Product description
What is AOD-9604?
AOD-9604 (Anti-Obesity Drug 9604) is a synthetic peptide consisting of 16 amino acids, constituting a modified fragment of the C-terminal domain of human growth hormone (hGH), including amino acids 177-191 with an additional tyrosine at the N-terminus. The compound was developed in the 1990s by Metabolic Pharmaceuticals Ltd. in Australia as a potential anti-obesity drug, intended to take advantage of the lipolytic properties of growth hormone without its broader metabolic and anabolic effects.
The chemical structure of AOD-9604 contains two cysteine residues forming a disulfide bridge, which stabilizes the conformation of the peptide. The molecular formula is C₇₈H₁₂₃N₂₃O₂₃S₂ and the molecular weight is approximately 1815 Da. The N-terminal modification with tyrosine was introduced to increase the metabolic stability of the compound.
The concept of AOD-9604 development resulted from the observation that full-length growth hormone, despite its strong lipolytic effect and reduction of adipose tissue, causes numerous side effects, including insulin resistance, joint pain and fluid retention. Scientists identified the C-terminal region of hGH as the region responsible for lipolytic activity and attempted to isolate this function in a smaller peptide fragment.
AOD-9604 is designed to stimulate lipolysis (the breakdown of fat) and inhibit lipogenesis (the formation of new fat) without affecting insulin-like growth factor 1 (IGF-1) levels, glucose homeostasis or muscle growth. Unlike full growth hormone, the peptide does not bind to the classic GH receptor, acting through independent mechanisms.
Mechanism of action
β3-adrenergic receptor activation - Studies in animal models have shown that AOD-9604 can mimic the way hGH stimulates β3-adrenergic receptors on adipocytes. Activation of these receptors promotes the breakdown of stored fats. The peptide increases β3-AR mRNA expression in obese mice to levels comparable to those observed in lean individuals.
Lipolysis stimulation - AOD-9604 induces the release of fatty acids from adipose tissue by activating hormone-sensitive lipase (HSL) and modulating acetyl-CoA carboxylase activity. The released fatty acids can then be used as an energy source by muscles and other organs.
Lipogenesis inhibition - The peptide reduces the formation of new fat cells and the accumulation of lipids in existing adipocytes. This mechanism involves reducing the activity of lipogenic enzymes without affecting protein synthesis or carbohydrate metabolism.
Increased fat oxidation - Studies in obese ob/ob mice have shown that AOD-9604 increases the rate of fat oxidation without affecting glucose oxidation. The peptide may also slightly increase energy expenditure.
No interaction with the GH receptor - In vitro experiments using BaF-BO3 cells transfected with the growth hormone receptor confirmed that AOD-9604 does not bind to the GH receptor and does not induce cell proliferation in a receptor-dependent manner. This distinguishes the peptide from full-length hGH.
Directions of scientific research
Research on AOD-9604 has focused primarily on its potential use in reducing obesity, although other areas have also been explored, including cartilage regeneration.
Preclinical studies in obesity
In pharmacological studies on adult obese Zucker rats treated with AOD-9604 (500 μg/kg/day orally) for 21 days, approximately 50% less body weight gain was observed compared to the control group and significantly higher lipolytic activity in adipose tissue. Unlike hGH, AOD-9604 did not affect insulin sensitivity. Similar results were obtained in obese ob/ob mice after 14 days of intraperitoneal treatment.
Phase II clinical trials
Between 2001 and 2007, Metabolic Pharmaceuticals conducted several clinical trials in humans. In a 12-week Phase IIa study of 300 participants, moderate weight reduction was observed (2.6 kg vs. 0.8 kg in the placebo group). However, a subsequent 24-week Phase IIb study in 536 subjects showed no statistically significant difference in weight loss between AOD-9604 and placebo, leading to the termination of the clinical development program in 2007.
Safety profile in clinical trials
Despite its lack of clinical efficacy, AOD-9604 demonstrated an excellent safety profile in controlled studies of over 900 participants. The peptide was well tolerated and did not cause effects typical of full growth hormone, such as an increase in IGF-1, an effect on glucose or insulin levels.
Cartilage regeneration research
In early studies in chondrocytes, AOD-9604 showed the ability to modulate proteoglycan synthesis, suggesting potential applications in cartilage regeneration. However, this evidence is limited to in vitro and animal models.
Scientific context
AOD-9604 is an example of a "peptide drug candidate" that has demonstrated promising biological activity in preclinical studies but has not demonstrated efficacy in large human clinical trials. The history of its development illustrates the challenges of translating results from animal models to clinical therapy.
Compared to other approaches to treating obesity, AOD-9604 offered the theoretical advantage of selectively targeting adipose tissue without affecting muscle growth, glucose homeostasis, or IGF-1 levels. However, this selectivity did not translate into significant clinical effectiveness.
Today, AOD-9604 remains a topic of interest in the biohacking community and among fitness enthusiasts, despite a lack of clinical evidence supporting its use. The peptide is promoted as a "fat burning fragment", although available scientific data does not support such claims.
Since 2007, when clinical development ended, AOD-9604 has not received approval from any major regulator (FDA, EMA, TGA). In December 2024, the FDA determined that AOD-9604 (both freebase and acetate forms) should not be included in the list of substances allowed for pharmacy formulation under Section 503A, citing concerns about limited long-term safety data, peptide impurities, and potential immunogenicity.
Research safety profile
Tolerance in clinical trials - In six controlled clinical trials involving over 900 participants, AOD-9604 demonstrated a very good safety profile. The incidence of side effects was comparable to the placebo group.
No hormonal effects - Unlike full growth hormone, AOD-9604 did not increase IGF-1 levels, affect blood glucose levels, or induce insulin resistance. There was also no effect on insulin or cortisol levels.
Potential side effects - Occasionally observed symptoms included: injection site reactions, mild headaches, nausea. The frequency of these symptoms did not differ significantly from the placebo group.
Regulatory Concerns - FDA has expressed concerns regarding: lack of long-term safety data, potential contaminants in peptide synthesis, possible immunogenicity (antibody formation). The peptide is not approved for clinical use.
WADA Status - AOD-9604 is on the World Anti-Doping Agency (WADA) Prohibited List as a growth hormone mimetic.
Bibliography - latest scientific research
- FDA. Evaluation of AOD-9604 for the 503A Bulks List. FDA Drug Evaluation. 2024. FDA
- Heffernan MA 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
- Heffernan MA et al. Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment. Int J Obes Relat Metab Disord. 2001;25(10):1442-1449. PubMed
- Ng FM et al. Metabolic effects of a growth hormone releasing peptide (AOD9604) in obese Zucker rats. Mol Cell Endocrinol. 2000;159(1-2):107-115. PubMed
- Stier H et al. Safety and tolerability of the hexadecapeptide AOD9604 in humans. Growth Horm IGF Res. 2005;15(6):suppl A. [Abstract]
- Thompson JL et al. AOD-9604: a novel lipolytic peptide with potential therapeutic applications in obesity. Drug Dev Res 2004;62(2):165-172. Wiley
- Sackmann-Sala L et al. Heterogeneity in signal transduction, gene expression profiles and metabolic effects of growth hormone. J Mol Endocrinol. 2012;48(1):R1-10. PubMed
- Obesity pharmacotherapy: Current perspectives and future directions. Metabolism. 2013;62(3):395-404. PMC
- Yuen KCJ et al. Growth hormone/insulin-like growth factor I axis in health and disease states. Front Endocrinol. 2024;15:1456195. PubMed
- Spengler J et al. Synthesis of AOD-9604 using N-methylbenzimidazolinone linker. J Pept Sci. 2018;24(S1):e3062. PubMed
