Amycretin: what it is, how it works and what studies have found

Amycretin is the first single molecule designed to act as both a GLP-1 receptor agonist and an amylin receptor agonist [1]. It moved from first-in-human dosing in 2022 to phase 3 in 2026, and it now carries the International Nonproprietary Name zenagamtide [2]. The evidence is still early: two phase 1 studies in people with overweight or obesity, two phase 2 studies in type 2 diabetes, and preclinical work. This overview sets out what those studies report, with each figure linked to its source. It reports published research and is not medical guidance.

What is amycretin?

Amycretin (INN zenagamtide; development code NNC0487-0111) is a unimolecular peptide agonist of the GLP-1, amylin and calcitonin receptors [2][3][4]. It joins a GLP-1 receptor agonist moiety and an amylin receptor agonist moiety in one chain, rather than giving two peptides together [5].

The rationale is that GLP-1 receptor agonists and amylin analogues both reduce body weight and glucose, and combining them has given greater weight loss than either alone. In the phase 3 REDEFINE 1 trial, the co-administered combination of cagrilintide and semaglutide produced -20.4% mean body-weight change at week 68 versus -3.0% with placebo [6]. The amycretin design goal was a single molecule equipotent in vitro to that combination at GLP-1 and amylin receptors [5].

Amycretin structure, sequence and molecular weight

Amycretin has 68 amino acids [5][3]. Residues 1 to 31 form a GLP-1(7-37) analogue with 2-aminoisobutyric acid (Aib) at position 2 for dipeptidyl peptidase-4 resistance; residues 32 to 36 are a linker of four glycines and one glutamic acid; residues 37 to 68 form the amylin receptor agonist, which ends in a C-terminal prolinamide [5][3]. A C18 diacid-based side chain is attached at Lys31 (position K37 in GLP-1(7-37) numbering), giving reversible albumin binding and a long systemic half-life [5].

Property	Amycretin
INN	Zenagamtide (formerly amycretin), INN number 13389 [2][3]
Development code	NNC0487-0111 [4]
CAS number	3005889-81-3 [3]
Molecular formula	C343H550N94O116 [5][3]
Average molecular weight	About 7,847 g/mol (GSRS calculated: 7846.686) [5][3]
Length	68 amino acids [5]
Sequence (one-letter)	H-X-EGTFTSDVSSYLEEQAAREFIAWLVRGRK-GGGGE-ASELSTAALGRLSAELHELATLPRTETGSGSP-NH2, X = Aib [3]
Side chain	Lys31: semaglutide-type C18 diacid side chain (17-carboxyheptadecanoyl-gamma-Glu-AEEA-AEEA) [3][5]
C-terminus	Prolinamide [3]
Receptors	GLP-1R, AMY1R to AMY3R, calcitonin receptor (agonist) [5][2]

At 68 residues amycretin is longer than the 40-amino-acid threshold US regulations use to define a protein (see what is a peptide API), yet the published material was made by chemical synthesis rather than recombinant expression [5].

Amycretin mechanism of action

In cAMP assays at human receptors (time-resolved fluorescence in COS-7 cells for the calcitonin-family receptors), amycretin had EC50 values of 1.30 pM at AMY1(a)R, 13.3 pM at AMY2(a)R, 17.2 pM at AMY3(a)R and 1.89 pM at the calcitonin receptor CTR(a), with negligible activity (EC50 above 100 nM) at the CGRP and adrenomedullin AM1 and AM2 receptors [5]. At the human GLP-1 receptor its potency was comparable with semaglutide [5]. It also activated mouse and rat GLP-1, amylin and calcitonin receptors [5]. Evidence level: in vitro.

In diet-induced obese rats, 21 days of amycretin reduced total energy intake by 47% and lowered body weight by 18% relative to vehicle while energy expenditure was maintained [5]. Amycretin reached brain areas that regulate food intake in mice, improved insulin sensitivity in a hyperinsulinaemic euglycaemic clamp in rats, and improved liver histology in a diet-induced MASH mouse model, mainly by reducing steatosis [5]. Evidence level: animal.

Amycretin is therefore a non-selective amylin agonist: it activates calcitonin receptors as well as amylin receptors, in contrast to selective agents such as eloralintide, which preferentially activates AMY1R [5][7].

Amycretin half-life and pharmacokinetics

Preclinical intravenous studies showed terminal half-life rising with species size: 5.92 hours in rats, 29.3 hours in non-human primates and 54.1 hours in minipigs [5]. Mouse half-life was short enough that mouse studies used twice-daily administration [5]. In the first-in-human oral study, plasma concentrations were consistent with dose proportionality across all groups [1]. The published abstracts do not report a human half-life; the clinical programme uses once-weekly subcutaneous and once-daily oral regimens [8][9].

Development history and timeline

Amycretin was designed and is developed by Novo Nordisk, which funded all published studies [5][1][2].

Date	Milestone	Ref
May 2022	First-in-human oral phase 1 (NCT05369390) begins enrolling	[1]
Sep 2023	Subcutaneous phase 1b/2a (NCT06064006) begins	[8]
Aug to Dec 2024	Phase 2 type 2 diabetes trial (NCT06542874) randomises participants	[2]
Jun 2025	Both phase 1 studies published in The Lancet	[1][8]
Jul 2025	Preclinical pharmacology published	[5]
Feb 2026	AMAZE 1 phase 3 obesity trial starts	[10]
Jul 2026	Phase 2 type 2 diabetes results published under the INN zenagamtide	[2][9]
Aug 2026	AMAZE 9 (oral, obesity) and AMBITION 7 (type 2 diabetes) start	[11][12]
Oct 2026	AMBIENCE cardiovascular outcomes trial registered, not yet recruiting	[13]

Amycretin clinical trials: key studies and findings

Study	Phase / design	Population	n	Duration	Primary endpoint	Main finding	Ref
NCT05369390 (oral)	1, single and multiple ascending doses vs placebo	Overweight or obesity	144	Up to 12 weeks	Treatment-emergent AEs	AEs in 62%, all mild or moderate; dose-proportional exposure	[1]
NCT06064006 (subcutaneous)	1b/2a, escalation vs placebo	Overweight or obesity, BMI 27.0–39.9	125	20 to 36 weeks	Treatment-emergent AEs	Weight -24.3% vs -1.1% at week 36 (highest-dose part)	[8]
NCT06542874 (subcutaneous)	2, dose-finding, six dose levels	Type 2 diabetes on metformin with or without SGLT2 inhibitor	262	36 weeks	HbA1c change	-0.9 to -1.7 points from 7.8%	[2]
NCT06542874 (oral)	2, dose-finding, three dose levels	Type 2 diabetes on metformin with or without SGLT2 inhibitor	186	36 weeks	HbA1c change	-0.9 to -1.4 points	[9]

First-in-human oral study

The first-in-human study enrolled 144 adults with overweight or obesity at one US site between May 2022 and January 2024, across single ascending-dose, 10-day multiple-dose and 12-week escalation parts [1]. There were 364 treatment-emergent adverse events in 89 (62%) participants, all mild or moderate and increasing with dose; gastrointestinal events made up 180 (49%) of events and occurred in 72 (81%) of the participants who reported any event; no deaths were reported [1]. Body-weight change was an exploratory endpoint [1]. Evidence level: phase 1.

Subcutaneous phase 1b/2a study

The subcutaneous study randomised 125 participants (101 amycretin, 24 placebo) with a BMI of 27.0 to 39.9 kg/m² to once-weekly escalation schemes reaching four different maintenance levels [8]. Estimated mean body-weight change versus placebo was -24.3% versus -1.1% at week 36 in the highest-dose part, -22.0% versus +1.9% at week 36, -16.2% versus +2.3% at week 28 and -9.7% versus +2.0% at week 20 in the lower-dose parts [8]. Gastrointestinal events were the most common adverse events, mostly mild to moderate [8]. Many participants withdrew, a high proportion for reasons unrelated to adverse events, which limits the precision of these estimates [8]. Evidence level: phase 1b/2a, single site, small groups.

Phase 2 in type 2 diabetes (subcutaneous and oral)

A single dose-finding programme at 83 sites in 11 countries tested both forms in adults with type 2 diabetes (HbA1c 7.0% to 10.0%) on metformin with or without an SGLT2 inhibitor, for 36 weeks [2][9]. In the subcutaneous arm, 262 participants were randomised to six dose levels or placebo; HbA1c changed by -0.9 percentage points at the lowest level (treatment difference versus placebo -0.77) to -1.7 points at the highest (difference -1.56) from a baseline of 7.8% [2]. In the oral arm, 186 participants were randomised to three dose levels or placebo; HbA1c changed by -0.9, -1.3 and -1.4 points (differences versus placebo -0.5, -0.99 and -1.09) [9]. The registry lists 448 participants across both forms [4]. Evidence level: phase 2.

Evidence from network meta-analysis

A 2026 network meta-analysis of six trials (4,642 participants) of amylin-based therapies in adults without diabetes ranked high-dose subcutaneous amycretin first for placebo-adjusted weight change (mean difference -23.95%), but its authors describe the underlying data as sparse and of low certainty, because the amycretin estimate rests on the small phase 1b/2a study [14][8].

Safety findings reported in amycretin studies

• Oral phase 1: treatment-emergent adverse events in 62% of participants, all mild or moderate, dose-dependent; gastrointestinal events most common; no deaths [1].
• Subcutaneous phase 1b/2a: mostly mild to moderate gastrointestinal events that resolved by end of study; the authors describe rates as similar to early-phase studies of GLP-1 and amylin agonists [8].
• Subcutaneous phase 2 (type 2 diabetes): most adverse events gastrointestinal, mild to moderate; serious adverse events in 21 (8%) of 261 exposed participants, spread across dose groups and placebo; no deaths [2].
• Oral phase 2 (type 2 diabetes): gastrointestinal events in 26%, 41% and 47% of the three dose groups versus 23% with placebo; serious adverse events in 7 (4%) of zenagamtide-treated participants and none with placebo; no deaths [9].
• Network meta-analysis: gastrointestinal adverse events, nausea, vomiting and constipation were more common with high-dose amylin-based therapies, especially oral amycretin [14].

Regulatory status of amycretin by region

Region	Status (October 2026)	Ref
United States	Investigational; phase 3	[10]
European Union	Investigational; phase 3	[10]
United Kingdom	Investigational; no marketing authorisation identified	[10]
India	Investigational; no marketing authorisation identified	[10]
China	Investigational; no approval identified	[10]
Japan	Investigational; no approval identified	[10]

The phase 3 programmes are AMAZE 1 (subcutaneous, obesity, 1,150 participants, recruiting since February 2026), AMAZE 9 (oral, obesity, 950 participants), AMBITION 7 (subcutaneous versus insulin glargine in type 2 diabetes with increased cardiovascular risk, 1,778 participants) and AMBIENCE (cardiovascular outcomes in established atherosclerotic disease, planned 8,500 participants) [10][11][12][13].

Amycretin in laboratory research

• Receptor panels. Published work used cAMP reporter-gene (CRE-luciferase) assays, run without albumin, in BHK cells expressing human, mouse or rat GLP-1R or rat AMY3(a)R and CTR(a), plus time-resolved fluorescence cAMP assays in COS-7 cells expressing the human amylin receptor subtypes, CTR(a), CGRP and adrenomedullin receptors, with salmon calcitonin, pramlintide, cagrilintide and semaglutide as comparators [5]. Including CGRP and adrenomedullin receptors in the panel confirms selectivity within the calcitonin family [5].
• Animal models. Diet-induced obese rats for energy intake, body composition and clamp studies; diet-induced MASH mice for liver histology; species-specific plasma immunoassays for pharmacokinetics [5].
• Modular dual agonists. For groups building their own GLP-1/amylin hybrids, a 2026 click-chemistry platform assembles GLP-1 and amylin agonist peptides on a PEG scaffold and reported balanced low-picomolar cAMP potency at both receptors [15].
• Analytical characterisation. Identity by LC-MS intact mass against about 7,847 g/mol and peptide mapping across the GLP-1 domain, linker and amylin domain; purity by reversed-phase HPLC or UPLC.

Synthesis, purity and impurities

The developers synthesised amycretin by Fmoc solid-phase peptide synthesis on commercial synthesisers, attached the fatty-acid side chain through an Fmoc-Lys(4-methyltrityl)-OH building block, purified by preparative reversed-phase HPLC on C18 columns with 0.1% TFA in water and acetonitrile, and lyophilised the product, describing the route as similar to those for semaglutide and cagrilintide [5]. See SPPS versus LPPS for route considerations.

At 68 residues, cumulative coupling losses make deletion sequences the dominant impurity risk. Other structure-linked classes are D-amino acid variants, deamidation at Gln and Asn residues, Trp oxidation in the GLP-1 domain, aspartimide formation, and incomplete or misplaced side-chain acylation. As a TFA-purified peptide, counter-ion content also has to be specified. See peptide API impurities and specifications.

Storage and stability of lyophilized amycretin

Research amycretin is supplied as a lyophilized (freeze-dried) powder. Typical laboratory practice is storage at -20 °C or below, protected from light and moisture, with vials equilibrated to room temperature before opening. Amylin-derived sequences are prone to aggregation in solution, so stock solutions are usually prepared fresh and checked for clarity. See lyophilised peptide stability and storage.

Amycretin versus related peptides

Feature	Amycretin	Cagrilintide + semaglutide	Eloralintide
Format	One 68-residue peptide [5]	Two separate peptides given together [6]	One 37-residue amylin analogue [7]
Receptors	GLP-1R, AMYR, CTR [5]	GLP-1R (semaglutide); AMYR and CTR (cagrilintide) [7]	AMY1R-preferring amylin agonist [7]
Most advanced phase	Phase 3 (2026) [10]	Phase 3 completed (REDEFINE 1) [6]	Phase 3 (ENLIGHTEN programme) [16]
Representative weight data	-24.3% vs -1.1% at 36 weeks, phase 1b/2a, highest-dose part [8]	-20.4% vs -3.0% at 68 weeks, phase 3 [6]	Up to -20% vs -0.4% at 48 weeks, phase 2 [17]

The weight figures come from trials of very different size and maturity: the amycretin result is from a small single-site phase 1b/2a study, whereas REDEFINE 1 randomised 3,417 participants [8][6]. They should not be read as a ranking. Eloralintide is reviewed in eloralintide: structure, mechanism and research findings.

How Winhycare Pharma supplies amycretin

Winhycare Pharma supplies amycretin as research-use-only material to research organisations and laboratories, at a purity of 99% or higher as stated in our product brochure, with a certificate of analysis covering HPLC purity and mass confirmation. Custom synthesis of amycretin analogues, fragments (GLP-1 domain, amylin domain) and labelled variants is available. Product details are on the amycretin research peptide page, and enquiries go through our research peptide contact form.

For laboratory research use only. Not for human or veterinary use.