Eloralintide: Research & Studies
Scientific evidence, clinical trials, and research findings
📌TL;DR
- •3 clinical studies cited
- •Overall evidence level: moderate
- •8 research gaps identified
Research Studies
Eloralintide, a selective amylin receptor agonist for the treatment of obesity: a 48-week phase 2, multicentre, double-blind, randomised, placebo-controlled trial
Billings LK, Hsia S, Bays H, Tidemann-Miller B, O'Hagan J, Tham LS, Butler A, Kazda C, Mather KJ, Coskun T (2025) • Lancet
Pivotal Phase 2 trial of 263 adults with obesity or overweight randomized to once-weekly eloralintide (1, 3, 6, or 9 mg, or dose escalation regimens) vs placebo for 48 weeks. All active arms met the primary endpoint with superior weight loss vs placebo.
Key Findings
- Mean weight loss ranged from 9.5% to 20.1% vs 0.4% placebo at 48 weeks
- Treatment-regimen estimand: 7.3% (1 mg) to 17.5% (9 mg) vs 2.3% placebo
- Dose-dependent improvements in waist circumference, blood pressure, and lipids
- Improvements in glycemic control and markers of inflammation
- Most common AEs were nausea (11-64%) and fatigue (0-46%), dose-dependent
- Slower dose escalation reduced GI adverse event incidence
Limitations: Phase 2 trial with 263 participants; 48-week duration; excluded patients with type 2 diabetes; not powered for cardiovascular outcome assessment
Eloralintide (LY3841136), a novel amylin receptor agonist for the treatment of obesity: From discovery to clinical proof of concept
Briere DA, Qu H, Lansu K, He MM, Moyers JS, Coskun T, Long A, Allen D, O'Farrell L, Bowen B, Pratt E, Tidemann-Miller B, Tham LS, Ibriga H, Alsina-Fernandez J, Mather KJ, Haupt A, Bhattachar SN (2025) • Molecular Metabolism
Comprehensive translational paper covering discovery, preclinical pharmacology, and Phase 1 clinical data for eloralintide. Characterized receptor selectivity profile and head-to-head preclinical comparisons with cagrilintide.
Key Findings
- 12-fold selectivity for AMY1R over calcitonin receptor (CTR)
- 11-fold selectivity for AMY1R over AMY3R
- Phase 1 single-dose weight loss of 2.5% (4 mg) and 4.4% (12 mg) at 4 weeks in 48 participants
- Significantly less conditioned taste avoidance than cagrilintide in rats
- Preferential fat mass loss with reduced lean mass loss vs cagrilintide in preclinical models
Limitations: Phase 1 data from 48 healthy participants; preclinical head-to-head comparisons may not directly translate to human clinical outcomes; receptor selectivity measured in vitro
Eloralintide, a selective, long-acting amylin receptor agonist for treatment of obesity: Phase 1 proof of concept
Bhattachar S, Tham LS, Tidemann-Miller B, Ibriga H, Qu H, Briere DA, Haupt A, Mather KJ, Pratt E (2026) • Diabetes, Obesity and Metabolism
Multiple ascending dose Phase 1 trial of 100 participants with obesity or overweight (mean BMI 32.6) treated with eloralintide for 12 weeks. Established dose-proportional pharmacokinetics and demonstrated clinically meaningful weight loss with minimal GI adverse events.
Key Findings
- Weight loss ranged from 2.6% to 11.3% across dose groups at 12 weeks
- Dose-proportional pharmacokinetic behavior confirmed
- Most common AEs: decreased appetite (19%), headache (12%), fatigue (11%)
- Minimal gastrointestinal adverse events compared with non-selective amylin analogs
- Well tolerated with no serious adverse events
Limitations: 12-week treatment duration; 100 participants; Phase 1 design not powered for efficacy comparisons between dose groups
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🔍Research Gaps & Future Directions
- •Phase 3 confirmatory efficacy and safety data (ENLIGHTEN program ongoing)
- •Efficacy in patients with type 2 diabetes (excluded from Phase 2)
- •Long-term weight maintenance beyond 48 weeks
- •Head-to-head comparison with GLP-1 receptor agonists in humans
- •Cardiovascular outcome data
- •Combination efficacy with tirzepatide or semaglutide (Phase 2 ongoing)
- •Effect on non-alcoholic fatty liver disease and hepatic steatosis
- •Durability of weight loss after treatment discontinuation
Research Overview#
Eloralintide (LY3841136) has been evaluated in a progressive clinical development program that includes extensive preclinical pharmacology, two Phase 1 studies, and a pivotal Phase 2 trial. The evidence base is anchored by the 48-week Phase 2 trial published in The Lancet, which demonstrated dose-dependent weight loss of 9.5% to 20.1% in adults with obesity or overweight.
The evidence level is classified as moderate based on a well-designed Phase 2 RCT in a top-tier journal with supporting Phase 1 data. Phase 3 confirmatory results under the ENLIGHTEN program will be needed to establish definitive efficacy and long-term safety.
Phase 2 Trial -- Lancet 2025#
Billings et al., Lancet 2025 (PMID: 41207310)#
The pivotal Phase 2 trial was a 48-week, multicentre, double-blind, randomized, placebo-controlled study conducted in adults aged 18-75 years with a BMI of 30 kg/m2 or higher, or BMI of 27 kg/m2 or higher with at least one weight-related comorbidity, without type 2 diabetes.
Study Design:
- 263 participants randomized to seven arms
- Fixed doses: placebo, 1 mg, 3 mg, 6 mg, or 9 mg once weekly SC
- Dose escalation arms: 6-to-9 mg and 3-to-6-to-9 mg
- Treatment duration: 48 weeks
- Primary endpoint: percent change in body weight from baseline
Efficacy Results (Efficacy Estimand):
| Dose Arm | Weight Loss (%) | vs Placebo |
|---|---|---|
| Placebo | -0.4% | -- |
| 1 mg | -9.5% | Superior |
| 3 mg | -10.5% | Superior |
| 6 mg | -13.8% | Superior |
| 9 mg | -20.1% | Superior |
| 6-to-9 mg | -15.8% | Superior |
| 3-to-6-to-9 mg | -14.6% | Superior |
Treatment-Regimen Estimand (intent-to-treat, accounting for discontinuations):
| Dose Arm | Weight Loss (%) |
|---|---|
| Placebo | -2.3% |
| 1 mg | -7.3% |
| 3 mg | -10.5% |
| 6 mg | -13.8% |
| 9 mg | -17.5% |
| 6-to-9 mg | -15.8% |
| 3-to-6-to-9 mg | -14.6% |
Cardiometabolic Improvements: Treatment with eloralintide was associated with dose-dependent improvements in waist circumference, systolic and diastolic blood pressure, lipid profiles, glycemic control markers, and inflammatory biomarkers.
Safety: Nausea was the most common adverse event, ranging from 11% (1 mg) to 64% (9 mg). Fatigue ranged from 0% to 46% across dose groups. Adverse events were generally mild to moderate in severity. Slower dose escalation regimens reduced the incidence of GI side effects.
Discovery and Preclinical Characterization#
Briere et al., Molecular Metabolism 2025 (PMID: 41109426)#
This comprehensive translational paper characterized eloralintide from discovery through clinical proof of concept.
Receptor Selectivity:
- AMY1R activation: 12-fold more potent than CTR
- AMY1R activation: 11-fold more potent than AMY3R
- This selectivity profile distinguishes eloralintide from cagrilintide, which activates amylin and calcitonin receptors without selectivity
Preclinical Head-to-Head vs Cagrilintide:
- Eloralintide induced significantly less conditioned taste avoidance (a proxy for nausea) in lean rats
- Body weight loss with eloralintide was driven primarily by fat mass loss with reduced loss of lean mass compared to cagrilintide
- These differences may be attributable to reduced calcitonin receptor activation
Phase 1 Data (48 participants):
- Single doses of 4 mg and 12 mg produced weight reductions of 2.5% and 4.4% at week 4
- Favorable GI tolerability profile
- Pharmacokinetics supported once-weekly dosing
Phase 1 Multiple Ascending Dose Study#
Bhattachar et al., Diabetes Obes Metab 2026 (PMID: 41559929)#
A more comprehensive Phase 1 study evaluating multiple ascending doses in 100 participants with obesity or overweight (mean BMI 32.6 kg/m2) over 12 weeks.
Key Results:
- Dose-proportional pharmacokinetics confirmed across the dose range
- Weight loss ranged from 2.6% to 11.3% across dose groups at week 12
- Most common treatment-emergent adverse events: decreased appetite (19%), headache (12%), fatigue (11%)
- Minimal gastrointestinal adverse events
- No serious adverse events reported
Evidence Quality Assessment#
| Criterion | Assessment | Details |
|---|---|---|
| Study design | Phase 2 RCT | Double-blind, placebo-controlled, multi-dose |
| Sample size | Moderate (263 in Ph2) | Adequate for dose-response characterization |
| Primary endpoint | Met across all arms | Dose-dependent weight loss vs placebo |
| Duration | 48 weeks (Ph2) | Appropriate for weight loss assessment |
| Safety characterization | Adequate | Dose-dependent AE profile established |
| Peer-reviewed publication | Yes | Lancet (Ph2), Mol Metab + DOM (Ph1) |
| Regulatory pathway | Phase 3 initiated | ENLIGHTEN program enrolling 2026 |
Key Research Gaps#
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Phase 3 confirmation: The ENLIGHTEN program includes trials for obesity monotherapy and for obesity with knee osteoarthritis, but results are pending.
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Type 2 diabetes population: The Phase 2 trial excluded patients with T2D. Efficacy and safety in this metabolically distinct population remain unknown.
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Long-term outcomes: Weight maintenance, cardiovascular events, and safety beyond 48 weeks have not been established.
-
Human head-to-head data: No randomized trial has directly compared eloralintide with GLP-1 agonists or with non-selective amylin analogs in humans.
-
Combination therapy: A Phase 2 study evaluating eloralintide combined with tirzepatide is ongoing. Whether the distinct mechanisms produce additive or synergistic weight loss remains to be demonstrated.
-
Hepatic outcomes: Effects on non-alcoholic fatty liver disease and hepatic steatosis have not been specifically studied.
Related Reading#
Frequently Asked Questions About Eloralintide
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