AOD-9604 (Tyr-hGH177-191)

Purity: ≥99% (HPLC) | Molecular Formula: C₇₈H₁₂₃N₂₃O₂₃S₂ | Sequence: Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe

Mechanism of Action

AOD-9604 is a synthetic 16-amino acid peptide fragment derived from the C-terminal region of human growth hormone (hGH), encompassing amino acids 176 through 191, with an additional tyrosine residue at the N-terminus for stabilization. In experimental models, AOD-9604 exhibits potent lipolytic and anti-lipogenic properties. It exerts these effects primarily by upregulating beta-3 adrenergic receptor expression in adipose tissue. Notably, investigations have confirmed that AOD-9604 does not bind to the classical hGH receptor, indicating that its mechanism operates through a distinct cellular pathway. Because of this structural isolation, the peptide stimulates targeted lipid oxidation without triggering the systemic elevation of insulin-like growth factor 1 (IGF-1), widespread cellular proliferation, or the disruptions in glucose metabolism traditionally associated with intact hGH administration.

Clinical Trials and Experimental Studies

Human Metabolic and Safety Evaluations

The clinical safety and tolerability of AOD-9604 were rigorously established across six randomized, double-blind, placebo-controlled trials involving approximately 900 adult subjects. These studies primarily measured the incidence of adverse events, serum IGF-1 levels, and carbohydrate metabolism parameters via oral glucose tolerance tests. The results demonstrated an excellent safety profile that was indistinguishable from placebo. The peptide produced no negative effects on carbohydrate metabolism, did not elevate IGF-1, and demonstrated zero immunogenicity, as no anti-AOD-9604 antibodies were detected in any human subjects.

Efficacy for lipid reduction was evaluated in a large Phase 2b trial (the OPTIONS study), which enrolled 536 human subjects over a 24-week period to measure total weight loss. Despite the established safety profile and promising preclinical data, the 24-week trial failed to demonstrate statistically significant weight loss compared to the placebo control arm. Consequently, formal clinical development of the peptide for an obesity indication was terminated in 2007.

Preclinical Cartilage and Osteoarthritis Models

Independent of metabolic research, AOD-9604 has been investigated in vivo for its potential in structural tissue regeneration. In a collagenase-induced knee osteoarthritis (OA) rabbit model, subjects were administered weekly intra-articular injections of AOD-9604 (0.25 mg), either alone or in combination with hyaluronic acid (HA). The studies measured gross morphological and histopathological scores of cartilage degeneration, as well as the duration of physical lameness. The results indicated that subjects receiving AOD-9604 exhibited significantly enhanced cartilage regeneration and shorter lameness periods compared to saline controls. The synergistic administration of AOD-9604 and HA yielded the most pronounced joint tissue repair and structural preservation.

Comparative Pharmacodynamics

• Versus Full-Length Human Growth Hormone (hGH): Intact hGH acts as a broad-spectrum pro-hormone that drives systemic cellular proliferation and significant alterations in insulin sensitivity. AOD-9604 represents only the isolated lipolytic domain of hGH; thus, it does not stimulate IGF-1 production. In comparative murine models, AOD-9604 successfully drove lipolysis and fat oxidation without inducing the hyperglycemia or insulin resistance consistently observed in hGH control groups.
• Versus GLP-1 Receptor Agonists (e.g., MA-1S, MA-2TZ): GLP-1 analogs govern metabolism centrally by suppressing appetite, delaying gastric motility, and modulating pancreatic insulin secretion. In contrast, AOD-9604 operates peripherally, targeting adipocyte beta-3 adrenergic receptors directly, and exhibits absolutely no effect on baseline feeding behavior or central satiety signaling. While AOD-9604 avoids the significant lean mass reduction occasionally associated with GLP-1-induced caloric restriction, the clinical trial data indicates that AOD-9604 lacks the robust, statistically significant clinical weight-loss efficacy demonstrated by the incretin class in human subjects.

Research References

1. Stier, H., Vos, E., & Kenley, D. (2013). Safety and Tolerability of the Hexadecapeptide AOD9604 in Humans. Journal of Endocrinology and Metabolism. View Study
2. 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. View Study
3. Kwon, D. R., & Park, G. Y. (2015). Effect of Intra-articular Injection of AOD9604 with or without Hyaluronic Acid in Rabbit Osteoarthritis Model. Annals of Clinical and Laboratory Science. View Study
4. Ng, F. M., et al. (2000). Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Hormone Research. View Study
5. Metabolic Pharmaceuticals. (2006). Phase 2B OPTIONS Study for obesity drug, AOD9604. BioSpace. View Press Release