AOD-9604

What it is

AOD-9604 is a synthetic 16-amino-acid peptide (a hexadecapeptide) built on a modified version of the C-terminal fragment 176-191 of human growth hormone (hGH), the region thought to carry the hormone's fat-metabolizing activity. Ng and colleagues in Australia described it as a synthetic lipolytic domain of hGH, and the Australian company Metabolic Pharmaceuticals took it through a series of human obesity trials before development for obesity ended.

Mechanism of action

The design idea was to keep growth hormone's fat-breakdown (lipolytic) action while leaving out its growth-promoting and insulin-opposing effects. In rats, Ng et al. (2000) reported that oral AOD-9604 increased lipolytic activity in adipose tissue and, in euglycemic clamp studies, did not impair insulin sensitivity, unlike chronic intact hGH. Heffernan et al. (2001) linked the fat-loss effect to the beta-3 adrenergic receptor, a receptor on fat cells that drives lipolysis: obese mice lost weight and fat with AOD-9604, but mice lacking the beta-3 receptor did not show the weight change or the rise in lipolysis. In humans, the pooled safety analysis by Stier et al. (2013) found no change in serum IGF-1, the main mediator of growth hormone's growth effects, which is consistent with an action separate from that axis. Exactly how the fragment engages beta-3 signaling has not been established.

What it’s most studied for

AOD-9604 was developed and studied almost entirely as an obesity drug. The rodent work asked whether the fragment reduced weight gain and body fat in obese rats and mice, and whether it did so without growth hormone's effects on insulin sensitivity. The human program then tested whether daily dosing produced weight loss in adults with obesity and whether the peptide avoided the IGF-1 and glucose effects expected from growth hormone. Because the efficacy trials were reported mainly through conference abstracts and company announcements, the most complete peer-reviewed human paper is a safety analysis rather than an efficacy report. Current interest comes largely from the unregulated peptide market rather than new research.

Notable findings

Each finding carries the species or population it was observed in and the dose that study used. Doses are reported as research context, exactly as published. They are not guidance.

Study quality

AOD-9604 has more human data than most compounds sold as research peptides, but almost none of the efficacy data has been published in full. The developer ran six randomized, double-blind, placebo-controlled trials, and the one peer-reviewed human paper is a pooled safety analysis (Stier et al. 2013) that found no IGF-1 change, no worsening of glucose tolerance and no serious adverse events attributed to the drug. Efficacy results appeared only as a conference abstract for the 12-week trial and as company and trade press reports; secondary sources state that the later low-dose phase IIb trial did not beat placebo on weight loss, after which the obesity program ended. The animal evidence consists of short studies in obese rats and mice (14 to 19 days) from the group behind the compound. The human safety data cover the doses and routes used in those trials, not unregulated products sold outside them.

References

1. 1
   Stier H, Vos E, Kenley D (2013). Safety and tolerability of the hexadecapeptide AOD9604 in humans. Journal of Endocrinology and Metabolism.
2. 2
   Herd C, Wittert G, et al. (2005). The effect of AOD9604 on weight loss in obese adults: results of a randomized, double-blind, placebo-controlled, multicenter study. Obesity Research (conference abstract).
3. 3
   Ng FM, Sun J, Sharma L, et al. (2000). Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Hormone Research. PMID 11146367
4. 4
   Heffernan M, et al. (2001). 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. PMID 11713213
5. 5
   Life Scientist (2005). Metabolic commences phase IIb obesity drug trial. Life Scientist (trade press).
6. 6
   US Food and Drug Administration, Pharmacy Compounding Advisory Committee (2024). December 4, 2024 Meeting of the Pharmacy Compounding Advisory Committee. U.S. Food and Drug Administration.