Eloralintide

Eloralintide (LY3841136) is a novel once-weekly, selective AMY1R amylin receptor agonist developed by Eli Lilly for the treatment of obesity. Unlike cagrilintide, which non-selectively activates amylin and calcitonin receptors, eloralintide demonstrates 11- to 12-fold selectivity for the human AMY1R receptor over CTR and AMY3R, a design choice believed to drive its markedly improved gastrointestinal tolerability while preserving robust weight-loss efficacy. In a 48-week Phase 2 trial (NCT06230523) in 263 adults with obesity, monotherapy produced dose-dependent mean body weight reductions of 9.5% to 20.1% versus 0.4% with placebo, with weight loss curves not yet plateauing at week 48. Eli Lilly announced plans to initiate Phase 3 monotherapy trials by year-end 2025, and is concurrently evaluating eloralintide in combination with tirzepatide in the ATTAIN Phase 2 program.

• Phase 2 Monotherapy Efficacy
• Curve Not Yet Plateauing
• Body Composition Quality

Once-weekly subcutaneous dosing supported by 13–15 day half-life. Up to 20.1% mean body weight loss at 48 weeks in Phase 2 with markedly improved GI tolerability versus non-selective amylin agonists. Potential combination partner for tirzepatide.

Subcutaneous injection allows the lipidated, albumin-binding peptide to achieve sustained plasma exposure. Eloralintide selectively activates AMY1R in the brainstem area postrema and hypothalamus, driving satiety and reduced food intake while sparing CTR-mediated GI side effects.

Peak plasma concentration: 4.2 days. Elimination half-life: 12.9 days – 15.3 days. Largely cleared by: 64.6 days – 76.3 days.

Research protocols from published literature — not dosing recommendations.

• Tirzepatide — Synergistic: Active investigation in the ATTAIN Phase 2 program (NCT06603571) evaluating eloralintide combined with tirzepatide. Complementary mechanisms — AMY1R-selective amylin agonism plus dual GIP/GLP-1 receptor activation — are hypothesized to drive additive weight loss while leveraging eloralintide's superior GI tolerability profile.
• Cagrilintide — Avoid Combination: Both compounds are amylin receptor agonists. Cagrilintide is non-selective (activates AMY1R, AMY3R, and CTR with comparable potency), while eloralintide is AMY1R-selective. Combining them would provide no additive benefit, would compound GI risk, and would defeat the tolerability rationale behind eloralintide's selective design.
• Pramlintide — Avoid Combination: Pramlintide is a short-acting amylin analog requiring 2–3 daily doses. Overlapping mechanism with eloralintide provides no incremental benefit and increases risk of cumulative GI side effects and excessive gastric-emptying delay.
• Semaglutide — Monitor Combination: No published direct combination trial with eloralintide. The closely-related cagrilintide + semaglutide combination (CagriSema) is well characterized, suggesting eloralintide + semaglutide would be pharmacologically reasonable but is not currently part of Lilly's published development program. Monitor for additive GI effects if attempted off-label.
• Retatrutide — Use Caution: Both produce significant GI effects, although eloralintide's AMY1R-selective design reduces GI burden relative to non-selective amylin agonists. Retatrutide's triple agonism is associated with substantial nausea/vomiting at higher doses. No combination data exists; concomitant use is not supported by clinical evidence.
• Insulin — Monitor Combination: Amylin agonists slow gastric emptying and reduce postprandial glucose excursions. Patients on insulin therapy may require dose reduction or timing adjustment to avoid hypoglycemia, particularly during dose escalation. Closely monitor blood glucose.
• Metformin — Compatible: No known pharmacokinetic interactions. Both target distinct pathways (AMP-kinase activation vs. amylin receptor signaling). Combination is expected to be well tolerated based on the broader class precedent for amylin analogs with metformin.
• SGLT2 Inhibitors — Compatible: Different mechanisms (renal glucose excretion vs. central satiety and gastric emptying). No known interactions expected; combination is consistent with broader cardiometabolic management standards.
• Oral Contraceptives — Requires Timing: Amylin-mediated delay of gastric emptying may alter absorption kinetics of orally-dosed medications, including oral contraceptives. Per class precedent, separate administration timing or use of a backup contraceptive method should be considered, particularly during dose escalation.

Supplies:

• Pre-filled pen or vial supplied by Eli Lilly (clinical trial supply only)
• Sharps disposal container
• Alcohol swabs for injection site preparation

1. 1Eloralintide is investigational and is supplied to clinical trial sites in unit-of-use presentations per Lilly trial protocol.
2. 2Allow medication to reach room temperature 15–30 minutes before injection.
3. 3Clean injection site (abdomen, thigh, or upper arm) with alcohol swab and allow to dry.
4. 4Inject subcutaneously at 45–90° angle per trial protocol; rotate sites weekly.
5. 5Dispose of needle in sharps container and follow trial sponsor reporting requirements for any reactions.

Weeks 1–4: Initial dose escalation; mild GI events (nausea, fatigue) possible, especially at faster escalation rates. Lower-dose arms (1–3 mg) had AE rates similar to placebo.. Weeks 4–12: Early appetite suppression and 3–6% weight loss apparent; curve steepens with continued dosing.. Weeks 12–24: Continued steady weight reduction across all active arms; cardiometabolic markers (lipids, hsCRP, BP) begin to improve.. Weeks 24–48: Peak weight-loss trajectory with mean reductions of 9.5–20.1% across dose arms; weight loss curve not yet plateauing at trial end..

Most common adverse events in Phase 2 were mild-to-moderate gastrointestinal symptoms (predominantly nausea) and fatigue.. Adverse event incidence was dose-related and substantially reduced with slower dose escalation.. Phase 1 (NCT05295940) reported only 2 of 36 eloralintide-treated participants with any GI adverse event across single doses up to 12 mg.. No clinically meaningful changes in vitals, ECG, or laboratory parameters reported in Phase 1.. Eloralintide is investigational and is not approved by FDA or any regulatory agency. Safety in pregnancy, lactation, pediatric populations, and chronic disease states has not been characterized..

Most common adverse events in Phase 2 were mild-to-moderate gastrointestinal symptoms (predominantly nausea) and fatigue.. Adverse event incidence was dose-related and substantially reduced with slower dose escalation.. Phase 1 (NCT05295940) reported only 2 of 36 eloralintide-treated participants with any GI adverse event across single doses up to 12 mg.. No clinically meaningful changes in vitals, ECG, or laboratory parameters reported in Phase 1.. Eloralintide is investigational and is not approved by FDA or any regulatory agency. Safety in pregnancy, lactation, pediatric populations, and chronic disease states has not been characterized..

Eloralintide should be stored at Refrigerated 2–8°C.