AOD-9604: what it is, how it works and what studies have found

AOD-9604 is a 16-residue synthetic peptide derived from the C-terminus of human growth hormone: residues 177–191 with an extra tyrosine added at the N-terminus, closed by one disulfide bond [1] [2]. It was developed as an anti-obesity drug on the idea that growth hormone’s fat-metabolising activity sits in this C-terminal region and could be separated from its growth, glucose and IGF-1 effects [3] [4]. Six human trials were run between 2001 and 2006; in 2007 the developer’s chief executive described its last phase 2b obesity trial as unsuccessful, and AOD-9604 was never approved [1] [5].

This overview covers its structure, the preclinical and clinical evidence, the safety data, its regulatory status, and the frequent confusion between AOD-9604 and “HGH fragment 176-191”. It is written for researchers and is not medical guidance.

What is AOD-9604?

Human growth hormone is a 191-residue single-chain protein with two disulfide bonds, the second linking cysteines near its C-terminus [6]. Work in the 1990s traced an antilipogenic activity to that C-terminal stretch: a synthetic hGH(177-191) peptide had antilipogenic activity identical to the intact hormone, though in that study it showed no significant lipolytic effect by glycerol release [7]. A follow-up peptide containing residues 177–191 (coded AOD9401) stimulated hormone-sensitive lipase and inhibited acetyl-CoA carboxylase in adipocytes, and reduced body weight gain in obese Zucker rats without causing insulin resistance [3].

AOD-9604 is the stabilised version: the same 177–191 sequence with an additional N-terminal tyrosine, which the developers state stabilises the peptide. It is made by solid-phase peptide synthesis, and studies of its secondary structure showed similarities to the homologous region of native growth hormone [1].

AOD-9604 structure, sequence and molecular weight

Property	AOD-9604
Name	AOD-9604 (AOD9604); Tyr-hGH(177-191) [1]
CAS number	221231-10-3 [2]
Molecular formula	C78H123N23O23S2 [2]
Molecular weight	1815.1 g/mol [2]
Sequence (one-letter)	YLRIVQCRSVEGSCGF [1]
Sequence (three-letter)	Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe
Length	16 residues
Disulfide	One, Cys7-Cys14 of the peptide, corresponding to Cys182-Cys189 of mature growth hormone [6] [2]
C-terminus	Free acid (Phe-OH), as in native growth hormone [2]
PubChem CID	71300630 [2]

The disulfide closes an eight-residue ring (CRSVEGSC), so the peptide is cyclic between positions 7 and 14 with linear tails at both ends. Correct oxidative folding to this single intramolecular disulfide, rather than dimers or reduced peptide, is the main chemistry control point.

AOD-9604 mechanism of action

The proposed mechanism is direct action on adipose tissue rather than signalling through the growth hormone receptor. The evidence, all preclinical, is:

• No growth hormone receptor binding. AOD-9604 did not compete with radiolabelled hGH for the hGH receptor in transfected cells and, unlike hGH, did not induce cell proliferation via that receptor [4].
• Lipolysis and fat oxidation. In obese ob/ob mice treated for 14 days, both hGH and AOD-9604 reduced body weight gain, increased fat oxidation and raised plasma glycerol (an index of lipolysis). Unlike hGH, AOD-9604 did not cause hyperglycaemia or reduce insulin secretion [4].
• Lipogenesis. The related 177–191 peptide stimulated hormone-sensitive lipase and inhibited acetyl-CoA carboxylase in adipocytes [3], and the earlier hGH(177-191) study found antilipogenic activity matching the intact hormone [7].
• β3-adrenergic receptor. Chronic treatment raised the repressed β3-adrenergic receptor RNA of obese mice to lean levels, but in β3-receptor knockout mice chronic treatment no longer reduced body weight or increased lipolysis, while an acute dose still increased energy expenditure and fat oxidation. The authors concluded the lipolytic action is not mediated directly through the β3 receptor, although increased β3 expression may contribute [8].

No specific receptor for AOD-9604 has been identified in this literature. The 2013 safety review adds a structural argument: full activation of the growth hormone receptor needs the hormone’s two binding sites to dimerise two receptors, and AOD-9604 contains only part of site 1 and none of site 2 [1].

Development history and timeline

Date	Event	Ref
1993	Monash University group reports antilipogenic action of synthetic hGH(177-191)	[7]
1998	Metabolic Pharmaceuticals created around AOD-9604, which was developed at Monash University	[5]
2000–2001	Rodent studies in Zucker rats and ob/ob and β3-receptor knockout mice	[9] [4] [8]
2001–2006	Six randomised, double-blind, placebo-controlled human trials (893 participants)	[1]
Late 2004	Earlier phase 2b obesity trial reported; results described as controversial	[5]
April 2007	Chief executive describes the latest, larger phase 2b trial as unsuccessful; company refers to “the loss of AOD9604 for obesity”	[5]
2013	Safety and tolerability data from all six trials published	[1]
2014	Developer announces a self-determined GRAS conclusion for use as a food ingredient; no FDA GRAS notice on record	[10] [18]
December 2024	FDA Pharmacy Compounding Advisory Committee votes 12 to 0 against placing AOD-9604 on the 503A bulks list	[17]
2026	Named in WADA S2.2.3; listed on FDA’s compounding safety-risk page among substances previously in category 2 whose nominations were withdrawn	[11] [12]

The phase 2b efficacy results have not been published in a peer-reviewed journal; the 2013 paper deliberately reports safety and tolerability only [1]. The 2007 interview with the company’s chief executive described the second trial as designed to be “a mini-phase III”, referred to “the loss of AOD9604 for obesity”, and said the company was considering AOD-9604 for osteoporosis instead [5]. That is a company account in the trade press, not a trial report, and should be read as such.

Key AOD-9604 studies and findings

Study	Design / phase	Model or population	n	Duration	Main finding	Ref
Ng 2000 (AOD9401)	Animal and in vitro	Obese Zucker rats; adipocytes	n/a	20 days	Reduced weight gain; adipocyte diameter 110 to 80 µm; no insulin resistance	[3]
Ng 2000 (AOD-9604)	Animal, oral	Obese Zucker rats	n/a	19 days	Body weight gain reduced by over 50% vs control; no adverse effect on insulin sensitivity by clamp	[9]
Heffernan 2001 (IJO)	Animal	ob/ob and lean mice	n/a	14 days	Less weight gain, more fat oxidation, no hyperglycaemia; no hGH receptor binding	[4]
Heffernan 2001 (Endocrinology)	Animal	Obese and β3-AR knockout mice	n/a	14 days	β3-AR RNA restored; chronic effect lost in knockouts	[8]
METAOD001–004	Phase 1 and 2a, single and 7-day	Healthy and obese men	15, 23, 17, 36	Single dose to 7 days	No effect on IGF-1 or glucose vs placebo	[1]
METAOD005	Phase 2b RCT, oral	Obese adults, BMI ≥35	300	12 weeks	Safety similar to placebo; no IGF-1 change; no antibodies	[1]
METAOD006	Phase 2b RCT, oral tablets	Obese adults, BMI 30–45	502	24 weeks	Safety similar across groups; efficacy results not published in peer-reviewed form	[1]
Kwon and Park 2015	Animal	Rabbit collagenase-induced knee osteoarthritis	32	8 weeks	Intra-articular AOD-9604 with hyaluronic acid gave lower cartilage degeneration scores than either alone	[13]

Preclinical obesity studies

The animal programme was consistent in direction. In obese Zucker rats, oral AOD-9604 for 19 days reduced body weight gain by over 50% (15.8 ± 0.6 versus 35.6 ± 0.8 g) compared with controls, increased lipolytic activity in adipose tissue and, unlike intact hGH, did not impair insulin sensitivity on euglycaemic clamp [9]. The ob/ob mouse studies added fat-oxidation and glycerol data and the receptor-binding results described above [4] [8]. All of this is rodent evidence from the developing group, and the human trials did not reproduce a clear weight-loss effect.

Human trials

The six human trials were all randomised, double-blind and placebo-controlled, involved 893 adults in total, and were run in Australia between 2001 and 2006. Two used intravenous infusion (METAOD001 and 002) and four used oral capsules or tablets (METAOD003 to 006). The first four were single-dose or 7-day studies, mostly in obese men; the last two were the long-term phase 2b studies of 12 and 24 weeks [1].

METAOD005 randomised 300 obese adults (54% men, median BMI 40) to placebo or one of five oral dose levels for 12 weeks. METAOD006 enrolled 534 and randomised 502 obese adults (44% men, median BMI 36.3) to placebo or one of three oral dose levels for 24 weeks, after a 4-week placebo run-in, at 16 Australian hospitals and medical centres [1]. Both had body-weight reduction as an efficacy objective, but the published paper reports only safety [1].

Safety findings reported in studies

The 2013 summary of all six trials reported [1]:

• IGF-1: no effect on serum IGF-1 in any trial, the key distinction from growth hormone.
• Glucose: no negative effect on oral glucose tolerance tests, including at 12 weeks in METAOD005.
• Immunogenicity: no anti-AOD-9604 antibodies at baseline or at weeks 4, 8 and 12 in METAOD005.
• Common adverse events: headache was the most frequent across studies, followed by gastrointestinal events; in the 7-day study the highest dose group had more headache, diarrhoea and flatulence.
• Euphoria: in the intravenous METAOD002 study, mild or moderate euphoria judged possibly related to treatment was reported by 5 of 23 subjects during AOD-9604 periods and none during placebo.
• Serious adverse events: none in METAOD001, 002 or 004; two in the single-dose oral study METAOD003, both in the highest dose group (diarrhoea, judged possibly related, and bronchial pneumonia, judged unrelated); five in METAOD005, all in AOD-9604 groups (four cancers, three of them skin cancers, and one lipoma), judged by the investigator as unrelated; in METAOD006, 18 patients (3.6%) had at least one, distributed similarly across groups. The paper’s abstract states that no serious adverse event related to AOD-9604 occurred, which sits uneasily with the possibly related METAOD003 case reported in its results.

The investigators judged none of the METAOD005 cancers to be treatment-related, citing no dose relationship, the high background skin-cancer rate in Australia and the participants’ high BMI [1]. A 12-week study cannot assess cancer risk, and the safety summary was not accompanied by published efficacy data. FDA’s current compounding page, in its table of nominated substances, states that compounded drugs containing AOD-9604 “may pose significant risk for immunogenicity for certain routes of administration” and that FDA “has also identified serious adverse events that may be associated with AOD-9604, though causality is not clear” [12]. A 2026 sports-medicine review covers AOD-9604 among peptides marketed directly to patients and notes that, for many unapproved peptides, rigorous human safety data are scarce [14].

AOD-9604 regulatory status by region

Jurisdiction	Status	Ref
Medicines (any jurisdiction)	No marketing approval found; obesity development stopped in 2007	[5]
United States, compounding	Listed on FDA’s safety-risk page among bulk substances previously in category 2 of the interim policies whose nominations were withdrawn, with FDA’s immunogenicity, impurity and adverse-event notes; FDA’s advisory committee voted 12 to 0 against placing it on the 503A bulks list (4 December 2024), as FDA had proposed	[12] [17]
United States, food	Developer announced a self-determined GRAS conclusion by an expert panel for food use (2014); no AOD-9604 entry in FDA’s GRAS Notice Inventory, so not reviewed by FDA; not a drug approval	[10] [1] [18]
Sport (all WADA signatories)	Prohibited at all times under S2.2.3 (growth hormone fragments, named with hGH 176-191)	[11]

AOD-9604 vs HGH fragment 176-191

This is the most confused point about the molecule. Numbering mature human growth hormone from 1 to 191, residue 176 is phenylalanine, so the native 176–191 fragment is FLRIVQCRSVEGSCGF [6]. AOD-9604 is residues 177–191 with tyrosine added in front, YLRIVQCRSVEGSCGF [1]. In effect, Phe176 is replaced by Tyr.

Property	AOD-9604	Native hGH 176-191
Sequence	YLRIVQCRSVEGSCGF [1]	FLRIVQCRSVEGSCGF [6] [15]
N-terminal residue	Tyrosine (added)	Phenylalanine (native residue 176)
Formula	C78H123N23O23S2 [2]	C78H123N23O22S2 [15]
Molecular weight	1815.1 g/mol [2]	1799.1 g/mol [15]
CAS (PubChem)	221231-10-3 [2]	66004-57-7 [15]
Clinical data	Six human trials [1]	None found
WADA	Named, S2.2.3 [11]	Named separately, S2.2.3 [11]

The difference is a single oxygen atom (16 Da), which LC-MS resolves easily. The two names are often used loosely, and even public databases are inconsistent: a vendor-deposited PubChem record titled “HGH Fragment 176-191” carries a formula, C80H127N23O24S2, that matches neither peptide [16]. WADA lists the two names as separate examples [11]. For research, the sequence and observed mass on the certificate of analysis define what was bought, not the product name.

AOD-9604 in laboratory research

Published research applications include lipolysis and lipogenesis assays in isolated adipocytes (glycerol release, hormone-sensitive lipase, acetyl-CoA carboxylase) [3], growth hormone receptor competition binding and receptor-dependent proliferation assays as negative controls [4], indirect calorimetry and substrate oxidation in obese mouse models [4], and cartilage models [13]. Each of these is preclinical, and the osteoarthritis finding comes from a single rabbit study.

For identity, LC-MS of the intact peptide should match 1815.1 g/mol for the oxidised (disulfide) form; the reduced peptide is 2 Da heavier and a disulfide-linked dimer roughly twice as heavy. Peptide mapping before and after reduction confirms the Cys7-Cys14 bridge and the N-terminal Tyr.

Synthesis, purity and impurities

AOD-9604 is made by solid-phase peptide synthesis; the clinical material was produced under cGMP [1]. After chain assembly and cleavage, the two cysteines are oxidised to form the intramolecular disulfide, and the product is purified by reversed-phase HPLC and lyophilized. Impurity classes specific to this peptide are the reduced (free-thiol) form, disulfide-linked dimers and oligomers, the des-Tyr peptide (hGH 177-191), and the Phe-for-Tyr analogue if the wrong building block is used, alongside general deletion sequences and Gln deamidation. See SPPS versus LPPS and peptide API impurities and specifications.

Storage and stability of lyophilized AOD-9604

Lyophilized AOD-9604 should be kept sealed, dry, cold and away from light, with containers brought to room temperature before opening. Disulfide exchange and dimerisation are favoured by moisture and higher pH, so residual water is the main stability lever. See our guide to lyophilised peptide stability and storage. This applies to laboratory material only.

How Winhycare Pharma supplies AOD-9604

Winhycare Pharma supplies AOD-9604 (Tyr-hGH 177-191, CAS 221231-10-3) as research-use-only material for laboratory work, at a purity of ≥99% as stated in our product brochure, with batch QC documentation stating sequence and observed mass. The native Phe-initiated hGH 176-191 and other growth hormone fragments are available through custom synthesis. Details are on the AOD-9604 product page, or contact us about research peptides.

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