All peptide guides
Weight Loss

AOD-9604

Growth Hormone Fragment - Fat Metabolism Guide

Clinical Disclaimer: This guide is for educational purposes only and does not constitute medical advice. Prescribers should exercise independent clinical judgment and verify all information before making treatment decisions.

Comprehensive Clinical Monograph: AOD-9604

1.0 Introduction and Overview

1.1. Executive Summary

AOD-9604 is a synthetic peptide fragment of human growth hormone (hGH) originally developed as a potential therapeutic agent for obesity. The primary strategic goal was to isolate the fat-reducing properties of hGH while avoiding the hormone's undesirable side effects. Despite promising preclinical data and early-phase clinical interest, the development of AOD-9604 for this indication was officially terminated after pivotal Phase IIb trials failed to demonstrate statistically significant weight loss compared to placebo. It is currently an unapproved research peptide, and the U.S. Food and Drug Administration (FDA) has formally evaluated the substance and cited significant concerns regarding its safety, efficacy, and chemical characterization. While no longer pursued for obesity, AOD-9604 (also known as LAT8881) is being investigated for other therapeutic applications, such as neuropathic pain and inflammatory conditions. This monograph provides a detailed review of the molecular characteristics and clinical history of AOD-9604.

1.2. Chemical and Structural Identity

Attribute

Description

Scientific Name

A synthetic hexadecapeptide analog of the C-terminal fragment of hGH (amino acids 177-191), stabilized by an additional tyrosine at the N-terminus and a disulfide bond. It is designated as Tyr-hGH177-191.

Structure

A hexadecapeptide (16 amino acids) containing a disulfide bond between two cysteine residues.

Molecular Forms

Exists as both AOD-9604 (free base) and AOD-9604 acetate. The FDA considers these to be distinct bulk drug substances.

Synonyms

AOD9604, LAT8881, TYR-HGH171191

The distinct molecular structure of AOD-9604 was designed to confer a specific mechanism of action, separating it from its parent hormone.

--------------------------------------------------------------------------------

2.0 Pharmacology and Mechanism of Action

2.1. Strategic Context

Understanding the pharmacology of AOD-9604 is essential to appreciating its clinical development history. Its primary value proposition was to deliver the lipolytic (fat-burning) benefits of hGH without inducing adverse effects such as impaired glucose tolerance, insulin resistance, or unwanted growth-promoting activity. The research aimed to create a targeted metabolic agent, not a systemic growth factor.

2.2. Lipolytic and Metabolic Effects

AOD-9604 was engineered to mimic the fat-reducing properties of the C-terminal region of hGH. Preclinical studies in animal models demonstrated a dual action on fat metabolism:

  1. Stimulation of Lipolysis: It was shown to increase the breakdown of lipids in adipose tissue.
  2. Inhibition of Lipogenesis: It was also found to inhibit the metabolic processes involved in the formation of new fat.

In preclinical studies involving obese rats and mice, chronic treatment with AOD-9604 reduced body weight gain and adipose tissue mass. Notably, these effects occurred without any significant changes in food consumption, indicating a direct metabolic action rather than appetite suppression.

2.3. Differentiation from Human Growth Hormone (hGH)

The key distinctions between AOD-9604 and full-length hGH are critical to its proposed safety profile.

  • Growth Hormone Receptor (GHR) Interaction: Unlike hGH, AOD-9604 does not compete for the hGH receptor, does not bind to or activate the GHR, and does not induce cell proliferation in GHR-expressing cells. This confirms that its metabolic effects are mediated through a different pathway.
  • Impact on Insulin and Glucose: Multiple studies in animal models and human trials confirmed that AOD-9604 did not induce hyperglycemia, insulin resistance, or negatively affect glucose oxidation. These are well-documented adverse effects associated with long-term hGH treatment.
  • IGF-1 Levels: In human clinical trials, treatment with AOD-9604 did not result in statistically significant increases in Insulin-like Growth Factor-1 (IGF-1) levels. This further distinguishes its activity from the growth-promoting axis of hGH.

2.4. Investigated Pathways

While the complete mechanism of action remains to be fully elucidated, research points to several molecular pathways.

  • Role of β3-Adrenergic Receptors (β3-AR): While AOD-9604 does not directly agonize the β3-AR, its long-term lipolytic efficacy is dependent on a functional β3-AR pathway. Preclinical evidence shows that it fails to induce weight loss in β3-AR knock-out mice and that it increases β3-AR mRNA expression, suggesting it may potentiate the lipolytic environment rather than directly triggering it.
  • LanCL Protein Interaction: More recent research, conducted under the peptide's designation as LAT8881, has identified an interaction with lanthionine synthetase C-like (LanCL) proteins. These proteins are thought to mediate the anti-inflammatory, tissue repair, and neuroprotective effects observed in newer investigational models.

The clinical development of AOD-9604 was based on its apparent ability to selectively target fat metabolism, a hypothesis that was rigorously tested in a series of human trials.

--------------------------------------------------------------------------------

3.0 Clinical Development and Efficacy for Obesity

3.1. Strategic Context

AOD-9604 underwent a comprehensive clinical development program for obesity, comprising six randomized, double-blind, placebo-controlled trials. This section critically reviews the outcomes of these studies, which ultimately led to the cessation of its development for this indication due to a lack of demonstrable commercial viability.

3.2. Early Phase Clinical Trials

Initial clinical trials showed promising, albeit modest, results. A 12-week Phase II study involving 300 obese adults demonstrated that a 1 mg daily oral dose of AOD-9604 resulted in a statistically significant average weight loss of 2.6 kg. This was compared to an average weight loss of only 0.8 kg in the placebo group, suggesting a therapeutic effect. However, a non-linear dose response was observed, with the largest effect seen at the 1 mg dose, while other doses (5, 10, 20, and 30 mg) were less effective.

3.3. The Pivotal OPTIONS Study and Termination of Development

The definitive trial for AOD-9604 was the OPTIONS study, a 24-week, multi-center Phase IIb trial designed to confirm its efficacy and safety in a larger population under conditions resembling a Phase 3 trial.

Trial Metric

OPTIONS Study (Phase IIb) Details

Participants

536 obese adults (BMI 30-45 kg/m²)

Intervention

Oral AOD-9604 (0.25 mg, 0.5 mg, 1.0 mg daily) or placebo

Program Context

All groups received a dietician-supervised diet and exercise program

Primary Endpoint

Statistically significant weight loss at 12 weeks compared to placebo

Outcome

Failed to meet primary endpoint. The weight loss observed in the AOD-9604 treatment groups was not statistically significant when compared to the weight loss in the placebo group.

The minimal additional weight loss conferred by AOD-9604 was deemed commercially non-viable when compared to the substantial results achieved by the diet and exercise program alone. Researchers concluded that the therapeutic effect of AOD-9604 was too low to provide a meaningful benefit over and above the intensive lifestyle modification program.

On February 21, 2007, Metabolic Pharmaceuticals publicly announced the termination of AOD-9604's development as a treatment for obesity, stating that the trial results did not support the drug's commercial viability for this condition. A thorough review of the safety and tolerability data collected during these trials is therefore warranted.

--------------------------------------------------------------------------------

4.0 Clinical Safety and Tolerability Profile

4.1. Strategic Context

Across six clinical trials involving nearly 900 subjects, AOD-9604 was generally found to be safe and well-tolerated, with an overall adverse event profile comparable to that of placebo. However, it is critical to note that the U.S. Food and Drug Administration (FDA) has since conducted its own evaluation and raised significant safety concerns related to the use of AOD-9604 in compounded preparations, which are detailed in the subsequent regulatory section.

4.2. Summary of Adverse Events from Clinical Trials

A pooled analysis of the safety data from the human clinical trials revealed the following profile:

  • Common Adverse Events: The most frequently reported adverse events were similar across both placebo and active treatment groups. These included headache, diarrhea, nasopharyngitis, and back pain.
  • Serious Adverse Events (SAEs): SAEs were documented in long-term studies, but their incidence and distribution were similar among all treatment groups, including placebo. Reported SAEs included diarrhea and chest tightness. Various cancers were also reported as SAEs, though the source material indicates there was insufficient information to assess their relatedness to the study drug.
  • Events Possibly Related to Treatment: The relationship between events and treatment varied by administration route. In studies involving intravenous (IV) administration, a severe "feeling of chest tightness" and mild/moderate "euphoria" were deemed possibly related to AOD-9604. In oral studies, a reported SAE of diarrhea was also deemed possibly related to the treatment.
  • Immunogenicity: Blood samples from subjects in clinical trials were analyzed for the presence of anti-AOD9604 antibodies, and none were detected. However, the FDA has since expressed a differing view, stating, "FDA is concerned about the potential for immunogenicity of AOD-9604...when formulated in an injectable dosage form for SC administration due to the potential for aggregation as well as potential peptide-related impurities."

4.3. Nonclinical Toxicology Findings

Nonclinical toxicology studies were conducted in rats and monkeys to assess the long-term safety profile.

  • Genotoxicity: A battery of genotoxicity studies was performed, with results deemed inconclusive. The studies reported equivocal signals in the AMES, chromosome aberration, and micronucleus assays.
  • Long-Term Studies: In long-term oral toxicity studies, researchers observed dose-dependent changes in serum osteocalcin in rats, suggesting effects on bone turnover. In monkeys, minimal periportal vacuolation in hepatocytes was noted, a potential indicator of effects on the liver.

These nonclinical signals regarding potential effects on bone turnover and liver, combined with inconclusive genotoxicity data, provide context for the FDA's subsequent determination that it lacks sufficient information to rule out potential harm in humans, particularly with long-term use. While the clinical trial data suggested a favorable safety profile, the current regulatory perspective has introduced critical new considerations for any potential use.

--------------------------------------------------------------------------------

5.0 Regulatory Status and Compounding Landscape

5.1. Strategic Context

For any prescribing professional, a clear understanding of a substance's regulatory status is paramount. Despite its history in formal clinical trials, AOD-9604 is not an approved drug and is subject to significant scrutiny and restrictions from regulatory bodies like the U.S. Food and Drug Administration (FDA).

5.2. U.S. Food and Drug Administration (FDA) Stance

The FDA's position on AOD-9604 is clear and has been detailed in its evaluation for pharmacy compounding.

  1. Lack of Approval: AOD-9604 is unequivocally not an FDA-approved drug product for any clinical indication.
  2. Compounding Status: The FDA has evaluated both AOD-9604 (free base) and AOD-9604 acetate and determined that the criteria weigh against placing them on the 503A Bulks List for pharmacy compounding. Although some legal challenges were raised regarding the FDA's process for categorizing peptides, AOD-9604 is currently listed by the agency as one of the "Other bulk drug substances that may present significant safety risks."
  3. Identified Safety Risks: The FDA has detailed several specific concerns related to compounded AOD-9604:
    • Poor Characterization: The substance is considered not physically and chemically well-characterized due to a lack of public data on "potential peptide-related impurities and aggregates." The FDA notes that "the presence of this disulfide bridge can lead to degradation...and aggregate formation."
    • Potential for Immunogenicity: Due to the potential for aggregation and impurities, particularly with injectable routes of administration, the FDA is concerned about the risk of an adverse immune response.
    • Insufficient Safety Data: The FDA states that it lacks sufficient information to know if the drug would cause harm, especially with long-term use for a chronic condition. Crucially, the agency found no pharmacokinetic or bioavailability data in humans for any route of administration.
    • Lack of Efficacy: The FDA's evaluation reaffirms the lack of evidence supporting its effectiveness for obesity, referencing the failure of the pivotal OPTIONS study.

These regulatory determinations followed legal challenges from compounding pharmacies arguing that the FDA's move to place certain peptides in "Category 2" was an overreach. In a settlement, the FDA agreed to consult its advisory committee before finalizing its decisions, but its formal evaluation remains highly critical of AOD-9604.

5.3. World Anti-Doping Agency (WADA) Classification

AOD-9604 is classified as a prohibited substance by the World Anti-Doping Agency (WADA) and is banned for performance-enhancing use in sport. As its path for obesity treatment closed, research has shifted to new therapeutic areas.

--------------------------------------------------------------------------------

6.0 Emerging Research and Alternative Indications

6.1. Strategic Context

Following the termination of its development for obesity, the peptide was re-designated as LAT8881 and is now being investigated for other conditions. This new line of research primarily leverages its potential anti-inflammatory, regenerative, and neuroprotective properties, which are thought to be mediated through the LanCL protein pathway.

6.2. Current Investigational Areas

Current research is focused on indications far removed from its original metabolic target.

  • Neuropathic Pain: Lateral Pharma completed a Phase 1b clinical trial investigating LAT8881 for chronic lumbar radicular pain (sciatica). The company reported that the trial demonstrated "proof-of-concept" and that the drug was safe and well-tolerated at the doses tested.
  • Osteoarthritis: Preclinical research in a rabbit model of osteoarthritis has shown that intra-articular injections of AOD-9604 enhanced cartilage regeneration, suggesting a potential role in joint repair.
  • Influenza: Preclinical studies have identified LAT8881 as a potential host-protective therapy for severe influenza A virus (IAV) infection. In animal models, it was shown to improve survival, limit viral replication, and reduce local inflammation and tissue damage.

These emerging areas of research are still in early stages, and the practical aspects of handling and administering the peptide are derived from these investigational contexts.

--------------------------------------------------------------------------------

7.0 Practical Considerations for Investigational Use

7.1. Strategic Context and Disclaimer

The following information is derived from clinical trial protocols and anecdotal reports from practitioners. AOD-9604 is not an FDA-approved drug, and no universally accepted medical guidelines for its dosing or administration exist. This information is for educational purposes only and does not constitute a recommendation for clinical use.

7.2. Formulation, Reconstitution, and Storage

When handled in a research setting, lyophilized AOD-9604 powder requires careful preparation to maintain its integrity.

  1. Storage (Lyophilized): The lyophilized powder should be stored under refrigeration (2°C to 8°C) or frozen (-20°C) for long-term stability.
  2. Reconstitution: A sterile solvent (e.g., bacteriostatic water) should be introduced slowly along the vial's glass wall to prevent foaming. The vial should then be gently swirled until the powder is fully dissolved. The solution should never be shaken, as this can denature the peptide. The final solution should be clear and free of particulates.
  3. Storage (Reconstituted): The reconstituted solution must be kept refrigerated at 2°C to 8°C. To ensure maximum potency, it should be used within 4 to 6 weeks.

7.3. Administration and Dosing Protocols

The following table summarizes common, non-validated protocols for AOD-9604 as cited in research literature and non-regulated settings.

Parameter

Non-Validated Investigational Protocols

Typical Daily Dose

300 mcg to 1000 mcg (1 mg)

Route of Administration

Subcutaneous (SC) injection is most commonly cited in research. Oral forms have also been studied.

Timing

On an empty stomach, typically in the morning.

Frequency

5 to 7 days per week.

These protocols have not been validated for clinical use and reflect practices within research or non-regulated settings.

--------------------------------------------------------------------------------

8.0 Conclusion and Clinical Pearls

8.1. Final Synthesis

AOD-9604 is a synthetic hGH fragment that, despite being generally well-tolerated in human trials, ultimately failed to demonstrate sufficient clinical efficacy for its primary indication of obesity, leading to the termination of its commercial development. Its clinical utility is severely limited by significant regulatory barriers, underscored by a formal FDA evaluation that highlights concerns about safety, purity, and efficacy. The combination of failed pivotal trials for its primary indication and the FDA's clear stance against its use in compounding renders its application outside of a formal, IRB-approved clinical trial clinically indefensible. While AOD-9604 has been abandoned for weight loss, its unique pharmacological profile has spurred new, albeit early-stage, research into its potential as an anti-inflammatory and regenerative agent for conditions like neuropathic pain.

8.2. Key Takeaways for the Prescribing Professional

  1. Not an Obesity Drug: AOD-9604 failed pivotal clinical trials for weight loss, and its development was terminated. It should not be considered an evidence-based therapy for obesity.
  2. Significant Regulatory Concerns: The FDA has explicitly weighed against its inclusion on the 503A bulks list for compounding and has listed it as a substance that may pose significant safety risks, citing concerns over chemical characterization, potential impurities, immunogenicity risk, and a lack of safety and efficacy data.
  3. Distinct from hGH: Its key theoretical advantage is the separation of lipolytic effects from the negative metabolic (insulin resistance, hyperglycemia) and growth-promoting (IGF-1 elevation) effects associated with full-length hGH.
  4. Strictly Investigational: Any use of AOD-9604 is considered investigational. It is not an approved medical treatment, and its quality, safety, and purity are not regulated when sourced outside of formal, controlled research settings.