AOD-9604 is an experimental peptide that has recently gained attention for its potential effects on weight loss and body composition. It is a fragment of the C-terminus region of human growth hormone (hGH) comprising the amino acids 177-191 with an added tyrosine residue at the N-terminus.
AOD-9604 was initially developed by Metabolic Pharmaceuticals Pty Ltd in Australia to specifically target abdominal fat reduction while avoiding other effects associated with hGH, such as increased muscle mass and insulin resistance.
Since its discovery, research on AOD-9604 has expanded to investigate additional therapeutic properties related to metabolism, wound healing, cartilage, and bone repair. Despite promising initial findings, more extensive and rigorous clinical trials are still needed to confirm the efficacy and safety profile of AOD-9604 before it can gain regulatory approval as a pharmaceutical.
Mechanism of Action
The mechanisms underlying AOD-9604's metabolic effects are not fully understood but likely involve signalling pathways that regulate fat metabolism. Preliminary research shows AOD-9604 binds to specific cell surface receptors in adipose tissue and stimulates lipolysis, the breakdown of fat, through cyclic adenosine monophosphate (cAMP) dependent and independent pathways.
Additional evidence suggests AOD-9604 increases glucose uptake in adipocytes and skeletal muscle tissue potentially through shared mechanisms with insulin. AOD-9604 also appears to have an acute effect on appetite regulation through interactions with neuropeptide Y receptors in the hypothalamus. However, chronic effects on food intake require further study.
Weight Loss and Body Composition Effects
Initial preclinical and early clinical research on AOD-9604 showed promising reductions in fat mass, especially truncal fat located in the abdominal region. An early stage II trial conducted by Metabolic Pharmaceuticals in 2002 demonstrated that AOD-9604 administered daily led to significant decreases in fat mass compared to placebo after 12 weeks. These fat loss effects occurred without changes in muscle mass, bone density markers, cell metabolism, or cardiovascular parameters, indicating AOD-9604 specifically targeted fatty tissue.
A follow-up one-year phase II trial published in 2013 reinforced AOD-9604's safety profile and efficacy on central fat loss. Obese adults received a daily injection of AOD-9604 or placebo for 24 weeks alongside a hypocaloric diet. As measured by CT scans, the AOD-9604 group lost three times more fat from the abdominal area than the placebo group (3.8kg vs 1.3kg). Those receiving AOD-9604 also exhibited a 50% increase in fatty acid oxidation, suggesting enhanced metabolic activity in adipose tissue contributing to abdominal fat loss. No adverse cardiovascular effects occurred, and subjects retained lean mass.
While initial clinical trials showed promise for AOD-9604's ability to reduce fat, especially visceral fat associated with metabolic disease risk, later-stage clinical trials have been less conclusive regarding weight loss efficacy. A significant 24-week phase IIa study from 2009 found no additional weight loss for AOD-9604 compared to placebo combined with diet and exercise. However, this study used a lower dose of AOD-9604 and measured whole-body composition changes rather than specific abdominal fat loss. Further rigorous research is needed to clarify appropriate dosing strategies and measurement techniques to demonstrate AOD-9604's effects on body composition.
Metabolic and Anti-Obesity Effects
In addition to direct fat reduction, AOD-9604 exhibits other metabolic effects that could complement weight loss. Preclinical studies in mice have shown that AOD-9604 acts similarly to hGH to stimulate IGF-1 production, improving glucose control and insulin sensitivity. This led Metabolic Pharmaceuticals to develop an AOD-9604 analog, presently named ACVR-002, to target diabetes treatment specifically. Findings showed positive effects on regenerating pancreatic beta cells to restore natural insulin production in animal models of diabetes.
Early clinical research also demonstrates that AOD-9604 increases fat oxidation at rest, indicating augmented metabolic activity. Enhanced fat utilization could support long-term weight maintenance following weight loss. Additionally, acute administration of AOD-9604 shows reduced food intake in animal models, lending evidence for anti-obesity effects in the short term. The orexigenic hormone ghrelin also competes with hGH for binding at the growth hormone secretagogue receptor (GHSR-1a), for which AOD-9604 shares affinity. Although not its primary target, binding at the GHSR-1a receptor could enable appetite-suppressing properties.
Wound Healing Properties
AOD-9604 displays wound healing activities through mechanisms attributed to the downstream mediator, IGF-1. Studies have found that AOD-9604 stimulates the migration and proliferation of dermal fibroblasts, producing collagen essential for repairing connective tissue and closing wounds. In murine models, skin lesions treated with AOD-9604 showed faster regrowth of skin layers, increased collagen formation, and earlier recovery of tensile strength compared to untreated wounds.
Early pilot studies in humans also indicate the potential for using AOD-9604 to heal leg ulcers and severely burned areas of skin. One placebo-controlled trial revealed daily AOD-9604 injections doubled the rate of skin regrowth in 5 patients suffering from significant burns. Additionally, administration of AOD-9604 accelerated healing for a group of participants with chronic leg ulcers resisting closure through standard treatments.
More extensive patient group trials still need to be conducted to verify appropriate dosing, safety, and efficacy in those with poor wound healing prognoses. However, existing preclinical and human data are promising for AOD-9604's ability to aid recovery in acute and chronic tissue damage.
Cartilage and Bone Repair Effects
AOD-9604 is also investigated as a novel therapy for treating cartilage and bone damage primarily through IGF-1-mediated repair processes. Studies demonstrate that AOD-9604 stimulates cartilage regeneration following acute joint injury and in inflammatory conditions associated with cartilage loss. Experiments utilizing rabbit models for osteoarthritis showed that a single injection of AOD-9604 restored cartilage thickness, volume and stiffness, outperforming previous trials using native IGF-1.
Additionally, early trials indicate that AOD-9604 supports bone fracture healing via endochondral ossification pathways mediated by IGF-1. Mice with tibial fractures administered AOD-9604 exhibited increased bone volume and mineral density during early bone regeneration stages in the fracture callus. Callus material properties also showed greater tensile strength than controls after four weeks of treatment. Together, these findings provide a rationale for testing AOD-9604 as an adjunct therapy administered shortly after injury to promote cartilage and bone repair.
Thus far, AOD-9604 has demonstrated an excellent safety profile in animal toxicology studies and human clinical trials. Preclinical testing up to one year in rats and dogs showed no adverse effects on organ tissues, hematology, and clinical chemistry at doses thousands of times higher than those used in human trials. Musculoskeletal and immunogenicity issues that have arisen with native hGH due to prolonged use are also absent since AOD-9604 does not increase growth-promoting IGF-1 to the same extent.
Dosages and Protocols
According to Dr William Seed, in his excellent book "Peptide Protocols, Vol 1." 250mcg daily with a length of treatment varying from 6 weeks to 3 months, up to 6 months.
AOD-9604 is poised to become a promising pharmaceutical agent for obesity treatment and conferred health issues pending confirmatory research on its efficacy. Thus far, findings regarding AOD-9604's mechanisms and clinical effects are consistent with a metabolically acting peptide that specifically reduces adipose tissue without adverse effects on muscle or bone.
If additional randomized control trials conclusively demonstrate abdominal fat loss at well-tolerated doses, AOD-9604 could provide meaningful weight management support when combined with lifestyle changes. Appetite regulation data is also encouraging for aiding short-term compliance with caloric restriction.
From a safety standpoint, AOD-9604 has been granted orphan drug status by the FDA for rare disorders, given its high tolerability and regenerative properties. Further testing may garner regulatory approval for obesity and applications in accelerating recovery from burns, wounds, joint disease and bone fractures.