. 2025 Dec:102:102271. doi: 10.1016/j.molmet.2025.102271.
Daniel A Briere 1,  Hongchang Qu 2,  Katherine Lansu 2,  Minxia Michelle He 2,  Julie S Moyers 2,  Tamer Coskun 2,  Annie Long 2,  Dawn Allen 2,  Libbey O'Farrell 2,  Breanna Bowen 2,  Edward Pratt 2,  Beth Tidemann-Miller 2,  Lai San Tham 2,  Hilda Ibriga 2,  Jorge Alsina-Fernandez 2,  Kieren J Mather 2,  Axel Haupt 2,  Shobha N Bhattachar 2
Affiliations

Affiliations

  • 1 Eli Lilly and Company, Indianapolis, IN, USA. Electronic address: [email protected].
  • 2 Eli Lilly and Company, Indianapolis, IN, USA.
PMID: 41109426 DOI: 10.1016/j.molmet.2025.102271
Abstract

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.

Keywords

Amylin receptor agonist; Cagrilintide; Eloralintide; LY3841136; Obesity.

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