AOD-9604 Obesity Research: Trial History
AOD-9604 is one of the most interesting cautionary tales in peptide drug development. Designed to capture the fat-burning properties of human growth hormone without its side effects, this 16-amino acid fragment showed striking results in obese mice.
AOD-9604 is one of the most interesting cautionary tales in peptide drug development. Designed to capture the fat-burning properties of human growth hormone without its side effects, this 16-amino acid fragment showed striking results in obese mice. Six human clinical trials followed, enrolling over 900 participants. Then, in 2007, the program collapsed when the pivotal Phase IIb trial failed to beat placebo.
This article traces the full research history of AOD-9604 -- from its biochemical origins in a Melbourne university lab to the clinical trial data that ended its development as a pharmaceutical, and the regulatory battles that continue today.
Table of Contents
- What Is AOD-9604?
- Origin Story: The Lipolytic Fragment of Growth Hormone
- Preclinical Animal Studies
- The Mechanism: Beta-3 Adrenergic Receptors and Fat Oxidation
- Human Clinical Trials: The Full Timeline
- Safety Data Across All Six Trials
- Why the Drug Failed: Translational Gaps
- After the Failure: GRAS Status and Nutraceutical Pivot
- Emerging Research: Cartilage and Osteoarthritis
- Current Regulatory Status
- Summary of All Human Trials
- FAQ
- The Bottom Line
- References
What Is AOD-9604?
AOD-9604 (Anti-Obesity Drug 9604) is a synthetic peptide corresponding to amino acids 176-191 of human growth hormone (hGH), with one modification: the phenylalanine at position 176 is replaced with tyrosine for stability. This 16-amino acid fragment was designed to isolate the fat-metabolizing region of hGH from the rest of the molecule's hormonal activity.
The logic was straightforward. Growth hormone has well-documented lipolytic (fat-burning) effects, but administering full-length hGH to treat obesity causes serious problems: insulin resistance, glucose intolerance, fluid retention, joint pain, and elevated IGF-1. If researchers could carve out just the piece responsible for fat metabolism, they might get the benefit without the harm.
Metabolic Pharmaceuticals Ltd., an Australian biotech company, developed AOD-9604 in partnership with researchers at Monash University in Melbourne during the 1990s.
Origin Story: The Lipolytic Fragment of Growth Hormone
The idea that a fragment of growth hormone could produce fat loss without the full molecule's side effects originated from research by Frank Ng and colleagues at Monash University. Their work identified the C-terminal region of hGH (amino acids 176-191) as the domain responsible for lipolytic activity.
Early in vitro studies showed that this fragment stimulated lipolysis in fat tissue samples without binding to the growth hormone receptor. That was a key finding -- it suggested AOD-9604 worked through a completely separate pathway from hGH, which meant it shouldn't trigger the same downstream effects on insulin, glucose, and IGF-1.
This biochemical selectivity made the compound attractive for obesity research. If it could reduce fat stores without disrupting metabolic health, it would represent a fundamentally different approach from anything on the market.
Preclinical Animal Studies
The animal data for AOD-9604 was genuinely promising. Multiple studies in obese mouse models produced consistent results.
Obese Mice (ob/ob and diet-induced):
Chronic intraperitoneal (IP) administration of AOD-9604 for 14 days reduced body weight and body fat in obese mice. The magnitude of fat loss was comparable to that seen with full-length human growth hormone. Researchers also observed increased fat oxidation -- meaning the compound wasn't just mobilizing fat from storage, it was promoting its conversion to energy.
Zucker Rats:
In genetically obese Zucker rats, 20 days of AOD-9604 treatment reduced body weight gain and shrank average adipocyte (fat cell) diameter from 110 to 80 micrometers. Unlike hGH, the peptide did not cause insulin resistance or glucose intolerance in these animals.
The Critical Safety Distinction:
Across all preclinical models, AOD-9604 did not stimulate IGF-1 production, did not bind the growth hormone receptor, and did not alter glucose metabolism or insulin secretion. In the safety-obsessed world of obesity drug development -- where multiple drugs have been pulled from the market for unexpected harm -- this profile was considered a major advantage.
These animal results were strong enough to justify human trials. But as researchers would learn, what works in a mouse does not always translate to a person.
The Mechanism: Beta-3 Adrenergic Receptors and Fat Oxidation
A 2001 study by Heffernan and colleagues at Monash University dissected AOD-9604's mechanism of action using both wild-type and beta-3 adrenergic receptor (beta-3 AR) knockout mice.
What They Found:
Both hGH and AOD-9604 upregulated the expression of beta-3 AR RNA in fat tissue. In obese mice, where beta-3 AR expression is typically suppressed, treatment restored it to levels comparable to lean mice. Beta-3 ARs are the primary lipolytic receptors in fat cells -- they drive the breakdown of stored triglycerides.
The Knockout Test:
When the researchers administered AOD-9604 to beta-3 AR knockout mice, the chronic effects disappeared. No sustained weight loss. No long-term increase in lipolysis. This confirmed that the beta-3 AR pathway was necessary for AOD-9604's chronic anti-obesity action.
However, in an acute (single-dose) experiment, AOD-9604 still increased energy expenditure and fat oxidation in knockout mice -- suggesting there are additional metabolic pathways at work beyond beta-3 AR.
Downstream Pathway:
The proposed mechanism proceeds as follows: AOD-9604 upregulates beta-3 AR expression, which increases intracellular cyclic AMP (cAMP) through adenylyl cyclase stimulation. Elevated cAMP activates protein kinase A (PKA), which phosphorylates hormone-sensitive lipase. That enzyme then breaks stored triglycerides into free fatty acids for oxidation.
This was an elegant mechanism on paper. The problem was that beta-3 AR biology differs substantially between rodents and humans -- a gap that would prove fatal to the program.
Human Clinical Trials: The Full Timeline
Between 2001 and 2006, Metabolic Pharmaceuticals conducted six clinical trials with AOD-9604, enrolling 893 participants. Here is what each trial found.
METAOD001: Phase I Dose Escalation
Year: 2001 Design: Double-blind, placebo-controlled, dose-escalation safety study Subjects: 15 healthy adult males with BMI 24-30 kg/m2 Administration: Intravenous (IV) Doses: 25, 50, 100, 200, and 400 micrograms/kg Duration: Single dose
Purpose: Establish safety, tolerability, and basic pharmacokinetics in humans.
Key Findings: AOD-9604 was well tolerated at all dose levels. No serious adverse events were reported. No changes in IGF-1 levels. No evidence of glucose intolerance. No anti-AOD-9604 antibodies detected.
This was strictly a safety study. It told researchers the peptide could be given to humans without immediate harm.
METAOD002: Phase IIa Intravenous Study
Year: ~2002 Design: Double-blind, placebo-controlled Subjects: 23 healthy clinically obese males (BMI 35 or greater) Administration: Intravenous (single doses) Doses: 25, 50, and 100 micrograms/kg
Key Findings: Again, good tolerability. No IGF-1 changes, no insulin resistance, no antibody formation. This study confirmed the safety profile in the actual target population (obese individuals).
METAOD003: First Oral Dosing Study
Year: ~2003 Design: Double-blind, placebo-controlled Subjects: 17 healthy clinically obese males (BMI 35 or greater) Administration: Oral capsules (single doses) Doses: 9 mg, 27 mg, and 54 mg
Key Findings: The first test of oral bioavailability. The peptide was absorbed and tolerated via oral administration -- a significant finding, since most peptides are destroyed in the gut. Safety endpoints remained clean.
METAOD004: Multiple Dose Safety Study
Year: ~2003-2004 Design: 7-day repeat-dose study Administration: Oral
Key Findings: This short study confirmed that repeated daily oral dosing maintained the safety profile seen in single-dose studies. It served as a bridge to the longer efficacy trials.
METAOD005: The Promising 12-Week Trial
Year: 2004-2005 Design: Randomized, double-blind, placebo-controlled Subjects: 300 clinically obese adults Administration: Oral, once daily Doses: 0 mg (placebo), 1 mg, 5 mg, 10 mg, 20 mg, and 30 mg Duration: 12 weeks Sites: Five trial centers
Key Results:
| Dose Group | Weight Loss (12 Weeks) | Vs. Placebo |
|---|---|---|
| Placebo | -0.8 kg | -- |
| 1 mg | -2.8 kg | +2.0 kg |
| 5 mg | Modest | Positive trend |
| 10 mg | Modest | Positive trend |
| 20 mg | Modest | Positive trend |
| 30 mg | Modest | Positive trend |
The 1 mg dose produced the most weight loss -- more than triple the placebo response. This was an unusual dose-response pattern (the lowest active dose worked best), but it generated optimism.
The trial also showed a small but consistent improvement in cholesterol profiles and a reduction in the number of patients with impaired glucose tolerance.
News-Medical.net reported at the time that the drug was "highly successful in trials." Metabolic Pharmaceuticals' stock rose. A pivotal Phase IIb trial was planned.
METAOD006 (OPTIONS): The Pivotal Failure
Year: 2005-2007 Design: Randomized, double-blind, placebo-controlled, multicenter Subjects: 536 obese adults (approximately equal men and women) BMI Range: 30-45 kg/m2 Waist Circumference: Greater than 102 cm (men) or 95 cm (women) Administration: Oral, once daily Doses: 0 mg (placebo), 0.25 mg, 0.5 mg, and 1 mg Duration: 24 weeks (4-week run-in, 24-week treatment, 30-day follow-up) Primary Endpoint: Weight loss at 12 weeks
Based on the METAOD005 result showing the 1 mg dose was most effective, the OPTIONS study tested three doses at or below 1 mg.
Results:
The trial failed. No dose group showed a statistically significant difference from placebo in weight loss at the primary endpoint.
In February 2007, Metabolic Pharmaceuticals announced that "Phase 2B results for AOD9604 did not support commercial viability for the obesity indication." Development was terminated.
Safety Data Across All Six Trials
Across 893 participants in six controlled trials, AOD-9604 demonstrated a remarkably clean safety profile.
What the Data Showed:
| Safety Parameter | Finding |
|---|---|
| IGF-1 levels | No change in any trial |
| Glucose tolerance | No impairment; some improvement in METAOD005 |
| Insulin sensitivity | No negative effect |
| Anti-AOD9604 antibodies | None detected |
| Serious adverse events related to drug | None |
| Withdrawals due to drug | None |
The Stier et al. (2013) publication in the Journal of Endocrinology and Metabolism compiled the safety data from all six trials and concluded that AOD-9604 displayed "a very good safety and tolerability profile indistinguishable from placebo."
The irony is clear: AOD-9604's safety was never the problem. The drug simply did not produce enough weight loss to justify continued development.
Why the Drug Failed: Translational Gaps
AOD-9604's failure in the pivotal trial raises a question that matters beyond this single compound: why did strong animal results not translate to humans?
Species Differences in Beta-3 AR Biology:
The mechanism that drove fat loss in mice -- upregulation of beta-3 adrenergic receptors -- operates differently in humans. Rodent adipose tissue expresses high levels of beta-3 ARs, and these receptors play a dominant role in lipolysis. Human fat tissue has far fewer beta-3 ARs, and lipolysis is primarily driven by beta-1 and beta-2 adrenergic receptors. This mismatch may explain why a compound that worked through beta-3 AR signaling in mice showed weaker effects in humans.
Oral Bioavailability Questions:
While AOD-9604 was absorbed orally (unusual for a peptide), the bioavailability and tissue-level concentrations achieved through oral dosing may not have been sufficient to produce the same effects seen with intraperitoneal injection in animals.
The Inverted Dose-Response Problem:
In METAOD005, the 1 mg dose worked best -- lower doses and higher doses were less effective. This U-shaped dose-response curve is difficult to interpret pharmacologically and made dose selection for the pivotal trial uncertain. The OPTIONS study chose doses at and below 1 mg, but perhaps the dose-response was not replicable.
Placebo Effect in Obesity Trials:
Obesity trials are notoriously plagued by strong placebo responses. Participants in structured clinical trials receive regular monitoring, dietary counseling, and motivation that can drive weight loss independent of the drug being tested. In the OPTIONS study, the placebo response may have narrowed or eliminated the drug's modest signal.
For comparison, many approved weight-loss drugs produce only 3-5% placebo-subtracted weight loss, and even some blockbuster GLP-1 drugs like semaglutide succeeded in part because they produced effects large enough to overcome placebo noise.
After the Failure: GRAS Status and Nutraceutical Pivot
After pharmaceutical development ended, AOD-9604's story took an unexpected turn. Rather than disappearing entirely, the compound was repositioned as a nutraceutical ingredient.
GRAS Determination:
Based on the extensive safety data from over 900 clinical trial participants, along with additional non-clinical toxicology studies (including Ames tests, chromosomal aberration assays, and chronic dosing in rats and monkeys), AOD-9604 received Generally Recognized as Safe (GRAS) status for use in foods, drinks, and dietary supplements.
A 2014 publication by More et al. in the Journal of Endocrinology and Metabolism detailed the non-clinical safety data supporting this determination. The compound showed no evidence of genotoxicity, and whole-body radiography in rats showed similar organ distribution whether administered intravenously or orally.
What GRAS Means (and Doesn't Mean):
GRAS status means the FDA has accepted that the substance is safe for inclusion in food products at specified levels. It does not mean the compound is effective for any health purpose. It is not the same as drug approval, and it does not permit marketing AOD-9604 with medical claims.
Emerging Research: Cartilage and Osteoarthritis
One of the more unexpected post-failure research directions involves AOD-9604's potential role in cartilage repair.
Kwon & Park (2015):
A study published in Annals of Clinical & Laboratory Science tested AOD-9604 injected directly into the joints of rabbits with collagenase-induced osteoarthritis. The study compared four groups: saline control, hyaluronic acid (HA) alone, AOD-9604 alone, and AOD-9604 combined with HA.
The combination group showed the best outcomes -- significantly lower cartilage degeneration scores and shorter periods of lameness compared to all other groups. AOD-9604 alone also outperformed the saline control but not as dramatically as the combination.
Proposed Mechanism:
The researchers suggested that HA provides a chondrocyte-protective environment while AOD-9604 may help activate developmental signaling cascades involved in cartilage regeneration. This mechanism remains speculative and has not been validated in larger studies or in humans.
A 2024 review in PMC listed AOD-9604 alongside BPC-157 and thymosin beta-4 as peptides with potential applications in cartilage regeneration for osteoarthritis. However, the evidence base for this application remains thin -- essentially a single rabbit study.
Current Regulatory Status
As of early 2026, AOD-9604 exists in regulatory limbo.
FDA:
In December 2024, the FDA's Pharmacy Compounding Advisory Committee (PCAC) reviewed AOD-9604 (both free base and acetate forms) for potential inclusion on the 503A Bulks List, which would have allowed licensed pharmacies to compound the peptide. The FDA determined it should not be included, citing concerns over limited long-term safety data, peptide impurities, and potential immunogenicity.
This means AOD-9604 cannot be legally compounded by 503A pharmacies in the United States. It joins several other peptides in this restricted category.
WADA:
The World Anti-Doping Agency prohibits AOD-9604 under category S.0 (non-approved substances) and S.2 (peptide hormones, growth factors, and related substances). Athletes have been sanctioned for its use.
The WADA ban gained public attention during the 2013 Australian Football League supplements scandal, when the Essendon Football Club was found to have administered AOD-9604 to players. Initial confusion about whether the substance was prohibited was resolved when WADA clarified its position.
No Country Approves Therapeutic Use:
AOD-9604 is not approved by any national health authority worldwide for any therapeutic indication. It remains available as a research peptide and, in some jurisdictions, as a component of nutraceutical products under GRAS status.
Summary of All Human Trials
| Trial | Phase | N | Route | Duration | Doses | Key Result |
|---|---|---|---|---|---|---|
| METAOD001 | I | 15 | IV | Single dose | 25-400 mcg/kg | Safe, tolerable |
| METAOD002 | IIa | 23 | IV | Single dose | 25-100 mcg/kg | Safe in obese subjects |
| METAOD003 | IIa | 17 | Oral | Single dose | 9-54 mg | Oral absorption confirmed |
| METAOD004 | IIa | ~36 | Oral | 7 days | Multiple | Repeat dosing safe |
| METAOD005 | IIb | 300 | Oral | 12 weeks | 1-30 mg | 1 mg dose: -2.8 kg vs. -0.8 kg placebo |
| METAOD006 | IIb | 536 | Oral | 24 weeks | 0.25-1 mg | Failed primary endpoint; no significant weight loss |
Total participants across all trials: 893 (approximately)
FAQ
Did AOD-9604 work at all in humans?
In the 12-week METAOD005 trial, the 1 mg dose group lost 2.8 kg compared to 0.8 kg for placebo -- a statistically meaningful difference. But this result did not hold up in the larger, longer OPTIONS study, which is the more definitive test.
Is AOD-9604 the same as hGH fragment 176-191?
Nearly identical. AOD-9604 is based on hGH residues 176-191 but substitutes tyrosine for phenylalanine at position 176 for greater stability. "hGH fragment 176-191" and "AOD-9604" are often used interchangeably, though technically they have a single amino acid difference.
Why is AOD-9604 still popular if it failed clinical trials?
Several reasons converge. The safety data is genuinely strong. The mechanism sounds compelling. And the compound entered the supplement and wellness market where efficacy standards differ from pharmaceutical regulation. Many users report subjective improvements, though controlled data does not support these experiences.
Can AOD-9604 be stacked with other peptides?
Some practitioners combine AOD-9604 with other compounds like CJC-1295 or growth hormone secretagogues. No controlled studies have evaluated these combinations. Our peptide stacking guide covers the general principles. The fact that AOD-9604 does not raise IGF-1 means it theoretically shouldn't compound IGF-1-related risks, but this has not been formally tested.
How does AOD-9604 compare to modern weight-loss peptides like semaglutide?
The comparison is stark. Semaglutide produces 15-17% body weight loss in clinical trials. AOD-9604 failed to beat placebo in its pivotal trial. They work through entirely different mechanisms (GLP-1 receptor agonism vs. growth hormone fragment lipolysis), and semaglutide has an FDA approval, multi-year safety data, and a massive outcomes trial program behind it. For a broader comparison, see our best peptides for fat loss guide.
The Bottom Line
AOD-9604 tells a story that plays out repeatedly in drug development: strong preclinical data, encouraging early-phase human results, and then failure when tested rigorously in a large, long-duration trial. The compound's safety profile was never in question -- over 900 participants across six trials showed no IGF-1 changes, no glucose problems, and no serious adverse events related to the drug.
The efficacy just wasn't there. A 2.0 kg advantage over placebo in a 12-week trial did not hold up in a 24-week study with 536 subjects. For a pharmaceutical, that is the end of the road.
The compound lives on in the wellness and supplement world, where it is marketed for fat loss, metabolic support, and joint health. Early-stage research into cartilage repair adds a new dimension, but the evidence there consists of a single rabbit study. The gap between AOD-9604's reputation and its clinical data remains wide.
For anyone considering AOD-9604 for fat loss or muscle recovery, the honest assessment is this: the compound is well-tolerated, but the best available human evidence does not support meaningful weight-loss efficacy. The FDA's December 2024 decision to exclude it from compounding pharmacies underscores this reality.
References
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Heffernan M, Summers RJ, Thorburn A, et al. The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knock-out mice. Endocrinology. 2001;142(12):5182-5189. PubMed
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Ng FM, Sun J, Sharma L, et al. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Hormone Research. 2000;53(6):274-278. ResearchGate
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Stier H, Vos E, Kenley D. Safety and tolerability of the hexadecapeptide AOD9604 in humans. Journal of Endocrinology and Metabolism. 2013;3(1-2):7-15. Full Text
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More MI, Kenley D, Gianello R. Safety and metabolism of AOD9604, a novel nutraceutical ingredient for improved metabolic health. Journal of Endocrinology and Metabolism. 2014;4(3):66-78. Full Text
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Kwon DR, Park GY. Effect of intra-articular injection of AOD9604 with or without hyaluronic acid in rabbit osteoarthritis model. Annals of Clinical & Laboratory Science. 2015;45(4):426-432. PubMed
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Obesity drug codenamed AOD9604 highly successful in trials. News-Medical.net. December 16, 2004. Link
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FDA Pharmacy Compounding Advisory Committee Meeting. December 4, 2024. FDA Document
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WADA statement on substance AOD-9604. World Anti-Doping Agency. Link