AOD-9604: complete guide to the hGH 177-191 fragment in research

AOD-9604 (Anti-Obesity Drug 9604) is a synthetic 16-amino-acid peptide that reproduces the C-terminal end of human growth hormone (hGH, residues 177-191), with a tyrosine added at the front. It came out of Frank Ng's group in the Department of Biochemistry at Monash University (Melbourne, Australia) and was developed by Metabolic Pharmaceuticals, with one goal: keep growth hormone's effect on fat and drop its effects on growth, blood glucose and IGF-1. In animals it delivered. In humans the clinical programme ended on 21 February 2007, when the OPTIONS phase 2b trial (536 participants) failed to show significant weight loss over placebo.

This guide sets out, source by source, what is actually known about AOD-9604: its structure, its lipolytic mechanism that bypasses the IGF-1 axis, its six clinical trials and their numbers (the failure included), the cartilage and osteoarthritis work, its GRAS status and its standing with the FDA, how it differs from "HGH Frag 176-191" and from GLP-1 agonists, and finally reconstitution, dosing maths and storage. The peptide is supplied strictly for in vitro and in vivo research use only (RUO).

Molecular identity and chemistry

AOD-9604 is a hexadecapeptide with the sequence Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe (one-letter code: YLRIVQCRSVEGSCGF). Its molecular formula is C₇₈H₁₂₃N₂₃O₂₃S₂, its molar mass about 1,815 g/mol and its CAS number 221231-10-3. The two cysteines (positions 7 and 14 of the peptide, 182 and 189 in hGH numbering) form a disulfide bridge that closes the molecule into a loop, just as in the full hormone.

Two numbering schemes describe the same chain. The original literature calls it "Tyr-hGH 177-191": the last fifteen residues of the hormone with a tyrosine added at the N-terminus. Vendors often call it "fragment 176-191", because position 176 of native hGH is a phenylalanine and AOD-9604 puts a tyrosine there. Both descriptions land on the same 16-residue sequence.

Apart from that tyrosine, the molecule is left as nature made it: no acylation, no unnatural amino acids. That is why its plasma half-life is so short (see below). It is sold as the acetate salt or the free base, and the FDA assessed both forms together in 2024.

Origins: from Monash University to the Metabolic programme

The starting idea was simple. Growth hormone burns fat, but at high doses it causes insulin resistance, high blood sugar and unwanted tissue growth. Frank Ng's team set out to find which part of the molecule carries the fat effect.

• 1993: Wu and Ng (Biochemistry and Molecular Biology International) show that the synthetic peptide hGH 177-191 matches the antilipogenic activity of the whole hormone in rat adipose tissue.
• 1994: Natera, Jiang and Ng report that chronic treatment of obese ob/ob mice with hGH 177-191 cuts cumulative weight gain and fat mass.
• 2000: Ng et al. (Hormone Research) test the modified analogue, now named AOD9604, in obese Zucker rats. Given orally at 500 µg/kg/day for 19 days, it cuts weight gain by more than half, raises the lipolytic activity of fat tissue and, unlike hGH, leaves insulin sensitivity intact on a euglycaemic clamp.
• 2001: two studies by Heffernan et al. (Endocrinology and International Journal of Obesity) in ob/ob mice confirm higher fat oxidation, higher plasma glycerol and less fat tissue, with no effect on glucose or insulin.

Metabolic Pharmaceuticals, a Melbourne biotech, patented the molecule in the late 1990s and took it through the clinic from 2001 to 2007.

Mechanism of action: fat breakdown without the IGF-1 axis

What sets AOD-9604 apart from growth hormone is that it does not bind the GH receptor. Heffernan et al. (2001) showed this in Ba/F3 cells expressing the receptor: between 0.1 pM and 10 nM, hGH displaced labelled hGH from its receptor and AOD-9604 did not. Between 0.1 pM and 0.1 mM, hGH made those cells proliferate and AOD-9604 did not. Without GH receptor activation there is no JAK2/STAT5 signal to the liver, so no rise in IGF-1 is expected. The human trials bore this out: no significant change in serum IGF-1 in any of the six studies (Stier et al., 2013).

On the effect side, rodent studies describe three converging actions on fat tissue:

• Less lipogenesis: fat cells make fewer new triglycerides (Wu and Ng, 1993).
• More lipolysis: higher plasma glycerol, a marker of triglyceride breakdown (Heffernan et al., 2001).
• More fat oxidation, measured by indirect calorimetry, with no drop in food intake (Heffernan et al., 2001).

The role of the β3-adrenergic receptor, the main lipolytic receptor in rodent fat cells, is nuanced. In obese mice, AOD-9604 brings the collapsed β3 receptor RNA back up to lean-mouse levels. In mice lacking the receptor (knock-outs), 14 days of treatment no longer produce weight loss or more lipolysis, yet a single acute dose still raises energy expenditure and fat oxidation. The authors conclude that the effect is not directly mediated by the β3 receptor, even if its higher expression may contribute. The FDA's November 2024 review puts it plainly: the molecular target of AOD-9604 remains unknown.

Pharmacokinetics

No human pharmacokinetic data have been published. The animal data come from the review by Moré and Kenley (Journal of Endocrinology and Metabolism, 2014):

• in pigs, after a 400 µg/kg intravenous bolus, the half-life is about 3 minutes;
• in vitro, in plasma, the half-life is about 4 minutes;
• in rats, oral availability is estimated at about 40%. In pigs the calculation comes out above 100%, which the authors put down to experimental error and the FDA considers unusable.

A half-life of a few minutes is a world away from today's metabolic peptides, which are acylated to last a week. It explains why the protocols described are daily, and why Metabolic bet on the oral route for its phase 2b trials.

Clinical programme: six trials, 2001 to 2007

Metabolic Pharmaceuticals funded six randomised, double-blind, placebo-controlled trials with roughly 900 participants in total. Their safety data were pooled by Stier, Vos and Kenley (Journal of Endocrinology and Metabolism, 2013), authors who were employees of or consultants to the company.

Trial	Phase	Participants	Route and doses	Duration
METAOD001	I	15 healthy men	IV, 25 to 400 µg/kg, single doses	Single doses, 7 days apart
METAOD002	IIa	23 obese men (BMI ≥ 35)	IV, 25, 50, 100 µg/kg	Single doses, 7 days apart
METAOD003	IIa	17 obese men	Oral, 9, 27, 54 mg	Single doses, 2 weeks apart
METAOD004	IIa	36 obese men	Oral, 9, 27 or 54 mg/day	7 days
METAOD005	IIb	300 obese adults	Oral, 1, 5, 10, 20 or 30 mg/day	12 weeks
METAOD006 (OPTIONS)	IIb	536 enrolled, 502 randomised	Oral, 0.25, 0.5 or 1 mg/day	24 weeks

The 12-week trial: a modest signal

METAOD005 (300 obese adults, five Australian hospitals) was presented as a conference abstract by Herd et al. in Obesity Research in 2005 and never published in full. Every dose beat placebo, with no dose-response: the lowest dose did best. Mean weight loss was 0.22 kg per week on 1 mg/day versus 0.07 kg per week on placebo, roughly 2.6 kg versus 0.8 kg over 12 weeks. Waist circumference fell significantly at every dose. The FDA noted in 2024 that the differences were small and that the abstract gave too little detail to interpret them.

The OPTIONS trial: the 2007 failure

Since 1 mg had been the best dose, Metabolic launched OPTIONS at 0.25, 0.5 and 1 mg/day for 24 weeks, with a supervised diet and exercise programme, under conditions close to a phase 3. The primary endpoint was significant weight loss at 12 weeks for at least one dose; the trial was powered to detect a 1.8 kg difference from placebo.

On 21 February 2007 the company told the Australian Securities Exchange that the results "do not support the commercial viability" of the drug for obesity and that development for that indication was terminated. After allowing for diet and exercise, weight loss attributable to the peptide was under 1 kg in every dose group, at 12 and at 24 weeks, too little to reach statistical significance. The company pointed to a responder subgroup and suggested the drug effect may have been swamped by the large weight loss in the placebo arm, but conceded that the overall population did not respond consistently. The detailed results were never published in a journal.

That is the key takeaway: in animals AOD-9604 clearly reduces fat mass. In obese humans, in the only large controlled trial, its effect on body weight could not be told apart from placebo.

Safety and side effects: what the data show

On tolerability, the published record is favourable. Stier et al. (2013) report across the six trials:

• no change in serum IGF-1 (in OPTIONS: +1.76 nmol/L at 12 weeks and +1.24 nmol/L at 24 weeks, no different from placebo, p = 0.51 and 0.76);
• no worsening of glucose tolerance on the oral glucose tolerance test, unlike hGH;
• no anti-AOD-9604 antibodies in the participants tested;
• an adverse-event profile similar to placebo (78.7% of OPTIONS participants had at least one event, across all groups). Headache dominated in the small trials; one case of chest tightness and some cases of mild euphoria were judged possibly related to the drug given intravenously.

Animal toxicology (Moré and Kenley, 2014) shows no major toxicity: no-observed-adverse-effect levels of at least 100 mg/kg/day in rats over 6 months and up to 50 mg/kg/day in monkeys over 9 months. The FDA reads the same data more cautiously: osteocalcin changes in rats, slight liver vacuolation in monkeys, genotoxicity tests it calls equivocal. Above all it notes that there are no human data at all for the subcutaneous route, the one most used today, and that a 16-amino-acid peptide can still be immunogenic if impurities or aggregates are not controlled.

Cartilage, osteoarthritis and bone

After the obesity programme ended, Metabolic pointed the molecule at bone and cartilage. Its February 2007 announcement listed an osteoporosis programme based on animal studies.

The reference paper on cartilage is Kwon and Park (Annals of Clinical and Laboratory Science, 2015). Knee osteoarthritis was induced in rabbits by collagenase injection. Intra-articular injections of AOD-9604, hyaluronic acid, or both, improved gross and histological cartilage scores versus saline and shortened the period of lameness. The combination worked better than either alone.

These results are preliminary: a chemically induced model, a single species, short follow-up, and no published human trial. When the FDA received a 2024 nomination that also covered osteoarthritis and osteoporosis, it did not assess those uses for lack of clinical studies. Cartilage is now one of the most active research angles on AOD-9604, but the human data have yet to be produced.

AOD-9604 vs "HGH Frag 176-191": what is the difference?

This question comes up constantly, and the answer is mostly about naming. The 177-191 fragment Wu and Ng studied in 1993 had no leading tyrosine. AOD-9604 is that same chain with a tyrosine in front. Commercially, "HGH Frag 176-191" usually refers to a peptide with the sequence YLRIVQCRSVEGSCGF, which is the AOD-9604 sequence.

In practice, two vials with different labels may hold the same molecule, and every published human data point concerns AOD-9604 as defined by Metabolic. To know what is in a vial, look at the sequence and the molecular mass confirmed by mass spectrometry on the certificate of analysis, not at the trade name.

AOD-9604 vs GLP-1 agonists

The comparison with GLP-1 agonists is unavoidable, since both target body weight. Yet their mechanisms and their evidence have nothing in common. For the full picture of that class, see our article on GLP-1 in metabolic research: semaglutide, tirzepatide, retatrutide.

Criterion	AOD-9604	Semaglutide / tirzepatide
Target	Unknown; acts on the fat cell, not via the GH receptor	GLP-1 receptors (plus GIP for tirzepatide)
Main effect	Lipolysis and fat oxidation (animal data)	Lower appetite, slower gastric emptying
Half-life	A few minutes (animal data)	About one week
Large human trial	OPTIONS: under 1 kg difference from placebo at 24 weeks	STEP-1: -14.9% at 68 weeks (semaglutide 2.4 mg); SURMOUNT-1: -20.9% at 72 weeks (tirzepatide 15 mg)
Status	No approved medicine	Approved obesity medicines

The research value of AOD-9604 lies elsewhere: it is a tool to study lipolysis separately from the GH/IGF-1 axis, blood glucose and appetite. GLP-1 agonists act on food intake; AOD-9604, in animals, acts on what happens to stored fat. To compare it with the secretagogues that do work through growth hormone, see our guide to GH secretagogues: CJC-1295, ipamorelin, GHRP.

AOD-9604 dosage in the literature

The doses below are those used in published studies, with their route. No subcutaneous dose has been evaluated in a published clinical trial.

Study	Model	Route	Dose
Ng et al., 2000	Obese Zucker rat	Oral	500 µg/kg/day, 19 days
Heffernan et al., 2001	ob/ob mouse	Intraperitoneal or minipump	250 µg/kg/day, 14 days
METAOD001-002	Human	Intravenous	25 to 400 µg/kg, single dose
METAOD005 (Herd et al., 2005)	Obese human	Oral	1 to 30 mg/day, 12 weeks; best result at 1 mg
OPTIONS (METAOD006)	Obese human	Oral	0.25, 0.5 and 1 mg/day, 24 weeks
GRAS panel (2014)	Food ingredient	Oral	Up to 1 mg per person per day

Reconstitution protocol (research use only)

AOD-9604 is supplied as a lyophilised powder. It is reconstituted in bacteriostatic water (sterile water with 0.9% benzyl alcohol), which allows several draws from the same vial. The maths never changes: amount of peptide divided by volume of water = concentration. On a U-100 insulin syringe, 100 units = 1 mL, so 1 unit = 0.01 mL.

Vial	Water added	Concentration	Amount in 10 units (0.1 mL)
AOD-9604 5 mg	2 mL	2.5 mg/mL	250 µg
AOD-9604 5 mg	1 mL	5 mg/mL	500 µg
AOD-9604 10 mg	2 mL	5 mg/mL	500 µg
AOD-9604 10 mg	4 mL	2.5 mg/mL	250 µg

Worked example: to draw 300 µg from a 5 mg vial reconstituted with 2 mL (2.5 mg/mL), draw 0.12 mL, that is 12 units on a U-100 syringe. Good practice: let the vial reach room temperature, swab the stopper, run the water slowly down the inside wall of the vial, then swirl gently without shaking until fully dissolved. A cloudy solution or one with particles should not be used.

Stability and storage

Lyophilised AOD-9604 should be kept dry and away from light. The safety data sheet cited by the FDA gives 3 years at -18 °C and 1 year at 0 to 7 °C. Once reconstituted it goes in the fridge at 2 to 8 °C and should be used within the following weeks, like other peptides reconstituted in bacteriostatic water; avoid repeated freeze-thaw cycles.

The molecule's specific weak point is its disulfide bridge: reducing agents (DTT, beta-mercaptoethanol) open it, and the FDA flags a risk of aggregation. For storage rules in detail, see our guide on how to store lyophilised peptides.

Regulatory status: GRAS, FDA, anti-doping

GRAS. In 2012 an expert scientific panel engaged by Metabolic granted AOD-9604 conditional GRAS (Generally Recognized As Safe) status, which took effect in 2014 once the safety data were published: use as a food or supplement ingredient at up to 1 mg per person per day. This is an independent assessment commissioned by the company, not an FDA approval, and it covers the safety of a food ingredient, not any efficacy.

FDA. In September 2023 the FDA placed AOD-9604 in "Category 2" of bulk substances nominated for compounding that raise significant safety risks, including immunogenicity. In September 2024 it was removed from that category on procedural grounds: the nominators had withdrawn their nominations. The FDA nevertheless took it to its Pharmacy Compounding Advisory Committee on 4 December 2024, proposing that it not be added to the 503A bulks list. The committee voted against inclusion 12 to 0. No AOD-9604 medicine is approved, in the United States or in Europe.

Anti-doping. AOD-9604 is on the World Anti-Doping Agency's prohibited list (class S2). In Australia it was added to the Poisons Standard among performance and image enhancing drugs.

AOD-9604 FAQ

Does AOD-9604 cause weight loss?

In obese rodents, yes: less weight gain, less fat mass, more fat oxidation. In humans, the 12-week trial showed a modest gap (about 2.6 kg versus 0.8 kg on placebo at 1 mg/day), but the larger 24-week OPTIONS trial did not confirm a significant effect: under 1 kg difference from placebo. Development for obesity was stopped in 2007 for that reason.

Does AOD-9604 raise IGF-1?

No, according to the six clinical trials pooled by Stier et al. (2013): no significant change in serum IGF-1, including over 24 weeks. That fits the cell data: the peptide does not bind the GH receptor.

What is the difference between AOD-9604 and growth hormone?

hGH has 191 amino acids and acts throughout the body via its receptor: growth, IGF-1, blood glucose, fat. AOD-9604 keeps only the 16-amino-acid tail and, in animals, retains the effect on fat without the effects on glucose or growth.

How long does reconstituted AOD-9604 keep?

In the fridge (2 to 8 °C), in bacteriostatic water, a few weeks, protected from light. Lyophilised and frozen, several years.

Is AOD-9604 FDA approved?

No. The 2014 GRAS status comes from an expert panel engaged by the company and only covers use as a food ingredient at up to 1 mg/day. The FDA has approved no AOD-9604 medicine, and its advisory committee voted against its use in compounding in December 2024.

Conclusion

AOD-9604 has a clear story. A Monash team isolated the part of growth hormone that acts on fat; in animals the fragment reduces fat mass without touching blood glucose or IGF-1, and the absence of any IGF-1 effect held up in humans. Weight loss did not: the 2007 OPTIONS trial did no better than placebo and the obesity programme was shut down. What remains is a precise research tool for studying lipolysis apart from the GH/IGF-1 axis, and a still-preclinical lead on cartilage.

AOD-9604 in stock and shipped from France: order the 5 mg vial or step up to 10 mg for your research protocols.