AOD-9604

AOD9604 (Anti-Obesity compound 9604) is a synthetic hexadecapeptide analog of the C-terminal fragment of human growth hormone (hGH), specifically corresponding to amino acid residues 177–191 with an additional tyrosine residue at the N-terminus to enhance stability [1][2]. It was originally developed at Monash University (Melbourne, Australia) by research teams led by Dr. Frank M. Ng to retain the lipolytic (fat-burning) properties of hGH without inducing its insulin-desensitizing or mitogenic (growth-promoting) reported observations in study populations [3][4].

The peptide was subsequently licensed to Metabolic Pharmaceuticals Ltd (ASX: MBP), which advanced AOD9604 through preclinical and early clinical development between 1999 and 2007. The compound has attracted renewed scientific interest in the context of musculoskeletal repair research, with studies exploring its effects on cartilage regeneration in animal models of osteoarthritis [5][6]. More recently, under the code name LAT8881, it has been investigated for potential host-protective properties against severe influenza A virus infection [7].

Structurally, AOD9604 is a 16-amino-acid peptide with a molecular weight of 1815.1 g/mol. It contains a disulfide bridge between Cys⁷ and Cys¹⁴ (corresponding to Cys¹⁸² and Cys¹⁸⁹ in native hGH), which forms a cyclic domain critical for biological activity [8]. The addition of a tyrosine residue at the N-terminus distinguishes AOD9604 from the native hGH(177–191) fragment, conferring improved metabolic stability and potency in preclinical lipid-metabolism assays [2][9].

The mechanism of action of AOD9604 centers on the regulation of lipid metabolism through a signaling cascade that is distinct from the growth-promoting pathways activated by full-length hGH. The key pathways are:

1. Beta-3 Adrenergic Receptor (β3-AR) Activation

In murine adipose tissue, the lipolytic effects of AOD9604 are critically dependent on functional beta-3 adrenergic receptors (β3-AR). Studies using β3-AR knockout mice demonstrated a complete abolition of AOD9604-induced lipolysis, confirming the receptor as an essential mediator [1]. In obese (ob/ob) mice, chronic research application with AOD9604 at 500 µg/kg/day i.p. for 14 days resulted in significant upregulation of β3-AR mRNA expression in white adipose tissue, effectively restoring lipolytic sensitivity that is typically blunted in the obese phenotype [1][10].

2. cAMP / Hormone-Sensitive Lipase (HSL) Pathway

Activation of β3-AR by AOD9604 stimulates adenylate cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP) levels. Elevated cAMP activates protein kinase A (PKA), which phosphorylates hormone-sensitive lipase (HSL), the rate-limiting enzyme in triglyceride hydrolysis. This cascade promotes the breakdown of stored triglycerides into free fatty acids and glycerol (lipolysis) [2][11].

3. Inhibition of Acetyl-CoA Carboxylase (ACC) / Anti-Lipogenesis

Concurrently, AOD9604 inhibits acetyl-CoA carboxylase (ACC), the enzyme that catalyzes the first committed step in de novo fatty acid synthesis (lipogenesis). By suppressing ACC activity, AOD9604 reduces the conversion of acetyl-CoA to malonyl-CoA, thereby inhibiting new fat formation [2][12]. This dual action—stimulating fat breakdown while inhibiting fat synthesis—accounts for the net reduction in adipose tissue mass observed in preclinical models.

4. Why AOD9604 Does NOT Activate IGF-1 or the hGH Receptor

A critical distinction of AOD9604 from full-length hGH is its inability to activate the growth hormone receptor (GHR). Full-length hGH binds two GHR molecules (receptor dimerization), triggering the JAK2/STAT5 signaling cascade that stimulates hepatic production of Insulin-like Growth Factor 1 (IGF-1) [13]. Because AOD9604 represents only the C-terminal tail of hGH (residues 177–191), it lacks the structural domains (helices A and B) required for high-affinity GHR binding and dimerization [8][14]. Consequently, AOD9604 does not:

• Elevate serum IGF-1 levels [3][15]
• Stimulate cell proliferation (no mitogenic activity) [8]
• Induce insulin resistance or hyperglycemia [2][16]

This selectivity for metabolic effects without growth-promoting reported observations in study populations was a key design objective in the development of AOD9604 [3].

Metabolic Research (Obesity & Lipid Metabolism)

AOD9604 was originally developed as a potential anti-obesity experimental. In preclinical studies, the peptide demonstrated significant effects on body composition:

• ob/ob Mouse Model: Chronic research application with AOD9604 at 500 µg/kg/day i.p. for 14 days produced an average body weight reduction of ~8.1 g (~5.5%) compared to saline-treated controls, without any change in food intake, blood glucose, or serum IGF-1 [1][2].
• Zucker Rat Model: In obese Zucker (fa/fa) rats, oral administration of AOD9604 at 200–600 µg/kg/day for 18 days resulted in a dose-dependent reduction in body fat mass with no effects on lean body mass, demonstrating selectivity for adipose tissue [11][12].
• Fat Oxidation: Metabolic chamber studies showed a 50–60% increase in fat oxidation rate in AOD9604-treated animals versus controls, as measured by respiratory quotient (RQ) shifts [2].

Despite these promising preclinical results, a large randomized Phase 2b clinical trial (n=536, 24 weeks, oral dosing 1–25 mg/day) failed to demonstrate statistically significant weight loss compared to placebo in humans, leading to the termination of the obesity development program by Metabolic Pharmaceuticals in 2007 [16][17].

Regenerative research compound (Cartilage & Musculoskeletal Repair)

AOD9604 has attracted significant interest in the field of musculoskeletal regeneration, particularly for cartilage repair in osteoarthritis (OA):

• Rabbit OA Model (Kwon & Park, 2015): In a collagenase-induced OA model, intra-articular injection of AOD9604 alone significantly improved gross morphological scores (scale 0–4) from a mean of 3.4 (severe damage) to 1.6 (mild damage) at 8 weeks. When combined with hyaluronic acid (HA), scores improved further to 0.8 (near-normal). Histopathological analysis (Mankin scoring system) confirmed enhanced proteoglycan staining and restored cartilage surface regularity in research application groups [5].
• Chondrocyte Proliferation: In vitro studies suggest AOD9604 may enhance chondrocyte proliferation and extracellular matrix (ECM) synthesis, although the precise molecular pathway remains under investigation [6].
• Synergistic Combinations: AOD9604 is frequently studied in combination with BPC-157 and HA for potential synergistic tissue-repair effects [6][18].

Influenza Research (LAT8881)

Under the designation LAT8881, AOD9604 has been evaluated by Lateral Pharma Pty Ltd for host-protective properties against severe influenza A infection. Preclinical data suggests potential immunomodulatory effects [7].

Animal Studies

• In ob/ob mice, 500 µg/kg/day i.p. for 14 days produced ~5.5% body weight reduction (p < 0.05 vs. control) with a 50–60% increase in fat oxidation. No changes in blood glucose, insulin, or IGF-1 [1][2].
• In Zucker (fa/fa) rats, oral administration at 200–600 µg/kg/day for 18 days showed dose-dependent fat-mass reduction with preservation of lean body mass [11].
• In β3-AR knockout mice, AOD9604 failed to induce lipolysis, confirming β3-AR dependence [1].
• In rabbit collagenase-induced OA, intra-articular AOD9604 improved gross morphological scores from 3.4 to 1.6; combination with HA improved scores to 0.8 [5].

Human Clinical Trials

• Phase 1 tolerability: Single-ascending-dose and multiple-dose studies (up to 24 weeks) demonstrated a reported tolerability profile indistinguishable from placebo. No increases in IGF-1, anti-AOD9604 antibodies, or adverse metabolic markers [15][19].
• Phase 2b (n=536): A large, randomized, double-blind, placebo-controlled trial at oral AOD9604 1–25 mg/day for 24 weeks failed to meet primary weight loss endpoint vs. placebo [16][17].

Regulatory Status

• FDA: Not registered for any medical use. Listed on the FDA Category 2 list [20].
• WADA: Prohibited under Section S2 (Peptide Hormones, Growth Factors) [21].
• Australia (TGA): Approved as a complementary research compound ingredient at low oral doses (2021) [15].