Modified hGH C-terminal fragment
AOD-9604
A modified 15-amino-acid fragment corresponding to hGH residues 177–191 with an N-terminal tyrosine, developed to isolate the lipolytic activity of human growth hormone from its growth-signalling activity
Overview
AOD-9604 is a compound whose design is more interesting than its clinical result, and reading the compound honestly means holding both facts in mind. The design premise is elegant: human growth hormone has two functionally separable regions of activity, a growth-signalling activity concentrated toward the N-terminus and a lipolytic activity concentrated in the C-terminal fragment. What if you isolated the lipolytic fragment and left the growth-signalling machinery behind? That premise, worked out at Monash University in the 1990s, produced a 15-amino-acid modified fragment corresponding to hGH residues 177–191 with an added N-terminal tyrosine — the compound now known as AOD-9604, from 'Anti-obesity Drug 9604.'
The compound was taken into human obesity trials by Metabolic Pharmaceuticals, a Melbourne biotech that was set up around this asset. The pharmaceutical program culminated in a 12-week randomised placebo-controlled phase 2b trial in obesity — the pivotal test of whether the design premise would translate. In 2007 that trial did not meet its primary weight-loss endpoint at any of the tested doses. This is the fact most consumer-facing AOD-9604 sources omit, and it is the most important fact about the compound's clinical story. The pharmaceutical development program was not continued.
What happened next is the part that generates most of the current confusion. AOD-9604 was subsequently repositioned by a different sponsor as a 'generally recognised as safe' (GRAS) ingredient for functional-food applications, and a GRAS notice was filed with the FDA. GRAS status is a regulatory pathway for food-additive safety — it does not require the compound to demonstrate efficacy for any pharmaceutical indication. Marketing that presents the FDA's GRAS 'no objection' letter as equivalent to an FDA drug approval is systematically misrepresenting what the regulatory documents mean. AOD-9604 has never been FDA-approved as a drug for any indication.
Independent of the obesity story, small human trials have explored AOD-9604 in osteoarthritis of the knee, with intra-articular administration and reported symptom improvement in a limited number of patients. These are not the same as a completed phase-3 program, and no arthritis indication has been pursued at scale. The compound retains genuine mechanistic interest in the adipose-biology literature. That interest is not the same as evidence of clinically meaningful weight loss in humans at trial scale.
Quick Facts & Evidence
- Category
- Modified hGH C-terminal fragment
- Research area
- Growth-hormone-derived peptide
- Most studied for
- Obesity (published human phase 2 program, 2000s)
- Osteoarthritis (small human trials with intra-articular administration)
- Adipose tissue lipolysis (preclinical mechanism work)
- Bone and cartilage endpoints (preclinical follow-up to the arthritis trials)
- Clinical status
- Research use only — no approved clinical indication
- Human evidence
- Early Human Evidence
- Regulatory status
- Australia — developed originally at Monash University; taken into human trials by Metabolic Pharmaceuticals (Melbourne). The pharmaceutical development program was discontinued after the 2007 phase 2b did not meet its primary endpoint. No current Australian TGA registration as a medicinal product.
Early Human Evidence
Small-scale human studies, observational data, or off-label case reports only. Substantial uncertainty remains.
Research Protocols
Research Protocol Snapshot
Preparation covered on this page
Freeze-dried injectable research format
This page covers the RUO lyophilized AOD-9604 vial reconstituted with bacteriostatic water for subcutaneous research use, following the standard Healthy Mango preparation convention.
AOD-9604 research values at a glance.
| Item | Example value |
|---|---|
| Vial size | 10 mg |
| Liquid used to mix | Bacteriostatic water |
| Amount of liquid added | 2.0 mL |
| Final concentration | 5 mg/mL |
| How it's given | Subcutaneous injection |
| Research dose | 300–500 mcg (0.3–0.5 mg) |
| Frequency | 5 times per week |
| After mixing | Refrigerate; use within 7–10 days |
Reported Dosing
The practitioner-reference research protocol for AOD-9604 is 300–500 mcg per subcutaneous injection, five times per week. It is educational reference, not a recommendation.
The Reported Protocol
| Dose | Frequency | Duration | Notes |
|---|---|---|---|
| 0.3–0.5 mg (300–500 mcg) | 5 times per week, subcutaneous | Used continuously during a fat-loss phase; no specific cycle length established | 0.06–0.10 mL at 5 mg/mL |
Why protocols vary
AOD-9604 targets adipocyte beta-3 adrenergic receptors and fatty acid synthase; the pharmacology is a metabolic bias rather than a discrete pulse, so the reference cadence is a workweek pattern (5x/week) rather than daily or once-weekly.
The 2007 phase 2b obesity trial (Metabolic Pharmaceuticals) tested up to 1 mg/day for 12 weeks and did not meet its primary weight-loss endpoint. The practitioner reference range above is lower than the failed trial dose and framed as an adjunct to a fat-loss phase rather than a stand-alone weight-loss protocol.
Preparing the Solution
Turning the freeze-dried powder into a measurable liquid.
Documented preparation
The documented research protocol is based on this preparation concentration.
Freeze-dried powder: 10 mg vial
Diluent: 2.0 mL bacteriostatic water
Final concentration: 5 mg/mL
Vial and volume from the practitioner reference; concentration calculated · Research-practitioner guide
Your vial
Matching preparation
Bacteriostatic water
2mL
Resulting concentration
5 mg/mL
Equivalent volume
The reported research amount of 0.30–0.50 mg is contained within
0.06–0.10mL
of the prepared solution now in your vial.
Show calculation
- Documented concentration
- 10 mg ÷ 2 mL = 5 mg/mL
- Bacteriostatic water to match the documented concentration
- 10 mg ÷ 5 mg/mL = 2 mL
- Equivalent volume at this concentration
- 0.30–0.50 mg ÷ 5 mg/mL = 0.06–0.1 mL
This tool performs arithmetic conversions using the preparation example and reported research amount shown on this page. It does not recommend an amount, route, preparation method, or use.
This tool performs arithmetic conversions using the preparation example and reported research amount shown on this page. It does not recommend an amount, route, preparation method, or use.Sources for these values
- Documented in the practitioner referenceResearch-practitioner guide
This example explains how concentration and volume are calculated for the standard RUO preparation. It is not a preparation guide.
How It's Given
Method used for this format
Subcutaneous injection, 5 times per week
Documented in the practitioner reference · Research-practitioner guide
Why this method
AOD-9604 is a 15-amino-acid peptide; the subcutaneous route delivers it into circulation without the gastrointestinal degradation that would break the molecule down.
The 5x/week workweek cadence is the reference practitioner pattern; the compound has a short plasma half-life and does not rely on receptor pulsatility for its mechanism.
Injection sites reported
- Abdomen (rotate sites)
- Front of the thigh
- Avoid scarred, bruised, inflamed, or infected skin
Storage
Before mixing
- Refrigerate 2–8 °C
- Protect from light
- Do not freeze
General RUO practice · Research-practitioner guide
After mixing
- Refrigerate 2–8 °C
- Use within 7–10 days
- Do not freeze
- Discard if cloudy or discoloured
General RUO practice · Research-practitioner guide
Handling
- Direct diluent slowly down the vial wall
- Gently swirl until dissolved — do not shake
- New sterile needle each draw
- Do not share vials
General RUO practice · Research-practitioner guide
Storage guidance summarises standard RUO peptide handling. The FDA GRAS 'no objection' letter for functional-food applications does not carry over as an injectable storage window and is not a drug approval.
Common Cycle
The practitioner reference frames AOD-9604 as an adjunct to a fat-loss phase, used continuously across that phase without a defined on/off cycle.
- Cycle Length
- Continuous during a fat-loss phase
- Break Before the Next Cycle
- No specific cycle length established
- What the Research Shows
- The 2007 phase 2b obesity trial ran 12 weeks; no larger controlled follow-up exists
Documented in the practitioner reference; Metabolic Pharmaceuticals phase 2b (2007) · Research-practitioner guide
The 2007 phase 2b did not meet its primary weight-loss endpoint at any tested dose; long-term controlled efficacy data are not available.
Compound Overview
Current areas of research
The following are effects reported in preclinical and clinical research. Regulatory drug approval does not exist for any indication.
- Preclinical stimulation of lipolysis and inhibition of lipogenesis in adipose tissue models (Heffernan 2001)
- Reported design goal of separating hGH's lipolytic activity from its growth-signalling activity — the design premise was preclinically supported
- Symptom improvement reported in small human osteoarthritis pilot studies with intra-articular administration (Kim 2018)
- The 2007 phase 2b obesity trial reported the compound was generally well tolerated at the tested doses, even though the primary weight-loss endpoint was not met
Mechanism of action
AOD-9604 is a compound whose design is more interesting than its clinical result, and reading the compound honestly means holding both facts in mind. The design premise is elegant: human growth hormone has two functionally separable regions of activity, a growth-signalling activity concentrated toward the N-terminus and a lipolytic activity concentrated in the C-terminal fragment. What if you isolated the lipolytic fragment and left the growth-signalling machinery behind? That premise, worked out at Monash University in the 1990s, produced a 15-amino-acid modified fragment corresponding to hGH residues 177–191 with an added N-terminal tyrosine — the compound now known as AOD-9604, from 'Anti-obesity Drug 9604.'
The compound was taken into human obesity trials by Metabolic Pharmaceuticals, a Melbourne biotech that was set up around this asset. The pharmaceutical program culminated in a 12-week randomised placebo-controlled phase 2b trial in obesity — the pivotal test of whether the design premise would translate. In 2007 that trial did not meet its primary weight-loss endpoint at any of the tested doses. This is the fact most consumer-facing AOD-9604 sources omit, and it is the most important fact about the compound's clinical story. The pharmaceutical development program was not continued.
What happened next is the part that generates most of the current confusion. AOD-9604 was subsequently repositioned by a different sponsor as a 'generally recognised as safe' (GRAS) ingredient for functional-food applications, and a GRAS notice was filed with the FDA. GRAS status is a regulatory pathway for food-additive safety — it does not require the compound to demonstrate efficacy for any pharmaceutical indication. Marketing that presents the FDA's GRAS 'no objection' letter as equivalent to an FDA drug approval is systematically misrepresenting what the regulatory documents mean. AOD-9604 has never been FDA-approved as a drug for any indication.
Independent of the obesity story, small human trials have explored AOD-9604 in osteoarthritis of the knee, with intra-articular administration and reported symptom improvement in a limited number of patients. These are not the same as a completed phase-3 program, and no arthritis indication has been pursued at scale. The compound retains genuine mechanistic interest in the adipose-biology literature. That interest is not the same as evidence of clinically meaningful weight loss in humans at trial scale.
- A modified hGH C-terminal fragment designed to isolate lipolytic activity from growth-signalling activity
- The 2007 phase 2b obesity trial did not meet its primary weight-loss endpoint at any tested dose — the pharmaceutical program was discontinued
- Subsequently repositioned via a GRAS notice for functional-food use; GRAS status is a food-additive pathway, not an FDA drug approval
Human research
The AOD-9604 research base has a clean structure: a preclinical mechanism story (adipose-tissue lipolysis, isolation from growth-signalling activity), a Metabolic Pharmaceuticals phase 2 pharmaceutical program that concluded in the mid-2000s, and a subsequent regulatory-pathway shift to GRAS-ingredient status. Each of those chapters answers a different question, and reading the compound honestly requires keeping them distinct.
The preclinical foundation is Heffernan et al. Endocrinology 2001, which characterised the compound's lipolytic activity in isolated fat cells and demonstrated separation of that activity from the anabolic signalling associated with full-length hGH. The design premise — that lipolysis and growth-signalling can be pharmacologically dissociated — was preclinically supported by that work and by follow-up mechanistic studies. The premise is genuine science.
The pivotal human study is the Metabolic Pharmaceuticals 2007 phase 2b obesity trial: 12 weeks, randomised, placebo-controlled, dose-ranging (0.25–1 mg subcutaneously daily). The primary weight-loss endpoint was not met at any of the tested doses. The pharmaceutical development program was discontinued after this result. This is the fact most consumer-facing sources on the compound omit, and it is the single most important fact about the compound's clinical status.
The AOD-9604 osteoarthritis literature — small intra-articular pilot studies, most notably Kim et al. 2018 — represents a separate research thread that emerged after the obesity program ended. It is a limited body of work and does not constitute a pharmaceutical program for an approved arthritis indication. The FDA GRAS 'no objection' letter (GRAS notice GRN 501 domain) documents a food-additive pathway, not a drug approval.
Heffernan Endocrinology 2001
Preclinical characterisation of AOD-9604's lipolytic activity in isolated fat cells and demonstration of the design premise — separation of hGH's lipolytic activity from its growth-signalling activity. The founding mechanistic paper for the compound.
Ng JCE 1994 (earlier hGH fragment work)
Foundational earlier study characterising the lipolytic activity of the hGH C-terminal region that AOD-9604's design derives from. The scientific groundwork on which the compound's premise was built.
Metabolic Pharmaceuticals phase 2b (2007) — obesity
The pivotal 12-week randomised placebo-controlled dose-ranging trial in obesity. Doses of 0.25 mg to 1 mg subcutaneously daily. The primary weight-loss endpoint was not met at any of the tested doses. The pharmaceutical development program was discontinued after this result.
Kim et al. 2018 (osteoarthritis pilot)
Small intra-articular pilot study of AOD-9604 in osteoarthritis of the knee, reporting symptom improvement. Represents a separate research thread from the obesity program; not a phase-3-scale demonstration of an arthritis indication.
FDA GRAS notice GRN 501 (2014)
The GRAS 'no objection' letter for AOD-9604 as a functional-food ingredient. Documents a food-additive safety pathway; NOT an FDA drug approval, and NOT a demonstration of efficacy for any therapeutic indication. Frequently misrepresented in consumer marketing.
AOD-9604 has never had an FDA-approved drug product for any indication. The pharmaceutical development program by Metabolic Pharmaceuticals culminated in a 12-week randomised placebo-controlled phase 2b trial in obesity in the mid-2000s that did not meet its primary weight-loss endpoint. That trial result is the pivotal clinical fact about the compound. The pharmaceutical program was subsequently discontinued.
The FDA GRAS 'no objection' letter that circulates in AOD-9604 consumer marketing is a food-additive-pathway document. GRAS status is a regulatory framework for evaluating the safety of substances added to food; it does not require or provide evidence of efficacy for any therapeutic indication, and it does not authorise the compound as a drug. Presenting the GRAS documentation as if it were an FDA drug approval systematically misrepresents what the FDA has and has not evaluated for this compound.
The compound is on the WADA prohibited list for competitive athletes under the S2 category (peptide hormones, growth factors, related substances, and mimetics) as an hGH-derived fragment.
Safety considerations
Human tolerability data come primarily from the Metabolic Pharmaceuticals phase 2 program. The following draws on published trial reports.
- Injection-site reactions
- Reported as generally well tolerated in the 12-week phase 2b trial at doses up to 1 mg daily — Tolerability observations from a negative-endpoint trial do not translate into support for long-term use
- Long-term safety beyond 12 weeks is not characterised in the pharmaceutical program — The program was discontinued after phase 2b; there is no extended follow-up dataset
- Post-marketing safety surveillance does not exist — There is no drug marketing — the GRAS pathway does not generate the same surveillance infrastructure as a drug approval
There is no approved-label list of contraindications because there is no approved drug indication. The considerations below draw on the compound's proposed mechanism and its distinctive regulatory history.
- Active malignancy — although the compound was specifically designed to avoid hGH growth-signalling activity, human safety in cancer populations is not characterised
- Pregnancy and breastfeeding — no human safety data
- Known hypersensitivity to the compound or excipients
- Uncontrolled diabetes — no specific contraindication established, but glucose response to any hGH-derived compound warrants attention
- Long-term use beyond the 12-week phase 2 window is not supported by the pharmaceutical program's safety data
Monitoring
- Injection-site reactions across rotation sites
- Weight and metabolic response over a defined trial window, given the phase 2b did not demonstrate weight-loss efficacy
- Any new symptoms suggesting unexpected metabolic or endocrine effect
Frequently asked questions
Did the phase 2b obesity trial actually fail?
Yes — this is the pivotal clinical fact about the compound. In the Metabolic Pharmaceuticals 2007 12-week randomised placebo-controlled phase 2b trial in obesity, AOD-9604 did not meet the primary weight-loss endpoint at any of the tested doses (0.25 mg to 1 mg subcutaneously daily). The pharmaceutical development program was discontinued after this result. Sources that describe AOD-9604 as a 'clinically demonstrated' weight-loss agent are not tracking the primary literature.
What is GRAS status and why does it not mean FDA-approved?
GRAS stands for 'generally recognised as safe' — it is a regulatory pathway for evaluating the safety of substances added to food. A GRAS notice submitted to the FDA describes safety data supporting the addition of a substance to food; if the FDA has no objection, it issues a 'no objection' letter. The GRAS framework does NOT require evidence of therapeutic efficacy, does NOT authorise the substance as a drug, and does NOT constitute FDA approval for any therapeutic indication. Marketing that conflates the GRAS 'no objection' letter with an FDA drug approval is systematically misrepresenting what the regulatory documents mean.
If AOD-9604 doesn't cause hGH-style growth signalling, doesn't that make it safer?
The design premise — that AOD-9604 lacks the anabolic growth-signalling of full-length hGH — was preclinically supported. In principle this reduces some of the theoretical hGH-related concerns (unwanted growth effects, glucose dysregulation from the growth-signalling pathway). In practice, human safety at scale is characterised only by the 12-week phase 2b window at doses up to 1 mg daily. That is a real dataset, but it does not support open-ended chronic use or use in vulnerable populations. Being 'not full-length hGH' is not the same as being 'as clinically established as hGH.'
Is AOD-9604 the same as 'hGH fragment 176-191' sold by research suppliers?
They are closely related. AOD-9604 is the modified fragment corresponding to hGH residues 177–191 with an added N-terminal tyrosine — the specific molecule developed by Metabolic Pharmaceuticals and used in the phase 2b obesity trial. 'hGH fragment 176-191' as sold by some research suppliers is the unmodified endogenous fragment (or a close analogue) without the tyrosine addition. In practice they are often conflated in consumer channels, but the compound with the published human phase 2 data is specifically the AOD-9604 variant.
Is AOD-9604 banned in competitive sport?
Yes. The World Anti-Doping Agency includes AOD-9604 on its prohibited list under the S2 category (peptide hormones, growth factors, related substances, and mimetics) as an hGH-derived fragment. A positive test carries the standard doping sanctions regardless of intent, and independently of the compound's negative phase 2b clinical result.
References
- [1]
The lipolytic domain of human growth hormone: structural and functional characterisation of the C-terminal region — Ng FM, Sun J, Sharma L, et al., Journal of Clinical Endocrinology and Metabolism (1994)
- [2]
The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta 3-AR knock-out mice — Heffernan M, Summers RJ, Thorburn A, et al., Endocrinology (2001)
- [3]
AOD9604 phase 2b clinical trial results in obesity — Metabolic Pharmaceuticals ASX announcement and program disclosure — Metabolic Pharmaceuticals Ltd, Clinical program disclosure (2007)
- [4]
AOD9604 combined with hyaluronic acid in the treatment of knee osteoarthritis: clinical pilot — Kim MJ, Kim JH, Park SG, et al., Journal of Orthopaedic Surgery and Research (2018)
- [5]
GRAS Notice GRN 000501: AOD9604 as an ingredient for use in dietary supplements — FDA 'no objection' response letter — US Food and Drug Administration (GRAS Notice Inventory), FDA GRAS Notice Inventory (2014)
https://www.cfsanappsexternal.fda.gov/scripts/fdcc/index.cfm?set=GRASNotices
- [6]
Peptides & Compounds — The No-Jargon Guide (v5) — Healthy Mango Editorial, Healthy Mango practitioner reference (2026)
Laboratory Reference Notice
This section summarizes procedures and study parameters reported in published scientific literature and laboratory protocols. It is provided for educational and research reference only and must not be interpreted as medical advice, clinical guidance, or instructions for personal use.
Editorial review pending
This page has not yet undergone external editorial review. Content is drawn from published sources and may be updated as review completes.
Related on Healthy Mango
Compare
Categories