AOD-9604: The hGH Fragment, Its Failed Trials and FDA Status

What is AOD-9604?

AOD-9604 (AOD stands for "anti-obesity drug") is a synthetic peptide modelled on the tail of human growth hormone, a 191-amino-acid protein. It takes the last 15 residues, positions 177 to 191, and adds a tyrosine at the front: Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe. A disulfide bond between the two cysteines closes part of the chain into a ring (FDA, 2024; PubChem).

It is often confused with "hGH fragment 176-191", the natural sequence. Position 176 of growth hormone is phenylalanine (UniProt P01241), so the two differ only in their first residue. They are separate substances, and data on one do not automatically apply to the other.

Where did AOD-9604 come from?

It grew out of work at Monash University in Melbourne on separating growth hormone's effects on fat from its other actions. In 1993 Frank Ng's group reported that synthetic hGH 177-191 reduced fat production (lipogenesis) in rat fat tissue as effectively as the whole hormone (Wu and Ng, 1993), and a year later that it reduced weight gain and fat mass in obese mice (Natera et al., 1994). The tyrosine-extended version, AOD9604, appears in the group's papers from 2000 (Ng et al., 2000). Metabolic Pharmaceuticals, a Melbourne biotechnology company, developed and patented it in the late 1990s, and phase 2a trials were under way by February 2002 (FDA, 2024; Wilding, 2004).

What did the animal studies show?

• Obese rats: 19 days of daily oral treatment more than halved body weight gain and raised the lipolytic (fat-breaking) activity of fat tissue. Unlike long-term intact hGH, it did not impair insulin sensitivity (Ng et al., 2000).
• Obese mice: over 14 days it reduced weight gain and raised fat oxidation and blood glycerol, a marker of lipolysis, without the high blood glucose seen with hGH. In cell assays it did not bind the growth hormone receptor or drive the growth of receptor-bearing cells (Heffernan et al., 2001a).
• Beta-3 receptors: it raised beta-3 adrenergic receptor RNA in fat, and in mice lacking that receptor long-term treatment no longer changed weight or lipolysis (Heffernan et al., 2001b).

These are small rodent studies, almost all from the originating group. FDA's 2024 review noted that none tested how effects changed with the amount given, that the statistics were not corrected for multiple comparisons, and that the molecular target remains unknown (FDA, 2024). The claim that AOD-9604 leaves IGF-1 unchanged rests mainly on a company-authored summary of the human trials, which reported no significant change (Stier et al., 2013); FDA found no nonclinical data directly supporting it.

What did the human trials show?

Metabolic ran six randomised, placebo-controlled trials between 2001 and 2007, with roughly 900 participants, all company funded (Stier et al., 2013; Calzada, 2013). The efficacy results were never published in full in a journal; they are known from a 2004 review, a conference abstract, company announcements and FDA's 2024 review.

• Early trials: small intravenous and oral studies, mostly in men with obesity, found rises in blood free fatty acids, a marker of fat breakdown, but no significant weight loss compared with placebo (Wilding, 2004; FDA, 2024).
• 12-week trial, 300 people: a conference abstract reported slightly more weight loss than placebo, significant only for women in one group, plus small waist reductions. FDA judged the differences small and of unclear clinical meaning (FDA, 2024).
• Phase 2b OPTIONS trial: 536 adults with obesity enrolled (502 randomised) for 24 weeks, alongside a supervised diet and exercise programme. The primary endpoint, significant weight loss compared with placebo at 12 weeks, was not met, and the difference was too small for significance at 24 weeks either. On 21 February 2007 the company said the results did not support commercial viability for obesity and terminated development for that use (FDA, 2024).

The human evidence for fat loss is therefore negative: the one trial built to test it properly failed.

On safety, the company summary described AOD-9604 as well tolerated, with no adverse effect on glucose tolerance and no antibodies in the patients tested (Stier et al., 2013). FDA found the summaries too thin to assess fully. It flagged serious adverse events in AOD-9604 groups in the 12-week trial, including skin cancers, a melanoma and a breast cancer, which investigators judged unrelated but which FDA could not assess for lack of detail (FDA, 2024). The longest trial lasted 24 weeks.

What came after the obesity programme?

By 2013 the company was looking at cartilage and joint repair, with only preclinical work done (Calzada, 2013). The main published study used 32 rabbits with knee osteoarthritis induced by the enzyme collagenase: AOD-9604 delivered into the joint, alone or with hyaluronic acid, gave lower cartilage damage scores than saline, with the combination doing best (Kwon and Park, 2015). It is a single small animal study, and we found no published human trial in osteoarthritis.

In June 2012 the company announced what its chief executive called a "self-affirmed conditional GRAS status": a panel of experts it had contracted concluded that AOD-9604 was generally recognised as safe as a food ingredient (Calzada, 2012). That is a food-law conclusion reached for the company, not an FDA review, and it does not make AOD-9604 a medicine.

What is the FDA position?

No FDA-approved drug contains AOD-9604 (FDA, 2024). Its US regulatory history concerns compounding pharmacies and FDA's list of bulk substances they may use under section 503A of the Food, Drug, and Cosmetic Act.

• 2023: FDA's list updated on 29 September 2023 announced that AOD-9604 would be added to Category 2, "bulk drug substances that raise significant safety risks" (FDA, 2023). FDA's stated concerns: possible immunogenicity (immune reactions against the peptide) with some routes, complexities with peptide-related impurities and characterisation of the active ingredient, no or only limited safety information, and serious adverse events that may be associated with AOD-9604, though causality is not clear (FDA, 2026).
• 2024: the two nominators withdrew their nominations and AOD-9604 left Category 2. This was not a safety clearance: FDA's safety-risk page still lists it, with the same concerns, under "nominated but withdrawn" (FDA, 2026).
• 4 December 2024: having reviewed it on its own initiative for obesity, FDA proposed not adding it to the 503A list, citing a lack of evidence of effectiveness and safety concerns. Its Pharmacy Compounding Advisory Committee voted 12 to 0 against adding it (FDA, 2024; FDA PCAC minutes, 2024).

Is AOD-9604 banned in sport?

Yes. The 2026 WADA Prohibited List names AOD-9604 and hGH 176-191 as examples of growth hormone fragments under S2.2.3, a class prohibited at all times, in and out of competition (WADA, 2026). Anti-doping scientists have published a urine detection method and identified a stable breakdown fragment that may extend the detection window (Cox et al., 2015).

AOD-9604 vs tesamorelin

Both come up in discussions of growth hormone and body fat, but their evidence is far apart. Tesamorelin is a growth hormone-releasing hormone (GHRH) analogue that prompts the pituitary to release the body's own growth hormone, so IGF-1 rises. In a 26-week phase 3 trial in 412 people with HIV and abdominal fat accumulation, visceral fat fell 15.2% with tesamorelin and rose 5.0% with placebo (Falutz et al., 2007), and FDA approved it in November 2010 for excess abdominal fat in HIV-associated lipodystrophy (Traynor, 2010).

See the side-by-side AOD-9604 vs tesamorelin comparison and our tesamorelin research review.

What is not known?

• Mechanism: the molecular target has never been identified.
• Translation: why clear effects in obese rodents did not become meaningful weight loss in people.
• Full trial data: the efficacy trials were never published in full, and no independent group has run a human trial.
• Long-term safety: no trial ran beyond 24 weeks, and the cancer reports were never resolved in published detail.
• Cartilage: one rabbit study; no human data.
• Material identity: FDA noted that some public sources quote a different CAS number and some supplier websites show structures that do not match the sequence (FDA, 2024).

The bottom line

AOD-9604 has an unusually clear record: promising rodent data on fat metabolism, a sizeable human programme and a negative result. The obesity work stopped in 2007 because weight loss was not meaningfully better than placebo, the cartilage interest rests on one animal study, and FDA's latest public assessment describes significant safety concerns. Its value is as a research tool for studying how a growth hormone fragment acts on fat tissue. Specifications for research material are on the AOD-9604 compound page.

References

1. Calzada Ltd. (2012). AOD9604 Receives GRAS Status. ASX announcement, 25 June 2012. ASX announcement
2. Calzada Ltd. (2013). AOD9604: Important Clarifications. ASX announcement, 26 April 2013. ASX announcement
3. Cox HD, et al. (2015). Detection and in vitro metabolism of AOD9604. Drug Testing and Analysis. PubMed 25208511
4. Falutz J, et al. (2007). Metabolic effects of a growth hormone-releasing factor in patients with HIV. New England Journal of Medicine. PubMed 18057338
5. US Food and Drug Administration. (2023). Bulk Drug Substances Nominated for Use in Compounding Under Section 503A of the Federal Food, Drug, and Cosmetic Act, updated 29 September 2023. Copy hosted by the Alliance for Pharmacy Compounding
6. US Food and Drug Administration. (2024). FDA Briefing Document, Pharmacy Compounding Advisory Committee, 4 December 2024: Evaluation of AOD-9604-related bulk drug substances. fda.gov
7. US Food and Drug Administration. (2024). Final Summary Minutes of the Pharmacy Compounding Advisory Committee Meeting, 4 December 2024. fda.gov
8. US Food and Drug Administration. (2026). Certain bulk drug substances for use in compounding that may present significant safety risks (content current as of 22 April 2026). fda.gov
9. Heffernan MA, et al. (2001a). Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment. International Journal of Obesity and Related Metabolic Disorders. PubMed 11673763
10. Heffernan M, et al. (2001b). 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. PubMed 11713213
11. Kwon DR, Park GY. (2015). Effect of Intra-articular Injection of AOD9604 with or without Hyaluronic Acid in Rabbit Osteoarthritis Model. Annals of Clinical and Laboratory Science. PubMed 26275694
12. Natera SH, et al. (1994). Reduction of cumulative body weight gain and adipose tissue mass in obese mice: response to chronic treatment with synthetic hGH 177-191 peptide. Biochemistry and Molecular Biology International. PubMed 7987248
13. Ng FM, et al. (2000). Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Hormone Research. PubMed 11146367
14. Stier H, et al. (2013). Safety and Tolerability of the Hexadecapeptide AOD9604 in Humans. Journal of Endocrinology and Metabolism. doi:10.4021/jem157w
15. Traynor K. (2010). FDA approves tesamorelin for HIV-related lipodystrophy. American Journal of Health-System Pharmacy. PubMed 21115997
16. Wilding J. (2004). AOD-9604 Metabolic. Current Opinion in Investigational Drugs. PubMed 15134286
17. World Anti-Doping Agency. (2026). World Anti-Doping Code International Standard: Prohibited List 2026. wada-ama.org
18. Wu Z, Ng FM. (1993). Antilipogenic action of synthetic C-terminal sequence 177-191 of human growth hormone. Biochemistry and Molecular Biology International. PubMed 8358331