The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. AOD-9604 represents a unique synthetic peptide. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials.
Overview of AOD-9604
AOD-9604 is a modified fragment of human growth hormone (HGH) that has garnered attention for its potential role in fat metabolism and weight loss. AOD‑9604 is a synthetic peptide derived from a fragment of human growth hormone (HGH), specifically amino acids 177-191 of the HGH molecule. Classified as an investigational compound under pre-clinical/clinical development, AOD-9604 is not approved for any therapeutic indication by the FDA or any major health authority worldwide. The peptide maintains structural similarities to the homologous region of naturally occurring human growth hormone while demonstrating improved stability through its synthetic modifications.
Key Features
- Mechanism of Action: AOD-9604 mimics the way natural HGH regulates fat metabolism, but it targets lipolysis (fat breakdown) specifically, while having minimal impact on glucose regulation or protein synthesis. AOD-9604 is studied for nudging the balance toward withdrawals by raising cyclic AMP inside adipocytes, which activates hormone-sensitive lipase to release fatty acids. Preclinical models also suggest it dampens new fat creation by downshifting lipogenic enzymes like fatty acid synthase and acetyl-CoA carboxylase.
- Regulatory Status: AOD-9604 is available through research chemical suppliers, with variable quality control standards. The peptide's regulatory status as an unapproved investigational compound limits clinical applications while maintaining research utility.
- 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.
- WADA Anti-Doping Status: 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.
Chemical Structure and Properties
Understanding the chemical structure and properties of AOD-9604 is crucial for research and potential applications.
Key Data
- 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
AOD-9604 exhibits rapid degradation in biological systems through amino-terminal truncation, with sequential amino acid removal being the primary metabolic pathway. Detection in plasma and urine is possible using specialized LC/MS/MS assay methods for up to several days post-administration.
Regulatory Status and Legal Considerations
The legal landscape surrounding AOD-9604 is complex and varies by region.
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Key Points
- No Approved Medical Use: AOD-9604 is not approved for clinical therapeutic applications by any major health authority.
- Research Chemical Status: It is commercially available through research chemical suppliers, subject to research chemical regulations.
- 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.
- WADA Anti-Doping Agency: Prohibits AOD-9604 in competitive sports under category S0 (Non-Approved Substances).
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
Mechanistic studies aim to elucidate how AOD-9604 works at the cellular and molecular levels.
Areas of Investigation
- 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
While primarily a research tool, AOD-9604 has potential therapeutic applications that warrant further investigation.
Potential Uses
- 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.
AOD-9604 Scientific Data Summary
AOD-9604 has demonstrated several effects in preclinical and clinical studies.
Key Findings
- Active both oral and injectable
- Up to several days (urine)
- 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
- 900+ participants (6 studies)
- Excellent safety profile, no serious adverse events
- 2.6 kg vs 0.8 kg weight loss (vs placebo)
- No statistically significant weight loss
- 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
- S0 Non-Approved Substance
- Not approved for human use
AOD-9604 vs. Other Peptides
To understand AOD‑9604’s role in fat loss, it’s helpful to compare its mechanism, effectiveness, and clinical data to other peptides commonly used for body recomposition.
AOD-9604 vs. HGH
Unlike growth hormone therapies, short human studies have not shown rises in GH or IGF-1 with AOD-9604. That’s the design goal: unlock stored fat without flipping the growth axis.
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AOD-9604 vs. Growth Hormone Secretagogues
Different lane than growth hormone secretagogues. Those raise endogenous GH and often bump IGF-1; AOD-9604 aims to work inside fat cells without moving that axis. If you want fat-specific signaling without IGF-1 shifts, this is the concept, but the clinical signal looks modest.
AOD-9604 vs. Tissue-Repair or Skin Peptide
It’s not a tissue-repair or skin peptide. Don’t expect collagen or wound-healing effects.
AOD-9604 vs. GLP-1 Medicine
And it isn’t a GLP-1 medicine. GLP-1 receptor agonists like semaglutide (think Ozempic) reduce appetite and improve glycemic control with robust randomized trial data for weight loss. It isn’t permitted as a dietary supplement ingredient, and it cannot be compounded for routine clinical use under section 503A.
Safety and Tolerability
Short studies in adults generally report tolerability similar to placebo, with mild effects like headache, GI discomfort, or local skin irritation when injected. The lack of GH or IGF-1 rise in these studies is reassuring, though it doesn’t replace multi-year safety data.
Who should generally avoid it
- Pregnancy or breastfeeding
- Active cancer or under cancer surveillance
- Adolescents and children
- Uncontrolled endocrine disease (for example, poorly controlled thyroid disease or diabetes)
- Elite or tested athletes subject to anti-doping rules
Labs and Biomarkers: Making It Measurable
If AOD-9604 does anything useful, it should show up downstream in body composition and metabolic markers, not in growth hormone labs.
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What to track
- Body composition: DEXA fat mass, waist-to-hip ratio, and visceral fat estimates
- Metabolic health: fasting glucose and insulin (with HOMA-IR), plus A1c when appropriate
- Lipids: triglycerides and HDL on a standard panel
- Liver health: ALT, AST, GGT, and imaging if fatty liver is in play
- Inflammation: high-sensitivity CRP
- GH/IGF axis: IGF-1 as a safety lens, not a performance score
Weight Loss and Clinical Trial Results
The drug - codenamed AOD9604 - was taken orally once daily by 300 obese patients at five trial sites over a 12-week period. The group receiving the 1mg dose lost the most weight, averaging a weight loss over the 12 weeks of 2.8 kilograms, more than triple the weight lost by those on placebo, who lost an average of 0.8 kilograms. The weight lost by the 1mg group was slightly more than that achieved by the world’s largest selling prescription obesity medication in similar trials over the same period, without its troublesome side effects. AOD9604 is based on a small part of the human growth hormone molecule.
Clinical Trial Findings
- In a clinical trial, the group receiving the 1mg dose lost the most weight, averaging a weight loss over the 12 weeks of 2.8 kilograms, more than triple the weight lost by those on placebo, who lost an average of 0.8 kilograms.
- The OPTIONS Study reached full recruitment with 536 subjects ahead of schedule in late April this year and as a result, the study will also finish ahead of schedule, in December 2006.
- The OPTIONS Study includes 24 weeks of randomised double-blind drug or placebo treatment, with the primary endpoint of weight loss at 12 weeks.
The Broader Context of Obesity and Pharmacotherapy
Obesity has progressed to epidemic proportions globally, with more than 1.6 billion adults overweight and at least 400 million of them clinically obese [1]. It is a leading contributor to the global burden of chronic diseases like type 2 diabetes, cardiovascular disease, hypertension, stroke, and certain forms of cancer. The health outcomes range from increased risk of premature death to serious chronic conditions that reduce the overall quality of life [1]. According to the guidelines of the National Institute of Health (NIH) regarding the treatment of obesity, “weight loss drugs approved by the FDA [US Food and Drug Administration] may only be used as part of a comprehensive weight loss program, including dietary therapy and physical activity, for patients with a BMI [body mass index] of ≥30 with no concomitant obesity-related risk factors or diseases, and for patients with a BMI of ≥27 with concomitant obesity-related risk factors or diseases”[3].The risk factors and diseases considered important enough to warrant pharmacotherapy at a BMI of 27--29.9 are hypertension, dyslipidemia, coronary heart disease (CHD), type 2 diabetes, and sleep apnea [3]. In 2007--2008, the prevalence of American adults having a BMI greater than 30 was 32.2% among men and 35.5% among women [4]. In light of the NIH guidelines, this startling preponderance of obesity indicates pharmacotherapy is warranted for more than one-third of all American adults. Yet, existing medicines to combat the problem are disappointingly few in number and efficacy.
Challenges in Obesity Treatment
In the past few years, understanding of the mechanisms involved in regulating feeding behavior and energy expenditure has evolved considerably, and targeting these mechanisms for drug development has garnered greater attention as well. The etiology of obesity is complex. Genetic, environmental, and psychological factors are implicated in its causation. Obesity is a disorder of energy balance. When food-derived energy chronically exceeds energy expenditure, the excess calories are stored as triglycerides in adipose tissue. Notwithstanding the marked fluctuations in daily food intake, body weight remains remarkably stable in most humans. In response to alterations in body adiposity, the brain triggers compensatory physiological adaptations that resist weight change. The two sides of the energy equation, i.e., consumption and expenditure, are finely regulated by neural and humoral mechanisms [5,6].
Pharmacological Approaches to Obesity Treatment
Obesity is a state of sustained disequilibrium between energy intake and energy expenditure. The pharmacotherapies for obesity are directed at the following: 1) decreasing energy intake (e.g. appetite suppressants and lipase inhibitors), 2) increasing energy expenditure, 3) modulating fat storage or adipocyte differentiation, or 4) mimicking caloric restriction [8,19] (Fig.
The history of the pharmacotherapy of obesity dates back to the 1930s. Many drugs used to treat obesity in the past have been discontinued because of their potential to be abused and their toxicities [20-27] (Table 1). Rimonabant is a cannabinoid receptor 1 antagonist that became available for long-term treatment of obesity in the United Kingdom and other countries beginning in 2006 [27]. In the United States, the FDA did not approve the agent because of its association with a risk of psychiatric disorders including depression and suicidal tendencies [27]. In 2009, the EMEA (European Medicine Agency) withdrew market authorisation for rimonabant in all countries of the European Union due to safety concerns [21]. Sibutramine, a popular antiobesity drug used worldwide since 1997, was withdrawn from the European and US markets in 2010 because of safety concerns [27,28]. In the Sibutramine Cardiovascular Outcomes (SCOUT) trial, the drug was shown to be associated with increased risk of major adverse cardiovascular events (a composite of non-fatal heart attack, non-fatal stroke, resuscitation after cardiac arrest, and cardiovascular death) in obese patients, as compared to placebo [29]. The medications currently approved by the FDA for use in the United States include phendimetrazine, benzphetamine, diethylpropion, phentermine, and orlistat. The US Drug Enforcement Administration classifies phendimetrazine and benzphetamine as schedule 3 drugs and diethylpropion and phentermine as schedule 4 drugs [20,30]. These drugs are recommended for the short-term (12 weeks or less) treatment of obesity [20,30]. Orlistat is the only drug currently approved by the FDA for long-term management of obesity [21,31]. It acts by reversibly inhibiting pancreatic lipase enzyme, thus preventing the hydrolyzation and absorption of dietary fat by approximately 30%, and thereby decreasing the caloric intake of obese patients [32]. A meta-analysis of 29 studies of orlistat for weight loss in adult patients reported a weight loss of 2.59 kg and 2.89 kg at 6 months and 12 months, respectively [33,34]. In comparison to patients on diet and placebo only, the patients treated with orlistat demonstrated a significant improvement in blood glucose concentrations, insulin resistance, waist circumference, total and low-density lipoprotein cholesterol (LDL-C), and blood pressure [35-37]. The only currently approved long-term therapy for obesity in the United States is not only having limited efficacy, but is also associated with number of side effects. Thus, a dire need exists for the development of novel antiobesity drugs with high efficacy and long-term safety. In recent years, there has been an explosion in knowledge of the mechanisms involved in the regulation of feeding behavior and the cellular mechanisms involved in energy expenditure. These include appetite suppressants and lipase inhibitors. Among the appetite suppressants, the targets are classified according to the energy pathways they modulate. These can either be stimulators of anorexigenic pathways or inhibitors of orexigenic pathways (Fig. 4).