AOD-9604

What it is

AOD-9604 (Anti-Obesity Drug 9604) is a 16-amino-acid synthetic peptide corresponding to the C-terminal fragment (residues 177–191) of human growth hormone, with a tyrosine residue added at the N-terminus. It was developed in the 1990s at Monash University in Australia by Frank Ng and colleagues and licensed to Metabolic Pharmaceuticals.

The peptide was originally developed on the hypothesis that the lipolytic effects of growth hormone could be separated from its mitogenic and diabetogenic effects by isolating the relevant fragment. It received GRAS (Generally Recognized As Safe) status in the US for limited food applications and is sold as a food supplement in some jurisdictions, but it has never received FDA pharmaceutical approval. AOD-9604 is not FDA-approved for any use in the United States.

Mechanism of action

Proposed mechanisms come from laboratory and animal research. In animal studies, the peptide was reported to stimulate lipolysis (breakdown of stored triglycerides) and inhibit lipogenesis (formation of new triglycerides) without binding the growth hormone receptor and without raising insulin-like growth factor-1 (IGF-1).

Mechanisms reported in preclinical models include:

• Increased β3-adrenergic receptor expression and downstream cAMP signaling in fat cells in animal models
• Increased fatty acid oxidation in muscle tissue in animal studies
• Changes in peripheral insulin sensitivity in some animal models
• No detectable effect on growth hormone receptor activation or IGF-1 levels in the preclinical testing reported

The reported plasma half-life is short, approximately 30 minutes.

Research findings

In animal studies using rodent obesity models, AOD-9604 was associated with reductions in body fat without reported effects on lean mass, IGF-1, or markers of insulin resistance.

The largest human trial was a 2007 phase IIb study by Heffernan and colleagues (Obesity) in which 534 participants with obesity were randomized to placebo or one of four oral AOD-9604 doses for 12 weeks. The trial did not establish a consistent effect; benefit in people has not been established.

Other routes of administration have not been evaluated in large randomized human trials. Well-controlled human trials establishing the effectiveness and safety of AOD-9604 are lacking.

Side effects and contraindications

Human safety has not been established in well-controlled trials, and long-term effects are unknown. Products sold outside regulated channels (for example, as “research peptides”) may vary in purity, dose, and sterility.

Because AOD-9604 is derived from a growth hormone fragment, its effects in people with cancer, and during pregnancy or breastfeeding, have not been studied.

What we don’t yet know

It is not known whether routes of administration other than the oral route used in the 2007 trial produce different effects, because no rigorous trials have compared them. Whether AOD-9604 has any meaningful effect on body composition in people, and what its long-term safety profile is, remain open questions that have not been answered by well-controlled studies.