Eloralintide (ZP4207): once-weekly weight-loss injection for obesity
An experimental once-weekly injection that mimics amylin, a hormone that signals fullness after meals, to help people with obesity lose weight; not yet an approved drug.
- Class
- Selective amylin receptor agonist (long-acting, once-weekly)
- Status
- Investigational — no regulatory approval in any jurisdiction; Phase 3 enrollment began late 2025
- Best-supported effect
- Dose-dependent body-weight reduction in overweight and obese adults (up to ~20% at 48 weeks in Phase 2 RCT); cardiometabolic marker improvements across all studied doses (human)
- Main caveat
- Phase 3 data are not yet available; long-term safety beyond 48 weeks is uncharacterized; no cardiovascular outcomes trial has been conducted; all eloralintide-specific human evidence is from a single sponsor
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Eloralintide (also called LY3841136) is an investigational once-weekly injection being developed by Eli Lilly as a weight-loss medication for adults with overweight or obesity. It mimics amylin, a hormone that the pancreas releases alongside insulin after meals to signal fullness and slow stomach emptying. Eloralintide is engineered to act selectively on amylin receptors while largely sparing the closely related calcitonin receptor — a selectivity profile intended to improve tolerability over the first-generation amylin analog pramlintide. It is not approved in any jurisdiction; Phase 3 enrollment began in late 2025 (Billings et al., Lancet 2025).
The stored 38-letter sequence (KCNTATCATQRLANFLVHSSNNFGPILSSTNVGSNTYQ) shows the amylin backbone only — the active drug is a 37-residue C-terminally amidated peptide in which Cys2 and Cys7 are joined by a non-reducible methylene thioacetal bridge (a mimic of the native disulfide) and Lys26 is acylated with a γ-Glu-γ-Glu spacer terminating in a C20 fatty diacid, the modification that reversibly binds serum albumin and gives the drug its roughly two-week half-life (Briere et al., Molecular Metabolism 2025). None of those modifications are visible in the raw letter sequence.
History
Eloralintide came out of an Eli Lilly medicinal-chemistry program aimed at overcoming the limitations of pramlintide — the first amylin analog (FDA-approved in 2005), whose mealtime injection schedule, mixed amylin/calcitonin receptor activity, and amyloid-aggregation tendency limited clinical uptake. The discovery work was published as a translational discovery-to-clinical-proof-of-concept report by Briere and colleagues in Molecular Metabolism (2025), describing the medicinal chemistry that yielded a peptide preferentially activating the human amylin 1 receptor (AMY1R) roughly 12-fold over the calcitonin receptor, with a C20 fatty-diacid acylation supporting once-weekly subcutaneous dosing.
The 12-week Phase 1 multiple-ascending-dose study was published by Bhattachar and colleagues in Diabetes, Obesity and Metabolism (2026), and the 48-week Phase 2 randomized controlled trial — 263 adults with overweight or obesity across 46 US sites — was published by Billings and colleagues in the Lancet (2025) and presented simultaneously at ObesityWeek 2025. Phase 3 enrollment was announced in late 2025. A Phase 2 combination study with tirzepatide (/card/pep-00017) is ongoing.
What it does
Eloralintide mimics amylin's natural role: it signals satiety to the brain, suppresses postprandial glucagon, and slows gastric emptying — all of which lower overall calorie intake. In the 48-week Phase 2 trial, participants on eloralintide lost roughly 9.5% (1 mg/week), 12% (3 mg/week), 18% (6 mg/week), and 20% (9 mg/week) of body weight versus about 0.4% on placebo, with cardiometabolic markers (waist circumference, blood pressure, lipid profile, glycemic control) improving across all active doses (Billings et al., Lancet 2025). The 12-week Phase 1 study had previously shown dose-proportional pharmacokinetics and a 2.6–11.3% weight-loss signal across dose levels in 100 participants (Bhattachar et al., Diabetes, Obesity and Metabolism 2026).
The mechanism operates on a pathway distinct from GLP-1 and GIP signaling used by semaglutide (/card/pep-00016) and tirzepatide (/card/pep-00017), which is why amylin agonism is being explored both as a standalone weight-loss strategy and as a partner for the GLP-1 class.
Evidence
- Human: One Phase 1 multiple-ascending-dose study (n=100, 12 weeks; Bhattachar et al., Diabetes, Obesity and Metabolism 2026) and one Phase 2 RCT (n=263, 48 weeks, 46 US sites; Billings et al., Lancet 2025). Phase 3 enrollment began late 2025; no Phase 3 results available. A Phase 2 combination study with tirzepatide is ongoing with no published results. All eloralintide-specific human evidence derives from Lilly-sponsored programs; independent replication has not occurred.
- Animal and in vitro: The discovery-to-clinical-proof-of-concept paper (Briere et al., Molecular Metabolism 2025) characterizes receptor pharmacology — eloralintide preferentially activated human AMY1R about 12-fold over the calcitonin receptor and 11-fold over AMY3R in vitro — and describes the preclinical optimization that supported clinical entry.
Myths and misconceptions
- "Eloralintide is available now through compounding pharmacies." No. Eloralintide is investigational and not approved in any jurisdiction. Anything offered under the eloralintide or LY3841136 name outside a Lilly-sponsored clinical trial is not the investigational drug and cannot be assumed to share its sequence, receptor selectivity, or pharmacokinetics. Its design — including the methylene-thioacetal bridge and C20 diacid acylation on Lys26 — is sequence- and chemistry-dependent and would not survive arbitrary third-party reproduction.
- "Eloralintide produces weight loss without side effects, unlike GLP-1 drugs." Partially true at best. Phase 2 data show a tolerability profile distinct from GLP-1 agonists — fatigue is prominent at the higher doses — but nausea remained common in the 6 mg and 9 mg arms and was dose-dependent across the trial (Billings et al., Lancet 2025). Tolerability is improved relative to pramlintide on certain axes, but the drug is not side-effect-free.
- "Eloralintide and pramlintide are essentially the same drug." No. Pramlintide is a mealtime injection co-administered with insulin for glycemic control; eloralintide is a once-weekly standalone agent being developed for obesity. Pramlintide co-activates calcitonin receptors; eloralintide is selectivity-engineered for AMY1. The two differ in sequence, half-life, receptor pharmacology, dosing schedule, and target indication (Briere et al., Molecular Metabolism 2025).
- "Because amylin is 'natural,' eloralintide is safer than semaglutide." Not established. Eloralintide is a synthetic engineered analog with backbone modifications and a fatty-acid conjugation; it is no more inherently "natural" than semaglutide. Safety is an empirical question answered by trial data, not by biological lineage.
Common questions
How does eloralintide differ from semaglutide and tirzepatide? Semaglutide acts on GLP-1 receptors; tirzepatide acts on both GLP-1 and GIP receptors. Eloralintide acts on amylin receptors — a distinct receptor system that converges on satiety and metabolic regulation through different signaling. That non-overlap is why Lilly is also studying eloralintide in combination with tirzepatide: the mechanisms are intended to be additive rather than redundant.
How does eloralintide compare to pramlintide (Symlin)? Pramlintide requires injection with every meal, co-activates both amylin and calcitonin receptors, and is approved for glycemic control in insulin-treated diabetes. Eloralintide is once-weekly, selective for amylin receptors over the calcitonin receptor, and is being developed for obesity. They share an amylin lineage but differ substantially in pharmacology, dosing, and intended use.
When might eloralintide be available? Phase 3 enrollment began in late 2025. If Phase 3 succeeds and regulatory review proceeds on a standard timeline, approval would not be expected before 2028–2029 at the earliest.
Known effects
- Body-weight reduction in overweight or obese adults — Phase 2 (48 weeks, n=263): roughly 9.5%, 12%, 18%, and 20% mean reduction at 1, 3, 6, and 9 mg per week versus 0.4% on placebo (Billings et al., Lancet 2025).
- Cardiometabolic marker improvement — Phase 2: improvements in waist circumference, blood pressure, lipid profiles, and glycemic control across all active doses (Billings et al., Lancet 2025).
- Early weight-loss signal — Phase 1 (12 weeks, n=100): 2.6–11.3% weight reduction across dose levels with dose-proportional pharmacokinetics (Bhattachar et al., Diabetes, Obesity and Metabolism 2026).
- Satiety and gastric slowing — expected pharmacological effect of amylin receptor agonism; decreased appetite reported as an adverse event in Phase 2 (Billings et al., Lancet 2025).
Safety signals
Nausea was dose-dependent across Phase 1 and Phase 2, more common at the 6 mg and 9 mg arms and reduced by slower titration (Billings et al., Lancet 2025; Bhattachar et al., Diabetes, Obesity and Metabolism 2026). Fatigue was prominent in Phase 2, particularly at the higher doses — a notable point of difference from the GLP-1 class, where nausea tends to be the dominant tolerability axis (Billings et al., Lancet 2025). Decreased appetite and headache were also reported in Phase 2. Long-term safety beyond 48 weeks has not been characterized; Phase 3 will be the first multi-year dataset. No cardiovascular outcomes trial has been conducted. Effects on bone density, lean-mass preservation, and pancreatic health are not addressed in the Phase 1 or Phase 2 publications. The safety profile of eloralintide in combination with tirzepatide is undefined pending the ongoing Phase 2 combination data. Cautions extending from the pramlintide class precedent — slowed gastric emptying altering absorption of orally administered drugs, and elevated hypoglycemia risk when combined with insulin or insulin secretagogues — apply by analogy; eloralintide-specific drug-interaction studies have not been conducted.
Regulatory status
- US (FDA): Not approved. Investigational; legally available only to participants in Lilly-sponsored clinical trials. Not legally available through compounding pharmacies, telehealth platforms, or research-chemical suppliers.
- International: Not approved in any jurisdiction; no commercial availability.
- WADA: Not listed by name; as a non-approved substance it is covered by S0 (substances not approved by any government regulatory health authority for human therapeutic use). As a peptide hormone analog it would be expected to fall under S2 upon approval. Athletes subject to WADA-aligned codes should treat eloralintide as prohibited in and out of competition.
Mechanism
Eloralintide is a selective agonist of the amylin receptor family — AMY1, AMY2, and AMY3 — which are heterodimers of the calcitonin receptor (CTR) with receptor activity-modifying proteins RAMP1, RAMP2, and RAMP3 respectively. Pramlintide and native amylin engage both amylin receptors and the bare calcitonin receptor; eloralintide is engineered to preferentially activate AMY1R while largely sparing CTR (about 12-fold AMY1R-over-CTR potency in vitro, with comparable selectivity over AMY3R), a profile intended to reduce off-target burden (Briere et al., Molecular Metabolism 2025).
The active molecule is a 37-residue C-terminally amidated peptide carrying a methylene thioacetal bridge between Cys2 and Cys7 — a non-reducible mimic of amylin's native disulfide — and a side chain on Lys26 consisting of two γ-glutamic-acid spacers terminating in a C20 fatty diacid. The fatty acid reversibly binds serum albumin, yielding an effective half-life of roughly two weeks and supporting once-weekly subcutaneous dosing (Briere et al., Molecular Metabolism 2025). Downstream, amylin-receptor signaling in the area postrema and nucleus tractus solitarius mediates satiety, suppresses postprandial glucagon release, and slows gastric emptying — the same physiology that underlies pramlintide's effects, applied here with a selectivity-engineered and long-acting scaffold.
Open questions
- Whether the Phase 2 weight-loss magnitude (up to roughly 20%) and tolerability profile replicate at Phase 3 scale and over multi-year exposure.
- Whether eloralintide reduces major adverse cardiovascular events — no cardiovascular outcomes trial exists; this is the benchmark now set by semaglutide.
- Long-term effects on bone density, lean mass, and pancreatic health beyond 48 weeks.
- Whether combination with tirzepatide adds efficacy at acceptable tolerability cost — Phase 2 results pending.
- Whether eloralintide's selectivity profile preserves the glycemic benefits pramlintide showed in insulin-treated T1D and T2D populations.
- Head-to-head efficacy and tolerability versus cagrilintide (/card/pep-10997) and the GLP-1/GIP class.
- Weight-regain dynamics after discontinuation, which have not been formally reported.
- All eloralintide-specific human evidence derives from Lilly-sponsored programs; independent replication has not occurred.
Related peptides
- Cagrilintide (/card/pep-10997) — the other long-acting amylin analog in late-stage obesity development (Novo Nordisk); the nearest direct competitor in the long-acting amylin class, also studied in combination with semaglutide.
- Semaglutide (/card/pep-00016) — GLP-1 receptor agonist; the current efficacy benchmark for incretin-class weight loss and the comparator most frequently invoked for amylin agonists.
- Tirzepatide (/card/pep-00017) — GIP/GLP-1 dual agonist; the partner molecule in the ongoing eloralintide Phase 2 combination study.
- Retatrutide (/card/pep-00018) — investigational GIP/GLP-1/glucagon triple agonist; a competing high-efficacy Lilly obesity program working through a different receptor axis.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could a once-weekly injection being developed for weight loss also help people resist alcohol cravings by acting on the brain's reward system through the same receptor?
Obesity and alcohol use disorder frequently occur together, and both have very limited effective treatments. A single once-weekly injection that could help with both conditions simultaneously would dramatically simplify treatment for a large number of patients and reduce the overall burden of two of the most prevalent and costly chronic diseases.
Does the non-natural ring structure at one end of Eloralintide boost its potency mainly by locking the peptide into the exact shape the receptor prefers, rather than just by making it more chemically stable?
If the ring's shape, not just its stability, is what matters, chemists would know to design future amylin drugs by focusing on making the ring even more precisely shaped, potentially achieving much higher potency with smaller doses and fewer side effects.
When you combine this amylin-based drug with a GLP-1 drug like semaglutide, do patients lose twice as much weight or just a bit more than with either drug alone?
Combination drug regimens are far more expensive and may carry more side effects. If the combination only adds rather than multiplies weight loss, doctors and payers can make more informed decisions about whether the extra treatment is worth the extra cost and risk for patients.
If the oily side-chain added to Eloralintide to make it long-acting were removed, would the remaining peptide stop being selective and start activating bone-related calcitonin receptors it was designed to avoid?
If selectivity is lost when the modification degrades, the body may be exposed to calcitonin-receptor effects at the tail end of each dosing interval, which could affect bone turnover. Knowing this would help doctors understand the true safety profile and dosing limits of this drug.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8668734431266785 | boltz-2 |
| ranking score | 0.8344197273254395 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10924,
sequence = {KCNTATCATQRLANFLVHSSNNFGPILSSTNVGSNTYQ},
target = {calcr},
author = {peptidemodel},
year = {2026},
status = {computed}
}