What Is AOD-9604?

AOD-9604 (Advanced Obesity Drug-9604) is a modified fragment of human growth hormone (hGH), consisting of amino acids 177-191 of the C-terminal region with an added tyrosine at the N-terminus. Developed by Metabolic Pharmaceuticals in Australia, it was designed to retain the fat-metabolizing properties of hGH without its growth-promoting or diabetogenic effects.

Base: hGH fragment 177-191 Modification: Added N-terminal tyrosine Amino Acids: 16 Molecular Weight: 1,815.1 g/mol Development: Metabolic Pharmaceuticals (Australia) Status: TGA approved (Australia) for specific use; research compound elsewhere

The concept was to isolate the "lipolytic" (fat-burning) activity from a small region of growth hormone, creating a targeted anti-obesity agent.

Key Characteristics

  • Origin: C-terminal fragment of human GH
  • Target: Fat metabolism without growth effects
  • No IGF-1 Increase: Doesn't raise IGF-1 levels
  • No Diabetogenic Effect: Doesn't impair glucose tolerance

Mechanism of Action

Fat Metabolism

Proposed mechanisms for fat-reducing effects:

  • Stimulates lipolysis (fat breakdown) in adipose tissue
  • Inhibits lipogenesis (fat storage)
  • May act through ฮฒ3-adrenergic-like pathway
  • Does not involve IGF-1 or GH receptor activation

Distinct from Full GH

AOD-9604 differs from growth hormone in important ways:

  • No anabolic effects: Doesn't promote muscle or bone growth
  • No IGF-1 increase: Doesn't stimulate IGF-1 production
  • No insulin resistance: Doesn't impair glucose metabolism
  • Targeted effect: Primarily affects fat tissue

Research History

Early Development

  • Developed based on research showing the C-terminal of GH has lipolytic activity
  • Pre-clinical studies showed fat reduction in obese mice
  • Promising animal data led to clinical trials

Clinical Trials

AOD-9604 underwent extensive human testing:

  • Phase I: Safety established, no serious adverse effects
  • Phase IIa: Some positive signals for fat loss
  • Phase IIb/III: Failed to show significant weight loss vs placebo
  • Outcome: Obesity indication abandoned by Metabolic Pharmaceuticals

Subsequent Development

  • Rights acquired by Calzada Ltd (now Phylogica)
  • Repurposed for osteoarthritis research
  • TGA approval in Australia for specific compounding use

Clinical Trial Results

Trial Phase Participants Outcome
Phase I ~50 Safe, well-tolerated
Phase IIa ~300 Modest fat loss signals
Phase IIb (oral) ~500 Failed primary endpoint

Current Status and Uses

Australia (TGA)

  • Approved for use by compounding pharmacies
  • Used in some anti-aging and weight management clinics
  • Available as injection or oral formulation

Osteoarthritis Research

  • Being investigated for cartilage repair
  • May stimulate chondrocyte function
  • Early research phase

AOD-9604 vs Fragment 176-191

Comparison

  • Fragment 176-191: Unmodified C-terminal fragment of hGH
  • AOD-9604: Same fragment with added N-terminal tyrosine
  • Difference: Tyrosine modification may improve stability/activity
  • Both: Aim to provide lipolysis without GH side effects

Safety Profile

Based on clinical trial data:

  • Generally well-tolerated in clinical trials
  • No significant adverse events reported
  • No effects on blood glucose or insulin
  • No cardiac or cardiovascular concerns noted
  • No effects on IGF-1 or other growth parameters

Administration

  • Routes studied: Subcutaneous injection, oral
  • Research doses: 200-500 mcg/day (injection)
  • Timing: Often morning, fasted
  • Duration: Weeks to months in studies

Why It Failed for Obesity

Despite promising preclinical data:

  • Human trials didn't show significant weight loss
  • Effect size too small to be clinically meaningful
  • Oral bioavailability challenges
  • Peptides generally difficult to develop as oral drugs
  • Couldn't compete with emerging alternatives (GLP-1s)

Research Status

AOD-9604 is not FDA-approved. While it has TGA approval in Australia for specific compounding use, it failed clinical trials for obesity and remains primarily a research compound in most jurisdictions. The clinical trial failure for its primary intended use (weight loss) is an important consideration.

Summary

AOD-9604 represents an interesting approach to metabolic therapy โ€” attempting to isolate beneficial fat-metabolizing properties of growth hormone without unwanted effects. While the concept was sound and safety data reassuring, clinical trials failed to demonstrate meaningful weight loss in humans. It serves as a reminder that promising preclinical results don't always translate to clinical success. The peptide continues to be used in some compounding contexts and is being investigated for other applications like osteoarthritis.

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