Peptigrade

Growth Hormone Axis — Fragment

AOD-9604

Anti-Obesity Drug 9604 — Tyr-hGH(177-191), a 16-amino-acid synthetic fragment of human growth hormone (sequence YLRIVQCRSVEGSCGF) with an N-terminal tyrosine addition and a Cys7-Cys14 intramolecular disulfide bond·Also known as: AOD9604, AOD-9401 (earlier designation), Tyr-hGH177-191, Lipotropin fragment (marketing), hGH 176-191 analog

FDARegulatory status

Not approved for human use. Phase 2b obesity clinical development was terminated by Metabolic Pharmaceuticals / Calzada in 2007 after the 24-week Phase 2b trial failed its primary weight-loss endpoint. AOD-9604 was subsequently repositioned as a nutraceutical ingredient and granted self-affirmed GRAS status for food use (Moré et al. 2014); the FDA has not issued an independent GRAS no-objection letter, and no NDA or BLA is open or pending. The April 15, 2026 FDA 503A Bulk Drug Substances Categories Update does not list AOD-9604 as an eligible substance for compounding in human drug products.

WADARegulatory status

Prohibited at all times under S2 (Peptide Hormones, Growth Factors, Related Substances and Mimetics) of the 2026 WADA Prohibited List (in force January 1, 2026). AOD-9604 falls within the GH-fragment class covered by S2.2 and is a target of anti-doping screening — Esposito et al. (2014) characterized its in-vitro metabolites for detection by LC-HRMS.

Regulatory note ·Sold legally in the United States only as a research chemical for in-vitro and animal studies. It is not approved by FDA, EMA, TGA, or any major regulator for human therapeutic use. The Australian sponsor (Metabolic Pharmaceuticals, later Calzada Ltd) ran six human clinical trials during 2000–2007 totaling >900 subjects before halting obesity development on the Phase 2b primary-endpoint failure. The compound's subsequent nutraceutical framing rests on a safety/toxicology dossier (Moré 2014) rather than an efficacy approval. Marketing claims that AOD-9604 is an 'FDA-approved fat-loss peptide' are incorrect — the compound has never received an FDA efficacy approval for any indication.

§ The quick take

TL;DR · Editor’s summary

AOD-9604 is the cleanest cautionary tale in the GH-fragment literature: a rationally designed 16-amino-acid analog of hGH(177-191) that was engineered in the 1990s by Ng and colleagues at Monash to isolate the lipolytic domain of growth hormone without the anabolic or diabetogenic liabilities, taken through six human trials in >900 subjects by Metabolic Pharmaceuticals / Calzada, and halted in 2007 when the 24-week Phase 2b obesity trial (n≈536) failed its primary weight-loss endpoint. The preclinical case remains interesting — Heffernan 2001 (Endocrinology 142:5182-5189) showed β3-adrenergic-receptor mRNA restoration in obese mice with β3-AR-knockout loss-of-function confirmation, Ng 2000 (Horm Res) reported roughly 50% reduction in body-weight gain in Zucker rats at 500 μg/kg/day oral dosing, and Moré 2014 added a negative genotoxicity and 6-month rat / 9-month cynomolgus monkey safety dossier — but the human efficacy signal never replicated: a prior 12-week Phase 2 RCT had shown only ~1.8 kg placebo-adjusted loss at 1 mg/day with a paradoxical non-linear dose-response (10 mg/day underperformed 1 mg/day), and the 24-week confirmatory trial did not clear its primary endpoint.

No sponsor has reopened obesity development since; no Phase 3 exists; the compound was repositioned as a nutraceutical ingredient on a self-affirmed GRAS basis rather than any FDA efficacy approval. Under the Peptigrade rubric this is a D for the flagship weight-loss indication (a well-powered Phase 2b primary-endpoint failure is negative evidence, not merely absent evidence) and C for the preclinical mechanistic outcomes.

WADA prohibits it at all times under S2; Esposito 2014 published the in-vitro metabolic profile used for anti-doping detection. Claims that AOD-9604 is an 'FDA-approved fat-loss peptide' are incorrect.

§ Grade matrix

The grade
per outcome.

One peptide can earn very different grades for different uses. Here is every outcome we’ve graded for AOD-9604, sorted by strength of evidence.

D

Body weight / fat-mass reduction in adults with obesity

Weak

The pivotal 24-week Phase 2b RCT in adults with obesity (Metabolic Pharmaceuticals, n≈536, completed 2007) failed to meet its primary weight-loss endpoint and led the sponsor to terminate obesity development. A preceding 12-week Phase 2 RCT (n≈300) reported a placebo-adjusted ~1.8 kg loss at 1 mg/day with a paradoxical non-linear dose-response (10 mg/day underperformed 1 mg/day). No replicated Phase 2 or any Phase 3 exists. No subsequent RCT has reopened the indication.

3 studiesUpdated 2026-04-20
C

β3-adrenergic-driven lipolysis (preclinical)

Mixed

Heffernan 2001 (Endocrinology 142:5182-5189) showed AOD-9604 restored β3-AR mRNA expression in obese mice to lean-mouse levels; β3-AR knockout mice were unresponsive to AOD-9604's lipolytic effect. Ng 2000 (Horm Res) reported ~50% reduction in body-weight gain in Zucker rats at 500 μg/kg/day oral for 19 days without insulin-sensitivity decrement. Mechanism consistent across two independent rodent systems; no human lipolysis-endpoint RCT.

6 studiesUpdated 2026-04-20
C

Fat oxidation and metabolic flexibility (preclinical)

Mixed

Heffernan 2001 (Int J Obes) documented a ~216% increase in whole-body fat oxidation in obese mice on chronic AOD-9604 administration relative to vehicle. Effect replicated only within the same research group's program. No human indirect-calorimetry trial is in the peer-reviewed literature.

3 studiesUpdated 2026-04-20
C

Insulin sensitivity / diabetogenicity (safety signal)

Mixed

Across rodent and monkey toxicology (Ng 2000; Moré 2014) AOD-9604 did not impair insulin sensitivity, unlike full-length hGH. The 6-month rat and 9-month cynomolgus monkey studies (Moré 2014) were negative for diabetogenic effects at therapeutic dose ranges. Supportive for mechanism-of-selectivity claim but does not constitute human-efficacy evidence.

4 studiesUpdated 2026-04-20
C

IGF-1 / linear-growth axis neutrality

Mixed

Published preclinical work (Ng 2000; Heffernan 2001 Endocrinology) and the Phase 1 PK program report that AOD-9604 does not meaningfully raise IGF-1, does not activate the classical hGH receptor, and does not drive JAK-STAT signaling — consistent with the lipolytic-domain-only design intent. Useful as a negative-control differentiation from GH and GHRH analogs; no human long-term IGF-1 surveillance dataset.

3 studiesUpdated 2026-04-20
Ins.

Cartilage / osteoarthritis (marketing claim)

Insufficient

Marketing assertions of chondroprotection or OA benefit trace to unpublished company claims and in-vitro bovine-cartilage experiments referenced in promotional materials; no peer-reviewed human RCT for AOD-9604 in knee, hip, or any OA indication is indexed in PubMed. The rubric does not support a graded claim from the current literature.

0 studiesUpdated 2026-04-20
Ins.

Hepatic fat / NAFLD

Insufficient

No controlled human trial of AOD-9604 for hepatic fat fraction, NAFLD, or NASH is in the peer-reviewed literature. Mechanistic rationale exists by analogy to the tesamorelin NAFLD data, but analogy is not evidence.

0 studiesUpdated 2026-04-20
C

Long-term human safety

Mixed

Over 900 subjects were exposed across the 2000–2007 clinical program with no serious tolerability signal reported in the sponsor trial summaries; Moré 2014 documented negative genotoxicity (Ames, chromosomal aberration, micronucleus) and clean 6-month rat / 9-month monkey oral toxicology. Exposure duration in humans maxes out at 24 weeks (Phase 2b). Longitudinal (>1 year) human safety data does not exist.

5 studiesUpdated 2026-04-20

§ Why this grade

Sub-scores for this outcome.

Body weight / fat-mass reduction in adults with obesity

Every grade rolls up six weighted sub-scores, each rated 1 to 5 with a written justification. Here is how the top-outcome grade was constructed.

Mechanism understood

3 / 5

β3-AR upstream-downstream chain is partially characterized with loss-of-function confirmation (Heffernan 2001 Endocrinology; β3-AR KO mice unresponsive). Proposed ACC inhibition is hypothesis-level. The primary molecular binding partner of AOD-9604 itself has never been identified. Human PK/PD is not in peer-reviewed literature.

Human studies (count + quality)

2 / 5

Six sponsor trials in >900 subjects during 2000–2007, including a 12-week Phase 2 RCT (n≈300) with a modest ~1.8 kg placebo-adjusted effect at 1 mg/day, and a 24-week Phase 2b confirmatory RCT (n≈536) that FAILED its primary endpoint. No peer-reviewed primary Phase 2b manuscript; trial-level detail is sponsor / regulatory summary. No replication, no Phase 3.

Effect vs placebo

1 / 5

The pivotal placebo-controlled Phase 2b did not beat placebo on its primary endpoint. A 12-week predecessor RCT showed a ~1.8 kg placebo-adjusted effect with a paradoxical inverse dose-response (10 mg < 1 mg). Under the Peptigrade rubric a well-powered primary-endpoint failure is negative evidence, not null.

Long-term safety data

2 / 5

Maximum published human exposure: 24 weeks in the Phase 2b program. Moré 2014 adds 6-month rat and 9-month cynomolgus monkey oral toxicology with no organ toxicity and negative genotoxicity (Ames, chromosomal aberration, micronucleus). No human >1-year cohort.

Side effect profile

4 / 5

Sponsor trial summaries across the 2000–2007 program report no serious tolerability signal in >900 subjects; generally tolerated at doses up to 10 mg/day. Moré 2014 negative across genotoxicity panel. Favorable compared with exogenous GH, which is the main mechanistic value of the molecule. A clean tolerability record is not an efficacy result.

Regulatory status

1 / 5

Not FDA-approved. WADA-prohibited at all times under S2. Metabolic Pharmaceuticals / Calzada terminated obesity clinical development in 2007. Subsequent self-affirmed GRAS nutraceutical framing is not an FDA efficacy approval. Not listed as an eligible 503A compounding substance in the April 15, 2026 FDA Categories Update.

§ What the science says

How AOD-9604
works.

Plain-English explanation of the molecule and its proposed mechanism, written at an 8th-grade reading level so anyone can engage with it. Every claim is linked to a primary source below.

What it is

AOD-9604 is a synthetic 16-amino-acid cyclic peptide (sequence Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe, molecular formula C₇₈H₁₂₃N₂₃O₂₃S₂, CAS 221231-10-3) corresponding to the C-terminal hGH(177-191) lipolytic domain with an added N-terminal tyrosine substituting the native Phe¹⁷⁶. An intramolecular Cys7-Cys14 disulfide bond constrains the molecule into a cyclic conformation that mimics the three-dimensional architecture of the lipolytic region within intact growth hormone. The tyrosine addition improves proteolytic stability and is the basis for the 'AOD-9604' designation (Anti-Obesity Drug 9604, distinguishing it from the earlier 'AOD-9401' construct). The molecule was designed by Frank Ng and colleagues at Monash University in the 1990s and developed clinically by Metabolic Pharmaceuticals (later Calzada Ltd) in Melbourne. Unlike full-length hGH, AOD-9604 does not bind or activate the classical hGH receptor, does not raise IGF-1, does not activate JAK-STAT signaling, and does not drive linear growth or muscle hypertrophy — the design intent was to isolate the lipolytic domain from the anabolic and diabetogenic domains. After the 2007 Phase 2b efficacy failure the asset was repositioned as a nutraceutical ingredient under a self-affirmed GRAS framework (Moré 2014). It has never been FDA-approved for any human therapeutic use.

How it works

  1. 01

    β3-adrenergic receptor upregulation in adipose tissue

    The primary mechanism characterized in vivo is restoration and sensitization of β3-adrenergic receptor (β3-AR) expression in adipocytes. Heffernan 2001 (Endocrinology 142(12):5182-5189) showed that both full-length hGH and AOD-9604 increased β3-AR mRNA in obese mouse adipose tissue to levels comparable with those of lean mice after 14 days of chronic intraperitoneal administration, and that β3-AR knockout animals were completely unresponsive to the lipolytic effect of AOD-9604 — a loss-of-function confirmation that is the strongest single piece of mechanistic evidence in the program. Downstream, β3-AR activation couples through Gαs–adenylyl cyclase–cAMP–PKA to phosphorylate hormone-sensitive lipase (HSL) and perilipin, mobilizing triglycerides from the lipid droplet.

  2. 02

    Absence of classical hGH receptor engagement

    A design-defining feature of AOD-9604 is what it does NOT do. Ng 2000 (Horm Res) and subsequent work confirmed that AOD-9604 does not bind or activate the hGH receptor, does not raise circulating IGF-1, does not activate hepatic JAK2-STAT5 signaling, and does not produce the insulin-resistance signal seen with exogenous GH in obese rodents. This receptor-negative profile distinguishes AOD-9604 from every GHRH analog (sermorelin, tesamorelin, CJC-1295) and from the ghrelin-receptor secretagogues (ipamorelin, MK-677) — all of which work by raising endogenous GH and IGF-1. The trade-off is that AOD-9604 also cannot borrow any of the well-characterized GH/IGF-1 axis efficacy evidence.

  3. 03

    Enhanced whole-body fat oxidation (rodent)

    Heffernan 2001 (Int J Obes Relat Metab Disord 25(10):1442-1449) used indirect calorimetry in obese mice and reported an approximately 216% increase in whole-body fat oxidation on chronic AOD-9604 relative to vehicle, with a corresponding shift in respiratory exchange ratio toward lipid substrate utilization. The mechanism is proposed to involve CPT-1-mediated mitochondrial fatty-acid import downstream of β3-AR-driven lipolysis, but the specific CPT-1, UCP, or PGC-1α findings have not been independently replicated outside the original program. No human indirect-calorimetry RCT exists.

  4. 04

    Proposed anti-lipogenic effect via acetyl-CoA carboxylase

    Company-sponsored preclinical work described by Moré 2014 (J Endocrinol Metab) and in the sponsor dossiers proposed that AOD-9604 additionally inhibits acetyl-CoA carboxylase (ACC), the rate-limiting enzyme for de novo lipogenesis, yielding a dual lipolytic / anti-lipogenic effect. This mechanism is less well characterized in independent peer-reviewed literature than the β3-AR arm and should be regarded as hypothesis-level rather than established.

  5. 05

    Pharmacokinetics and route of administration

    Moré 2014 summarized pig PK studies after oral and intravenous administration and supported oral bioavailability as the basis for nutraceutical framing. Human PK from the 2000–2007 clinical program was not published as a standalone manuscript — only sponsor summaries describe it. Esposito 2014 (PMID 25208511) characterized the in-vitro metabolic profile of AOD-9604 for anti-doping LC-HRMS detection, identifying the major proteolytic cleavage products relevant to urine- and plasma-based WADA screening.

  6. 06

    What is NOT known about the mechanism

    The loss-of-function β3-AR data is strong, but the molecular-level binding partner (receptor or surface protein) that AOD-9604 itself engages to upregulate β3-AR mRNA has not been identified — the β3-AR is a downstream effector, not the primary target. Human pharmacokinetics, distribution, and adipose-tissue bioavailability are not published in peer-reviewed form. The proposed ACC inhibition remains poorly characterized. Whether the 2007 Phase 2b efficacy failure reflects a receptor-desensitization / tachyphylaxis phenomenon, a dose-response inversion (the 1 mg > 10 mg paradox in the 12-week trial suggests non-monotonic pharmacology), or simply a mechanism that does not translate from mice to humans at clinically feasible exposures is unresolved.

§ Investigated uses

What it’s
been studied for.

Investigated does not mean proven. This list shows every use that appears in the published literature, regardless of evidence strength. See the grade matrix above for which ones have actually held up.

  • Obesity / body-weight reduction in adults

    Phase 2b 24-week RCT (n≈536) failed primary endpoint 2007; development halted. 12-week Phase 2 (n≈300) showed ~1.8 kg placebo-adjusted loss at 1 mg/day with paradoxical dose-response.

  • Adipose-tissue lipolysis (β3-AR pathway)

    Preclinical: Heffernan 2001 (Endocrinology) with β3-AR knockout loss-of-function confirmation; Ng 2000 (Horm Res) in Zucker rats.

  • Nutraceutical / food-ingredient use for metabolic health

    Self-affirmed GRAS dossier (Moré 2014); no FDA no-objection letter, no efficacy approval.

  • Osteoarthritis / cartilage repair (commonly marketed)

    No peer-reviewed human RCT. In-vitro bovine-cartilage claims reference only in sponsor/promotional materials.

  • Hepatic steatosis / NAFLD

    No human trial. Mechanistic inference only.

  • Anti-doping detection (research use)

    Esposito 2014 characterized in-vitro metabolites for LC-HRMS screening — WADA S2.

§ The honest gaps

What we don’t
know yet.

Every peptide page on this site is required to include this section. Absence of evidence is information. If we don’t flag the gaps, we’re lying by omission.

  • !

    No positive confirmatory Phase 2 or Phase 3 RCT for weight loss exists. The 2007 Phase 2b primary-endpoint failure has not been followed up by any independent sponsor or academic group — the indication is effectively abandoned rather than unresolved.

  • !

    The molecular receptor (or surface-interaction partner) that AOD-9604 itself engages to trigger β3-AR mRNA upregulation has not been identified. The β3-AR knockout data establishes the downstream effector, not the upstream target.

  • !

    Human pharmacokinetics, plasma half-life, oral bioavailability, and tissue distribution are not published as a standalone peer-reviewed manuscript — only sponsor and nutraceutical-dossier summaries describe them.

  • !

    The paradoxical non-linear dose-response observed in the 12-week Phase 2 trial (10 mg/day underperformed 1 mg/day) was never mechanistically resolved before program termination, leaving the question of whether receptor desensitization, β3-AR down-regulation, or counter-regulatory pathway activation explains the efficacy ceiling.

  • !

    No human trial for the commonly marketed osteoarthritis / cartilage-repair indication exists in the peer-reviewed literature. The chondroprotection claim rests on unpublished sponsor data and in-vitro bovine-cartilage work.

  • !

    Long-term (>6 months) human safety data does not exist. The longest published exposure is the 24-week Phase 2b program; chronic rodent and monkey data (Moré 2014) supports a clean toxicology signal but is not a substitute for >1-year human surveillance.

  • !

    Immunogenicity and anti-drug antibody formation during repeated dosing have not been formally characterized in humans.

  • !

    Whether any subcutaneous or oral AOD-9604 exposure at currently-available research-peptide concentrations achieves rodent-comparable adipose-tissue drug levels is unverified in published work.

§ On YouTube

What experts and
influencers say.

We index YouTube content discussing AOD-9604and tag every speaker by credential and trust level. The goal is not to summarize the internet — it’s to tell you which voices to weight.

  • AOD-9604: What the Phase 2b obesity trial actually showed

    Peter Attia MD·MD, longevity medicine

    Walks through the Heffernan and Ng preclinical data and is explicit that the 2007 24-week Phase 2b trial failed its primary endpoint. Positions AOD-9604 as a research tool, not a clinical weight-loss therapy, and contrasts it with GLP-1 receptor agonists where Phase 3 evidence is unambiguous.

    Verified credentials

  • GH fragments in clinical practice — hype vs. evidence

    Dr. Kyle Gillett·MD, Family Medicine

    Covers AOD-9604, fragment 176-191, and CJC-1295 side-by-side. Flags the non-monotonic dose-response in the 12-week Phase 2 and the absence of any positive confirmatory RCT. Notes the common marketing misstatement that AOD-9604 is 'FDA-approved.'

    Verified credentials

  • I Took AOD-9604 for 8 Weeks — Before & After

    Anonymous fitness influencer·Unverified

    Anecdotal weight-loss claim with no control, no blinding, and confounded by concurrent caloric restriction. Representative of the content pattern that overstates benefit against a drug whose best-powered human trial failed its primary endpoint. Do not weight against published evidence.

    Caution — anecdotal

§ Citations

Every claim,
linked to source.

All 9 sources informing this page, with DOI or PubMed identifiers. Click through to the primary literature.

  1. [01]

    The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice

    Heffernan M, Summers RJ, Thorburn A, Ogru E, Gianello R, Jiang WJ, Ng FM · Endocrinology · 2001

    AnimalPMID 11713213
  2. [02]

    Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment

    Heffernan MA, Thorburn AW, Fam B, Summers R, Conway-Campbell B, Waters MJ, Ng FM · Int J Obes Relat Metab Disord · 2001

    AnimalPMID 11673763
  3. [03]

    Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone

    Ng FM, Sun J, Sharma L, Libinaka R, Jiang WJ, Gianello R · Horm Res · 2000

    AnimalPMID 11150871
  4. [04]

    Detection and characterization of in vitro metabolites of AOD9604 for doping-control purposes

    Esposito S, Deventer K, Goeman J, Van der Eycken J, Van Eenoo P · Rapid Commun Mass Spectrom · 2014

    In vitroPMID 25208511
  5. [05]

    Safety and metabolism of AOD9604, a novel nutraceutical ingredient for improved metabolic health

    Moré MI, Freitas U, Rutenberg D · J Endocrinol Metab · 2014

    AnimalDOI
  6. [06]

    Obesity pharmacotherapy: current perspectives and future directions

    Misra M · Curr Cardiol Rev · 2013

    Systematic reviewDOI
  7. [07]

    Metabolic Pharmaceuticals announces Phase 2b AOD9604 obesity trial did not meet primary endpoint (press release, 2007)

    Metabolic Pharmaceuticals Ltd / Calzada Ltd · ASX sponsor announcement · 2007

    RegistrationLink
  8. [08]

    WADA 2026 Prohibited List (in force January 1, 2026) — Section S2 Peptide Hormones, Growth Factors, Related Substances and Mimetics

    World Anti-Doping Agency · WADA · 2026

    RegulatoryLink
  9. [09]

    FDA 503A Bulk Drug Substances Categories — April 15, 2026 Update (AOD-9604 not listed as eligible compounding substance)

    U.S. Food and Drug Administration · FDA · 2026

    RegulatoryLink

§ Adjacent peptides

Worth reading
alongside this.

Compare

Fragment 176-191

The native 15-amino-acid hGH(176-191) sequence that AOD-9604 modifies with an N-terminal tyrosine. Same mechanistic ancestor, same lipolytic-domain rationale, same gap between preclinical promise and controlled human evidence.

Read its grades

Compare

IGF-1 / LR3-IGF-1

The anabolic axis AOD-9604 was specifically designed NOT to activate. Useful contrast if you are trying to understand why GH-fragment design decisions separate lipolytic from anabolic signaling.

Read its grades

Compare

Sermorelin

GHRH analog in the same GH-axis neighborhood but working through a completely different mechanism (endogenous GH/IGF-1 pulse restoration). Stronger regulatory history than AOD-9604; different efficacy profile.

Read its grades

Compare

CJC-1295

Another GH-axis peptide commonly stacked in wellness-clinic protocols that include AOD-9604. Worth comparing because CJC-1295 raises IGF-1 and AOD-9604 explicitly does not — the two molecules are often marketed together despite opposite axis engagement.

Read its grades

Where to research further

Looking for AOD-9604
for laboratory research?

Peptigrade does not sell peptides. RiboCore is one supplier we track that publishes batch-level certificates of analysis (mass spec, HPLC purity) for research-grade material. We have no commercial relationship with them — listing here is editorial.

For research use only · Not for human consumption · Verify legality in your jurisdiction

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