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AOD-9604

AOD-9604 is a synthetic 16-amino acid peptide fragment derived from the C-terminal domain of human growth hormone (amino acids 176-191) with a stabilizing tyrosine substitution at the N-terminus. Originally developed by Metabolic Pharmaceuticals Ltd. in Australia during the 1990s as an "Anti-Obesity Drug," it was designed to harness growth hormone's lipolytic properties while avoiding broader metabolic and growth-promoting effects.

Despite completing six human clinical trials involving over 900 participants, AOD-9604 failed to achieve statistical significance in its largest Phase IIb trial and development was terminated in 2007. The peptide lacks regulatory approval from any major health authority worldwide. Its selective mechanism targeting adipose tissue without affecting IGF-1 pathways or glucose homeostasis distinguishes it from full-length growth hormone therapy, offering unique research applications in metabolic studies and potential cartilage repair applications.

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Overview

AOD-9604 exhibits rapid degradation in biological systems through amino-terminal truncation, with sequential amino acid removal being the primary metabolic pathway. The peptide maintains structural similarities to the homologous region of naturally occurring human growth hormone while demonstrating improved stability through its synthetic modifications. Detection in plasma and urine is possible using specialized LC/MS/MS assay methods for up to several days post-administration.

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Chemical structure & Properties

  • Molecular Formula: C₇₈H₁₂₃N₂₃O₂₃S₂
  • Molecular Weight: 1815.1 Daltons
  • Sequence: Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe
  • Disulfide Bridge: Cys7-Cys14 (cyclic structure)
  • CAS Number: 221231-10-3
  • Half-life: Approximately 4 minutes in plasma (rapid degradation)
  • Stability: Enhanced compared to native hGH C-terminus through N-terminal tyrosine modification

Mechanism of Action

AOD-9604 exerts its biological effects through multiple interconnected molecular mechanisms:

Beta-3 Adrenergic Receptor Activation

The peptide primarily functions through:

  • Selective activation of beta-3 adrenergic receptors in adipose tissue
  • Enhanced expression of beta-3-AR RNA in fat cells
  • Increased lipolytic sensitivity and responsiveness to metabolic stimuli
  • Direct stimulation of hormone-sensitive lipase activity

Lipolytic and Anti-Lipogenic Effects

AOD-9604 influences fat metabolism by:

  • Promoting the breakdown of stored triglycerides into free fatty acids and glycerol
  • Stimulating lipolysis preferentially in obese fat cells over lean adipocytes
  • Inhibiting lipogenesis (conversion of non-fat substrates into fatty acids)
  • Enhancing fat oxidation and energy expenditure

Selective Metabolic Targeting

The peptide demonstrates targeted effects through:

  • Absence of IGF-1 elevation, avoiding growth hormone-mediated anabolic effects
  • No significant impact on insulin sensitivity or glucose tolerance
  • Preservation of natural hormonal feedback mechanisms
  • Tissue-specific action limited primarily to adipose tissue

Alternative Metabolic Pathways

Research indicates additional mechanisms including:

  • Potential induction of apoptosis in white adipocytes
  • Enhanced energy expenditure independent of beta-3-AR activation
  • Direct cellular metabolic effects not mediated through traditional growth hormone pathways
  • Possible cartilage regenerative properties through undefined mechanisms

Clinical Applications and

Research Evidence

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Current Clinical Evidence

Published Human Studies

Phase I and II Clinical Trials (2001-2007):

  • Study Population: Over 900 participants across six randomized, double-blind, placebo-controlled trials
  • Dosing Regimens: Various doses including 0.25 mg, 0.5 mg, and 1.0 mg daily
  • Administration Routes: Both intravenous and oral formulations tested
  • Primary Outcomes: Safety, tolerability, and weight reduction assessment

Phase IIb Efficacy Study (12-week trial):

  • Study Population: 300 obese adults
  • Intervention: AOD-9604 1 mg daily
  • Results: Average weight loss of 2.6 kg vs 0.8 kg in placebo group
  • Significance: Modest but statistically significant weight reduction

Phase IIb Pivotal Trial (24-week study):

  • Study Population: 534 obese participants (BMI 30-45 kg/m²)
  • Intervention: Daily doses of 0.25 mg, 0.5 mg, or 1.0 mg
  • Results: No statistically significant weight loss compared to placebo
  • Outcome: Development termination due to insufficient efficacy

Long-term Safety Analysis:

  • Study Design: Comprehensive safety evaluation across all clinical trials
  • Primary Focus: IGF-1 levels, glucose tolerance, and immunogenicity
  • Results: Excellent safety profile with no significant adverse events
  • Key Findings: No antibody formation, no glucose metabolism disruption

Research Limitations

Current clinical evidence is constrained by:

  • Limited Efficacy Data: Conflicting results between early and late-stage trials
  • Development Termination: Insufficient commercial viability led to discontinued research
  • Narrow Study Focus: Primary concentration on obesity with limited investigation of other applications
  • Short-term Data: Lack of long-term safety and efficacy information
  • Population Specificity: Studies conducted primarily in obese populations

Safety Profile and Considerations

Clinical Safety Data

Extensive human clinical trials demonstrate:

  • Excellent Tolerability: Safety profile indistinguishable from placebo across all studies
  • No Serious Adverse Events: No withdrawals or serious complications related to AOD-9604
  • Minimal Side Effects: Occasional injection site reactions, mild fatigue, or headache
  • No Immunogenicity: Absence of antibody formation against the peptide

Metabolic Safety

AOD-9604 demonstrates favorable metabolic effects:

  • No IGF-1 Elevation: Avoids growth hormone-mediated complications
  • Glucose Homeostasis Preservation: No negative impact on insulin sensitivity or glucose tolerance
  • Cardiovascular Safety: No adverse effects on blood pressure or cardiac function
  • Endocrine Stability: Minimal disruption of natural hormonal systems

Theoretical Concerns

Potential considerations include:

  • Limited Long-term Data: Insufficient information on extended use effects
  • Individual Variability: Variable responses observed in clinical populations
  • Drug Interactions: Potential interactions with metabolic medications require monitoring
  • Population-Specific Effects: Different responses may occur in various demographic groups

Contraindications

AOD-9604 should be avoided in:

  • Active Malignancy: Theoretical concerns about growth promotion in cancer
  • Pregnancy and Lactation: Insufficient safety data for reproductive use
  • Severe Metabolic Disorders: Caution in uncontrolled diabetes or metabolic dysfunction
  • Known Peptide Hypersensitivity: Allergic reactions to synthetic peptides

Regulatory Status and

Legal Considerations

Global Regulatory Status

No Approved Medical Use:

  • FDA Status: Not approved for any therapeutic indication
  • International Status: No regulatory approval from any major health authority worldwide
  • Development Status: Classified as investigational compound under pre-clinical/clinical development

WADA Anti-Doping Status

Prohibited Substance Classification:

  • Category: S0 - Non-Approved Substances (prohibited at all times)
  • Rationale: No current approval for human therapeutic use
  • Athletic Use: Banned in all competitive sports
  • Detection: Urine testing available for anti-doping purposes

Legal Availability

Research Chemical Status:

  • Commercial Availability: Available through research chemical suppliers
  • Quality Control: Variable standards depending on supplier
  • Regulatory Oversight: Subject to research chemical regulations
  • Medical Use: Not approved for clinical therapeutic applications

Regional Variations:

  • United States: Research use only, not FDA-approved
  • Australia: Schedule 4 prescription-only medicine classification
  • European Union: No medical approval, research use restrictions apply

Administration and Dosing

Considerations

Reconstitution and Storage:

  • Formulation: Lyophilized powder requiring reconstitution
  • Storage Conditions: 2°C to 8°C before reconstitution
  • Stability: Use within specified timeframe after reconstitution
  • Injection Sites: Abdominal subcutaneous tissue with rotation

Clinical Considerations

Important Limitations:

  • No Established Medical Dosing: Absence of approved therapeutic protocols
  • Research Use Only: Not intended for clinical therapeutic applications
  • Individual Variability: Response varies significantly between individuals
  • Medical Supervision: Professional oversight required for any investigational use

Mechanistic Studies:

  • Elucidation of non-beta-3-AR mediated lipolytic pathways
  • Investigation of cartilage repair mechanisms
  • Cellular and molecular target identification
  • Tissue-specific metabolic effects characterization

Clinical Research Needs:

  • Large-scale efficacy trials in diverse populations
  • Long-term safety assessment and monitoring
  • Optimal dosing strategies for various applications
  • Combination therapy investigations with other peptides

Therapeutic Applications:

  • Cartilage repair and osteoarthritis treatment validation
  • Metabolic syndrome and NAFLD research
  • Age-related metabolic dysfunction studies
  • Selective adipose tissue research applications

Emerging Research Areas

Novel Applications Under Investigation:

  • Joint and Cartilage Health: Potential osteoarthritis treatment and cartilage regeneration
  • Metabolic Research: Tool for studying selective fat metabolism pathways
  • Combination Therapies: Synergistic effects with other peptides (e.g., BPC-157)
  • Tissue Engineering: Applications in regenerative medicine research
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Conclusion

AOD-9604 represents a unique synthetic peptide with well-characterized safety profile but limited proven efficacy for its originally intended obesity indication. The extensive clinical safety database from over 900 participants across six controlled trials establishes AOD-9604 as well-tolerated with minimal adverse effects. However, failure to demonstrate consistent efficacy in large-scale trials led to development termination in 2007.

Its selective mechanism targeting adipose tissue metabolism without affecting IGF-1 pathways or glucose homeostasis makes it valuable for research applications studying fat metabolism and emerging cartilage repair investigations. The peptide's regulatory status as an unapproved investigational compound limits clinical applications while maintaining research utility.

Until comprehensive efficacy data becomes available, AOD-9604 remains primarily a research tool rather than a validated therapeutic intervention. Healthcare providers and researchers must carefully evaluate risk-benefit profiles within appropriate research frameworks and ensure regulatory compliance when considering AOD-9604 applications.

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AOD-9604 SCIENTIFIC

DATA SUMMARY

MOLECULAR CHARACTERISTICS
PRECLINICAL EFFICACY DATA
CLINICAL EVIDENCE SUMMARY
SAFETY PROFILE
REGULATORY STATUS
Parameter
Molecular Weight
Amino Acid Length
Half-Life
Bioavailability
Detection Window
Value
1815.1 Da
16 residues
~4 minutes (plasma)
Active both oral and injectable
Up to several days (urine)
Application
Fat Loss
Beta-3 Receptor Activity
Cartilage Repair
Metabolic Effects
Studies
Multiple animal studies
Knockout mouse studies
Rabbit OA model
Various species
Dose Range
250-500 μg/kg
Various doses
Direct injection
0.25-1 mg daily
Outcome
50% reduction in weight gain (obese rats), enhanced lipolysis
Enhanced beta-3-AR expression, lipolytic sensitivity
Improved cartilage structure, reduced joint dysfunction
No IGF-1 elevation, preserved glucose tolerance
Study Type
Phase I/II Trials
12-Week Efficacy Study
24-Week Pivotal Trial
Population
900+ participants (6 studies)
300 obese adults
534 obese participants
Results
Excellent safety profile, no serious adverse events
2.6 kg vs 0.8 kg weight loss (vs placebo)
No statistically significant weight loss
Limitations
Mixed efficacy results
Modest effect size
Long-term data needed
Parameter
Acute Toxicity
IGF-1 Effects
Glucose Metabolism
Immunogenicity
Long-term Safety
Finding
No acute toxicity observed in animal studies
No elevation of IGF-1 levels in humans
No impairment of glucose tolerance or insulin sensitivity
No antibody formation detected
Minimal reported in clinical studies
Authority
FDA
WADA
Australia TGA
EU/UK
Classification
Investigational Compound
S0 Non-Approved Substance
Schedule 4 Medicine
Unscheduled
Status
Not approved for human use
Prohibited in sports
Prescription-only
Research use only

Disclaimer: This information is provided for educational purposes only and does not constitute medical advice. AOD-9604 is not approved by the FDA or any major regulatory authority for therapeutic use. The peptide is classified as a research chemical and prohibited for use in competitive athletics by WADA.

Patients and researchers should consult with qualified healthcare providers and ensure compliance with applicable regulations before considering any use of AOD-9604.