Livoletide
A cyclic fragment of the ghrelin hormone's inactive-looking form, tested against the relentless hunger of Prader-Willi syndrome
Ghrelin circulates in two forms: acylated ghrelin, which carries a fatty acid and drives hunger, and unacylated ghrelin, which lacks it and seems to oppose some of its effects. Livoletide (AZP-531) is a cyclised eight-amino-acid piece of unacylated ghrelin, built to last longer in the body. A two-week trial in people with Prader-Willi syndrome found less food-seeking behaviour, but the larger three-month phase 2b/3 trial did not, and it was stopped. It was never approved.
Used in human trials: 3–4 mg, once daily for 14 days, subcutaneous (Studied dose) Details ↓
Recommended Dosing
Used in human trials
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
What is it?
Prader-Willi syndrome is a genetic disorder in which constant hunger, called hyperphagia, usually appears in childhood and drives severe obesity. People with the syndrome have high levels of acylated ghrelin, the hunger hormone, with relatively little of the unacylated form. Unacylated ghrelin had been shown in animals to blunt the appetite effect of acylated ghrelin, which gave the rationale for livoletide: supply an unacylated-ghrelin mimic and push the balance back. A 2013 review from its developer described it as a cyclised analogue of the 6-13 fragment with better pharmacokinetics than the natural hormone.
The cyclisation mattered. In human blood samples the linear fragment broke down quickly while the fully cyclised AZP-531 was untouched by peptidases, and after injection under the skin of rats and dogs its bioavailability was 85% to 95%, against 10% to 15% for the linear version. In mice on a high-fat diet, four weeks of infusion prevented insulin resistance and adipose inflammation and stopped acylated ghrelin from rising. Other animal work found it shrank heart damage after a blocked artery was reopened, and slowed the growth of breast cancer cells grown in three dimensions and as tumours in mice.
In people it was first given to 112 volunteers: healthy adults received single doses up to 120 micrograms per kilogram, and overweight adults and people with type 2 diabetes took it daily for 14 days. It was well tolerated, peaked about an hour after each injection and had a half-life of two to three hours. In the overweight group, doses of 15 micrograms per kilogram or more improved glucose without raising insulin, and weight fell 2.6 kg against 0.8 kg on placebo (PMID 27063928).
The Prader-Willi trial that followed randomised 47 patients to 3 or 4 mg a day, by body weight, or placebo for 14 days. Scores on the Hyperphagia Questionnaire improved significantly more with livoletide, most in those with the worst hunger at the start, and waist and fat mass fell, though weight did not change. The larger phase 2b/3 trial (158 patients, about 60 or 120 micrograms per kilogram a day for three months) was terminated: its registry record says livoletide did not significantly improve hyperphagia and food-related behaviour, with score changes of -5.1 and -3.6 against -3.3 on placebo (NCT03790865). Development stopped there.
At a Glance
Every value in this table is printed from the Grey Peptides dataset, the same record the compound explorer and comparison tool read, so the three can never disagree.
Educational information, not medical advice. The doses on this page come from approved labels, published studies and, where no study exists, amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Mechanism of Action
What the studies measured about how unacylated-ghrelin analogues act.
Against acylated ghrelin
Unacylated ghrelin analogues lowered plasma acylated ghrelin in animals (2013 review), and AZP531 prevented the rise in acylated ghrelin on a high-fat diet in mice (2013).
Glucose without more insulin
In overweight volunteers it lowered glucose without raising insulin, which the authors read as better insulin sensitivity (2016).
Not through the ghrelin receptor
The fragment family acts like unacylated ghrelin independently of binding the acylated-ghrelin receptor (2012).
Published Research
These are the studies of livoletide read from their PubMed abstracts on October 30, 2026. Three titles name only unacylated or des-acyl ghrelin analogues; they are carded because each abstract names AZP531 or AZP-531 as the substance tested.
14 days in Prader-Willi syndrome
47 patients with hyperphagia had daily injections of 3 or 4 mg, by body weight, or placebo. It was well tolerated; Hyperphagia Questionnaire total, 9-item and severity scores improved significantly more than on placebo, appetite fell, waist and fat mass decreased with no change in weight, and post-meal glucose fell.
First in humans
44 healthy adults had single doses of 0.3 to 120 micrograms per kilogram; 32 overweight adults and 36 with type 2 diabetes had 14 days of daily doses. Peak levels came about an hour after injection and the mean half-life was 2-3 hours. Overweight subjects lost 2.6 kg against 0.8 kg; at 60 micrograms per kilogram, HbA1c fell 0.4% against 0.2% in diabetes.
Why the ring matters
Of three unacylated-ghrelin fragments, the fully cyclised AZP531 resisted peptidases completely in human blood samples and reached 85-95% bioavailability under the skin in rats and dogs, against 10-15% for the linear fragment.
High-fat diet in mice
Four weeks of continuous infusion of des-acyl ghrelin or AZP531 prevented the glucose intolerance, insulin resistance and fat inflammation that a high-fat diet caused, and AZP531 also stopped acylated ghrelin rising.
Heart damage after reperfusion in mice
Given at reperfusion after a blocked coronary artery was reopened, AZP-531 reduced infarct size, activated Akt, ERK and mTORC1 signalling, and reduced apoptosis markers and mitochondrial oxidant production.
Breast cancer cells and xenografts
Unacylated ghrelin inhibited breast cancer cells grown in three-dimensional matrix through Gαi and reduced MAPK signalling, and AZP-531 suppressed the growth of breast cancer cells in culture and as xenografts in mice.
The developer's case for the drug class
Reviews attempts to block acylated ghrelin and argues that unacylated ghrelin and its analogues, which lower acylated ghrelin and improve glucose metabolism, are better candidates for type 2 diabetes and Prader-Willi syndrome; describes AZP-531 as a cyclised UAG(6-13) analogue then in development.
Side Effects & Contraindications
Reported Side Effects
From the two published human trials, each lasting up to 14 days.
Contraindications & Cautions
There is no label. These cautions follow from what was studied.
Legal Status
Livoletide was never approved.
Frequently Asked Questions
?What is livoletide?
A cyclised eight-amino-acid fragment of unacylated ghrelin (AZP-531), developed to curb the hunger of Prader-Willi syndrome.
?Did it work?
A 14-day trial in 47 patients improved hunger-related behaviour scores, but the 158-patient three-month phase 2b/3 did not show a significant improvement and was terminated.
?What doses were used?
3 or 4 mg a day by body weight in the 14-day Prader-Willi trial, and about 60 or 120 micrograms per kilogram a day in the phase 2b/3. These were trial doses, not recommendations.
?How long does it last?
Its half-life after injection under the skin was 2 to 3 hours, which suited once-daily dosing in the trials.
References
- [rct] Allas S, et al. "AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial." PLoS One, 2018;13(1):e0190849. PMID: 29320575.
- [clinical-trial] Allas S, et al. "Safety, tolerability, pharmacokinetics and pharmacodynamics of AZP-531, a first-in-class analogue of unacylated ghrelin, in healthy and overweight/obese subjects and subjects with type 2 diabetes." Diabetes Obes Metab, 2016;18(9):868-74. PMID: 27063928.
- [pubmed] Julien M, et al. "In vitro and in vivo stability and pharmacokinetic profile of unacylated ghrelin (UAG) analogues." Eur J Pharm Sci, 2012;47(4):625-35. PMID: 22841845.
- [pubmed] Delhanty PJ, et al. "Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis." FASEB J, 2013;27(4):1690-700. PMID: 23299855.
- [pubmed] Harisseh R, et al. "Unacylated ghrelin analog prevents myocardial reperfusion injury independently of permeability transition pore." Basic Res Cardiol, 2017;112(1):4. PMID: 27995363.
- [pubmed] Au CC, et al. "Three-dimensional growth of breast cancer cells potentiates the anti-tumor effects of unacylated ghrelin and AZP-531." Elife, 2020;9. PMID: 32667883.
- [review] Allas S, et al. "Clinical perspectives for ghrelin-derived therapeutic products." Endocr Dev, 2013;25:157-66. PMID: 23652401.
- [clinicaltrials] ClinicalTrials.gov NCT03790865: "A Phase 2b/3 Study to Evaluate the Safety, Tolerability, and Effects of Livoletide (AZP-531), an Unacylated Ghrelin Analogue, on Food-related Behaviors in Patients With Prader-Willi Syndrome" Millendo Therapeutics SAS. Phase 2/Phase 3, terminated, March 2019 to February 2020 (primary completion), 158 participants. Registry record read October 28, 2026.
Sources & Citations
Every study on this page was read from its PubMed record on October 30, 2026; the phase 2b/3 outcome is from its ClinicalTrials.gov record. Grey Peptides sells nothing and links to no vendor.
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