Eloralintide
Also known as: LY3841136, LY-3841136
4 notable studies · 7 references
TLDR
Eloralintide is an investigational long-acting, preferential AMY1 amylin-receptor agonist that produced approximately 20% average weight reduction at higher doses in a 48-week Phase 2 obesity trial and has now advanced into Phase 3 development, but its long-term safety, outcomes, and advantages over other amylin-based therapies remain under investigation. https://pubmed.ncbi.nlm.nih.gov/41207310/
Research Supports
- Studied for effects on body weight and obesity through selective amylin-receptor agonism
- Investigated for satiety and food-intake regulation
- Studied for selective AMY1R activation versus broader amylin/calcitonin receptor agonism
- Investigated for gastrointestinal tolerability relative to less selective amylin agonists
- Studied in combination with tirzepatide (EloraTZP) for weight loss and glycemic measures
Observations Reported in Research
- 48-week Phase 2 trial: highest doses produced about 18-20% average weight reduction versus 0.4% with placebo (Billings et al., 2025)
- Receptor assays showed about 12-fold selectivity for AMY1R over the calcitonin receptor and 11-fold over AMY3R (Briere et al., 2025)
- Single-dose Phase 1 study: 12 mg produced -4.4% weight change at 4 weeks versus +0.6% with placebo
- In diet-induced obese rats, produced less conditioned taste avoidance than cagrilintide while retaining food-intake and weight effects (Briere et al., 2025)
- EloraTZP Phase 2b: combination produced 23.3% average weight loss versus 14.8% with tirzepatide alone (manufacturer-reported, not yet peer-reviewed)
These are brief summaries of what the referenced research examined or reported — not conclusions about safety or effectiveness, and not medical advice. See Notable Studies and Sources & References below for the full context and citations.
At a Glance
Classification: Long-acting selective amylin receptor agonist; preferential AMY1 receptor agonist
Eloralintide is a long-acting investigational amylin analogue being developed primarily for obesity and weight management. Unlike cagrilintide, which activates amylin receptors as well as the calcitonin receptor, eloralintide was deliberately designed for greater amylin-receptor selectivity. In human receptor experiments, eloralintide showed approximately 12-fold greater potency at AMY1R than the calcitonin receptor and 11-fold greater potency than at AMY3R. https://pubmed.ncbi.nlm.nih.gov/35324283/ That distinction may matter because researchers are investigating whether selective amylin signaling can retain strong effects on satiation and body weight while reducing some gastrointestinal or aversive effects associated with broader amylin/calcitonin receptor activation. The clinical evidence has advanced quickly. In a 48-week randomized Phase 2 trial, the highest-dose eloralintide groups produced average body-weight reductions of approximately 20%, compared with 0.4% with placebo. https://pubmed.ncbi.nlm.nih.gov/41207310/ Eloralintide remains investigational and is now in Phase 3 development. https://investor.lilly.com/news-releases/news-release-details/lillys-eloratzp-combination-eloralintide-and-tirzepatide
What Is Eloralintide?
Eloralintide is an engineered long-acting analogue of the pancreatic hormone amylin. Natural amylin is secreted alongside insulin from pancreatic beta cells following food intake and participates in satiation and metabolic regulation. Amylin receptors are unusual. They are formed when the calcitonin receptor (CTR) associates with one of three receptor activity-modifying proteins: • RAMP1 → AMY1R • RAMP2 → AMY2R • RAMP3 → AMY3R This receptor architecture helps explain why different amylin-related peptides can have substantially different pharmacological profiles. https://pubmed.ncbi.nlm.nih.gov/35324283/ Eloralintide was engineered to favor amylin-receptor signaling—particularly AMY1R—while producing substantially less activation of CTR. That makes it scientifically different from cagrilintide despite both being described broadly as amylin analogues.
What Are Researchers Studying?
Obesity and body-weight regulation
Obesity is the primary clinical development target for eloralintide. The major Phase 2 trial enrolled 263 adults with obesity or overweight plus at least one weight-related complication, without type 2 diabetes. After 48 weeks, average weight reductions were approximately: 1 mg: −9% 3 mg: −12% 6 mg: −18% 9 mg: −20% 6→9 mg: −20% 3→9 mg: −16% compared with approximately −0.4% with placebo. https://pubmed.ncbi.nlm.nih.gov/41207310/ These results moved eloralintide into large Phase 3 development.
Satiety and food-intake regulation
Like other amylin analogues, eloralintide is being investigated as a pharmacological way to enhance physiological signals involved in meal termination and satiation. Preclinical studies demonstrated dose-dependent reductions in food intake and body weight. In diet-induced obese rats, weight reduction occurred primarily through reductions in fat mass. https://pubmed.ncbi.nlm.nih.gov/41109426/ The broader goal is to determine whether selective AMY1R signaling can produce sustained reductions in energy intake with acceptable tolerability.
Selective amylin-receptor signaling
This is arguably the most scientifically distinctive part of the eloralintide program. In human receptor assays, eloralintide preferentially activated AMY1R: ~12× versus CTR ~11× versus AMY3R This differs meaningfully from less selective amylin/calcitonin receptor agonists. https://pubmed.ncbi.nlm.nih.gov/41109426/ Researchers are investigating whether that receptor profile changes the balance between weight reduction and adverse effects.
Gastrointestinal tolerability
Nausea and vomiting are important limitations of many pharmacological systems that reduce food intake. One hypothesis behind selective amylin-receptor agonism is that separating AMY1R activity from stronger calcitonin-receptor activation could improve tolerability. In preclinical experiments, eloralintide produced significantly less conditioned taste avoidance than cagrilintide in lean rats while retaining effects on food intake and body weight. https://pubmed.ncbi.nlm.nih.gov/41109426/ That does not prove superior gastrointestinal tolerability in humans, but it provided part of the rationale for clinical development. In the 12-week Phase 1 multiple-dose human trial, common adverse events included decreased appetite, headache and fatigue. https://pubmed.ncbi.nlm.nih.gov/41559929/
Combination with incretin therapy
Researchers are now investigating whether selective amylin signaling can complement incretin-based therapies. The most important current example is EloraTZP, which combines eloralintide with tirzepatide. Tirzepatide activates GIP and GLP-1 receptors, while eloralintide primarily targets amylin receptors. On September 30, 2026, Lilly announced results from a 48-week Phase 2b trial involving 367 adults with obesity or overweight and type 2 diabetes. Participants receiving the highest studied EloraTZP regimen lost an average 23.3% of body weight, compared with 14.8% with tirzepatide 15 mg alone. HbA1c reductions reached 2.9 percentage points versus 2.4 with tirzepatide alone. https://investor.lilly.com/news-releases/news-release-details/lillys-eloratzp-combination-eloralintide-and-tirzepatide These are currently manufacturer-reported Phase 2b results and should be labeled accordingly rather than treated as peer-reviewed evidence.
Obstructive sleep apnea
The Phase 3 development program is expanding beyond body weight alone. The ENLIGHTEN-3 trial is evaluating eloralintide in adults with obesity or overweight and moderate-to-severe obstructive sleep apnea. The trial began in 2026 and is expected to run through 2028. https://clinicaltrials.gov/study/NCT07369011 No efficacy conclusions should be drawn until trial results become available.
Long-term metabolic risk
Large Phase 3 trials are now positioned to evaluate outcomes beyond short-term weight reduction. ENLIGHTEN-1 includes a long extension for participants with prediabetes, allowing investigators to study longer-term metabolic outcomes and progression toward type 2 diabetes. https://trials.lilly.com/en-US/trial/664295 These data are not yet available.
How Does It Work?
Eloralintide activates the amylin receptor family, with a strong preference for AMY1R. Amylin receptors are complexes consisting of the calcitonin receptor plus a receptor activity-modifying protein. Eloralintide's pharmacology therefore differs from several neighboring metabolic peptides: Eloralintide → preferential AMY1R agonism Cagrilintide → broader amylin + calcitonin receptor agonism Semaglutide → GLP-1 receptor agonism Tirzepatide → GIP + GLP-1 receptor agonism Retatrutide → GIP + GLP-1 + glucagon receptor agonism These pathways can ultimately converge on decreased energy intake and body weight despite beginning at different receptors. Amylin signaling acts through central nervous system pathways involved in satiation and meal termination. The exact contribution of individual amylin-receptor subtypes to weight reduction, nausea, food aversion and other physiological effects remains an active area of research.
What Does the Research Show?
Human research
Eloralintide now has both Phase 1 and Phase 2 human evidence. Single-dose Phase 1 The first-in-human program included 48 healthy participants. Single doses between 0.04 and 12 mg were evaluated. At four weeks, mean body-weight change after a single exposure was: 4 mg: −2.5% 12 mg: −4.4% Placebo: +0.6% Most reported adverse events were mild. https://pubmed.ncbi.nlm.nih.gov/41109426/ Multiple-dose Phase 1 A subsequent 12-week randomized trial enrolled 100 adults with overweight or obesity. The study evaluated weekly dosing without dose escalation. The most common treatment-emergent events included decreased appetite, headache and fatigue, while pharmacokinetic measurements supported once-weekly dosing. https://pubmed.ncbi.nlm.nih.gov/41559929/ Phase 2 The major 48-week Phase 2 study enrolled 263 participants at 46 U.S. research centers. At the higher doses, average body-weight reductions reached approximately 18–20%, versus 0.4% with placebo. https://pubmed.ncbi.nlm.nih.gov/41207310/ Phase 3 Eloralintide has now entered the ENLIGHTEN Phase 3 program. ENLIGHTEN-1 alone plans to enroll approximately 1,980 participants and includes a prolonged extension in participants with prediabetes. https://trials.lilly.com/en-US/trial/664295 ENLIGHTEN-3 is a Phase 3 master protocol evaluating eloralintide in adults with moderate-to-severe obstructive sleep apnea and obesity or overweight; it began in 2026 and is expected to run through 2028. https://clinicaltrials.gov/study/NCT07369011 This means the evidence base is evolving rapidly.
Animal research
Preclinical experiments investigated eloralintide in rats and monkeys. In diet-induced obese rats, eloralintide: • Reduced food intake • Produced dose-dependent weight reduction • Reduced predominantly fat mass • Demonstrated prolonged pharmacokinetics compatible with eventual weekly administration Researchers also compared eloralintide with cagrilintide using conditioned taste avoidance. Eloralintide produced less conditioned taste avoidance in the experimental model. https://pubmed.ncbi.nlm.nih.gov/41109426/ This finding supports a hypothesis about differing tolerability profiles but cannot establish superiority in humans.
In-vitro research
Receptor pharmacology is particularly important for eloralintide. Researchers tested the compound in cells selectively expressing human AMY1R, AMY3R or CTR. Eloralintide preferentially activated human AMY1R, showing approximately: 12-fold selectivity over CTR 11-fold selectivity over AMY3R. https://pubmed.ncbi.nlm.nih.gov/41109426/ This provides a mechanistic basis for distinguishing eloralintide from broader amylin/calcitonin receptor agonists. The underlying amylin-receptor architecture has also been characterized structurally: AMY receptors consist of CTR associated with different RAMP proteins, which alter receptor pharmacology and peptide selectivity. https://pubmed.ncbi.nlm.nih.gov/35324283/
Notable Studies
Eloralintide (LY3841136), a Novel Amylin Receptor Agonist for the Treatment of Obesity: From Discovery to Clinical Proof of Concept
humanResearchers characterized eloralintide from receptor pharmacology through animal models and first-in-human testing. Eloralintide preferentially activated human AMY1R compared with AMY3R and CTR. In obese rats, it reduced food intake and body weight primarily through fat-mass reduction. Forty-eight healthy humans subsequently participated in a single-ascending-dose study. Four weeks after single 4 mg and 12 mg exposures, average weight changes were −2.5% and −4.4%, respectively, compared with +0.6% with placebo. The pharmacokinetic profile supported development as a once-weekly compound. https://pubmed.ncbi.nlm.nih.gov/41109426/
Limitations: The human portion was an early Phase 1 study involving only 48 participants. Single-dose weight changes cannot establish long-term efficacy or safety. Much of the mechanistic and tolerability comparison with cagrilintide was preclinical.
View publication →Eloralintide, a Selective, Long-Acting Amylin Receptor Agonist for Treatment of Obesity: Phase 1 Proof of Concept
humanResearchers randomized 100 adults with overweight or obesity across five multiple-dose cohorts. Participants received weekly eloralintide without dose escalation or placebo for 12 weeks. The study characterized repeated-dose pharmacokinetics, tolerability and changes in body weight. Pharmacokinetic exposure was approximately dose proportional, supporting once-weekly administration. Common treatment-emergent adverse events included decreased appetite, headache and fatigue. https://pubmed.ncbi.nlm.nih.gov/41559929/
Limitations: The study lasted only 12 weeks. It was designed primarily for proof-of-concept, pharmacokinetics and tolerability rather than long-term clinical outcomes.
View publication →Eloralintide, a Selective Amylin Receptor Agonist for the Treatment of Obesity: A 48-Week Phase 2, Multicentre, Double-Blind, Randomised, Placebo-Controlled Trial
humanResearchers randomized 263 adults across 46 U.S. research centers. At 48 weeks, average body-weight changes were approximately: 1 mg: −9% 3 mg: −12% 6 mg: −18% 9 mg: −20% 6→9 mg: −20% 3→9 mg: −16% Placebo: −0.4% The study provided the first substantial longer-duration evidence that selective amylin-receptor agonism can produce large reductions in body weight as monotherapy. https://pubmed.ncbi.nlm.nih.gov/41207310/
Limitations: The trial included only 263 participants and excluded people with type 2 diabetes. It was not designed to determine cardiovascular outcomes, mortality, or multi-year durability.
View publication →EloraTZP Phase 2b Study in Adults With Obesity or Overweight and Type 2 Diabetes
humanResearchers evaluated combinations of eloralintide and tirzepatide in 367 adults with obesity or overweight and type 2 diabetes. At 48 weeks, the highest reported EloraTZP regimen produced average weight reduction of 23.3%, compared with 14.8% with tirzepatide 15 mg alone. Average HbA1c reduction reached 2.9 percentage points versus 2.4 percentage points with tirzepatide alone. Lilly announced plans to move EloraTZP into Phase 3 development in Q4 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-eloratzp-combination-eloralintide-and-tirzepatide
Limitations: These are manufacturer-reported topline results, not yet a peer-reviewed primary trial publication. The findings apply to the eloralintide + tirzepatide combination and cannot be attributed to eloralintide alone.
View publication →What We Still Don't Know
Major unanswered questions include: • Long-term safety over multiple years • Cardiovascular outcomes • Mortality outcomes • Durability of weight reduction • Degree of weight regain after discontinuation • Long-term preservation or loss of lean mass • Whether selective AMY1R activation genuinely improves gastrointestinal tolerability relative to broader amylin/calcitonin agonism • Contributions of AMY1R versus other amylin-receptor subtypes • Long-term effects in people with type 2 diabetes • Effects on progression from prediabetes to diabetes • Whether weight reduction eventually plateaus at the levels observed in Phase 2 • Comparative effectiveness versus GLP-1/GIP therapies • Comparative effectiveness versus cagrilintide • Whether combining eloralintide with tirzepatide meaningfully improves long-term outcomes rather than simply increasing weight reduction • Safety and tolerability of prolonged multi-receptor combination therapy Phase 3 should answer several of these questions. https://trials.lilly.com/en-US/trial/664295
Related Compounds
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Sources & References
- Briere DA, Qu H, Lansu K, et al. Eloralintide (LY3841136), a Novel Amylin Receptor Agonist for the Treatment of Obesity: From Discovery to Clinical Proof of Concept. Molecular Metabolism. 2025;102:102271. doi:10.1016/j.molmet.2025.102271.
- Billings LK, et al. Eloralintide, a Selective Amylin Receptor Agonist for the Treatment of Obesity: A 48-Week Phase 2, Multicentre, Double-Blind, Randomised, Placebo-Controlled Trial. The Lancet. 2025. doi:10.1016/S0140-6736(25)02155-5.
- Eloralintide, a Selective, Long-Acting Amylin Receptor Agonist for Treatment of Obesity: Phase 1 Proof of Concept. Diabetes, Obesity and Metabolism. 2026.
- Cao J, et al. A Structural Basis for Amylin Receptor Phenotype. Science. 2022;375:eabm9609. doi:10.1126/science.abm9609.
- Eli Lilly and Company. EloraTZP Phase 2b Results in Adults With Obesity or Overweight and Type 2 Diabetes. September 30, 2026.
- Eli Lilly and Company. ENLIGHTEN-1: A Study of Eloralintide in Participants With Obesity or Overweight Without Type 2 Diabetes. Phase 3; NCT07321886.
- Eli Lilly and Company. ENLIGHTEN-3: A Study of Eloralintide in Participants With Obstructive Sleep Apnea and Obesity or Overweight. Phase 3; NCT07369011.
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