Peerless Peptides

AOD-9604

Tyr-extended hGH 177-191 hexadecapeptide, 16 amino acids

AOD-9604 is a synthetic 16-amino-acid Tyr-extended hexadecapeptide corresponding to residues 177-191 of human growth hormone, first described by the Frank M. Ng group at Monash University and commercialized by Metabolic Pharmaceuticals Limited. Development was terminated on February 21, 2007 after the Phase 2b OPTIONS trial (METAOD006, 536 obese adults) missed its weight-loss primary endpoint. The FDA Pharmacy Compounding Advisory Committee voted against 503A bulks-list inclusion on December 4, 2024.

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Biochemical Profile

CAS Number
221231-10-3
Molecular Formula
C78H123N23O23S2
Molecular Weight
1815.10 g/mol
Purity
≥99% (HPLC-UV (214 nm peptide bond and 280 nm Tyr/Phe), with LC-MS confirmation of the intramolecular Cys-7 to Cys-14 disulfide)
PubChem CID
71300630
Amino Acid Sequence
Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe

Receptor Targets and Signaling Pathway Context

AOD-9604 is a 16-residue Tyr-extended hexadecapeptide corresponding to the C-terminal segment of human growth hormone (hGH, UniProt P01241, residues 177-191) with an added N-terminal tyrosine that is not present in the native hGH sequence at this position. The native Cys-182 to Cys-189 disulfide in hGH is preserved within the synthetic 16-mer as an intramolecular Cys-7 to Cys-14 bridge. AOD-9604 is structurally distinct from full-length hGH: the 16-mer has a molecular weight of 1815 Da, while full hGH is a 191-residue, ~22,124 Da protein. The two molecules differ by more than 12-fold in mass, and AOD-9604 has been reported to lack measurable affinity for the growth hormone receptor in the published binding literature[1][2].

The foundational mechanism paper from the Ng laboratory at Monash University reported that oral administration of AOD-9604 at 500 micrograms per kilogram body mass for 19 days in obese Zucker rats was associated with approximately 50% reduction in body-weight gain versus pair-fed controls, with no impairment of the euglycaemic clamp readout for insulin action[1]. The follow-up Heffernan and colleagues paper in Endocrinology examined chronic 14-day intraperitoneal AOD-9604 administration in C57BL/6 obese wild-type mice and in beta-3 adrenergic receptor (beta-3-AR) knockout mice. In wild-type animals the authors reported reductions in body weight and adipose mass alongside increased beta-3-AR mRNA expression in adipose tissue; in beta-3-AR knockout animals the long-term weight-reduction phenotype was not observed, although acute single-dose AOD-9604 still raised energy expenditure[2]. The authors interpreted these findings as evidence for a beta-3-AR-upregulation mechanism in adipocyte preparations, while noting that the acute energy-expenditure effect in knockout animals indicates at least one additional pathway is operative.

In the six Metabolic Pharmaceuticals Phase 1 and Phase 2 trials aggregated by the Stier 2013 retrospective safety review (approximately 900 healthy and obese adult subjects across oral, intravenous, and seven-day multiple-dose regimens), AOD-9604 was reported to have no effect on serum IGF-1 levels, no detectable anti-AOD-9604 antibodies in screened subjects, and no negative effect on carbohydrate metabolism on oral glucose tolerance testing[3]. The IGF-1 null finding across both rodent preclinical models and the human clinical program is the most reproducibly reported pharmacologic feature in the AOD-9604 literature and supports the structural inference that the 16-mer fragment does not engage the GH receptor or JAK2-STAT5 axis characteristic of full-length somatotropin signaling.

The receptor target underlying the rodent-model adipocyte observations remains incompletely mapped in the published peer-reviewed literature. The reported beta-3-AR upregulation finding has not been replicated by an academic group outside the Ng / Monash research orbit, and no high-affinity receptor for AOD-9604 has been formally identified. Across the approximately 16 AOD-9604 papers indexed on PubMed as of May 2026, essentially the entire primary mechanism corpus traces to the Ng laboratory at Monash, with the WADA anti-doping analytical chemistry papers (Cox 2015, Orlovius 2013) and the Metabolic / Calzada-affiliated safety review (Stier 2013) constituting the bulk of the remaining citations[4][5][6]. The bioavailability, plasma half-life, and tissue-distribution profile of subcutaneously administered AOD-9604 have not been characterized in any registered human trial.

Research Applications

Adipocyte and Rodent Obesity-Model Research

Obese rodent preparations have provided the largest body of published AOD-9604 preclinical work. The Ng group's foundational 2000 paper reported that 19-day oral dosing of AOD-9604 in obese Zucker rats at 500 micrograms per kilogram body mass was associated with reduced body-weight gain relative to controls (15.8 ± 0.6 g versus 35.6 ± 0.8 g) and increased in-vitro adipose-tissue activity in the assays used by the authors[1]. The euglycaemic clamp readout for insulin action in the same study was reported as unchanged, in contrast to the impairment associated with chronic full-length hGH administration in the same animal model.

The Heffernan and colleagues 2001 paper in Endocrinology extended the rodent preclinical program to C57BL/6 obese wild-type mice and to beta-3-AR knockout animals. Chronic 14-day intraperitoneal administration was associated with body-weight reductions and adipose-mass reductions in wild-type animals, alongside an observed rise in adipose-tissue beta-3-AR mRNA expression. In beta-3-AR knockout animals the long-term phenotype was not observed, although acute single-dose administration still raised energy expenditure[2]. Across all rodent obesity-model papers in the AOD-9604 primary literature, the originating laboratory is the Department of Biochemistry and Molecular Biology at Monash University; no academic group outside the Ng / Monash research orbit has published an independent replication of the rodent obesity-model findings in a peer-reviewed journal.

Cartilage and Rabbit Osteoarthritis-Model Research

A single rabbit osteoarthritis preparation by Kwon and Park at the Catholic University of Daegu School of Medicine in South Korea has been the principal preclinical osteoarthritis citation in the AOD-9604 literature[7]. Thirty-two mature New Zealand white rabbits received bilateral intra-articular collagenase type II injections to induce knee osteoarthritis, then weekly intra-articular injections in one of four arms: saline; hyaluronic acid alone; AOD-9604 alone; or AOD-9604 plus hyaluronic acid as a co-administered intra-articular injection. Gross morphology scores and histopathology scores were assessed at four to seven weeks.

The authors reported that the co-administered AOD-9604 plus hyaluronic acid arm was associated with lower lesion scores than either monotherapy. The headline effect was contingent on the hyaluronic acid co-administration in the same intra-articular injection; the AOD-9604 monotherapy arm did not outperform the hyaluronic acid monotherapy arm on the primary readout[7]. The Kwon 2015 study is a single 32-rabbit preparation from a single Korean institution that has not been replicated by an independent laboratory in the eleven years since publication, and no registered human osteoarthritis trial of AOD-9604 has appeared in the peer-reviewed clinical record.

Non-Clinical Chronic Safety in Rat and Cynomolgus Monkey

The most extensive non-clinical safety dossier in the AOD-9604 literature was compiled in support of the 2014 US FDA self-affirmed GRAS notification (GRN 000534) and reported by Moré and colleagues in the Journal of Endocrinology and Metabolism[8]. The study program covered chronic oral administration in rats and in cynomolgus monkeys at exposures up to and exceeding the proposed human daily intake of 1 milligram per person per day.

The authors reported no genotoxic signal in the standard battery, no organ-specific toxicity in necropsy, and no abnormal histopathology at the exposures tested[8]. This non-clinical safety dossier and the aggregated Stier 2013 clinical review[3] together constitute the regulatory basis on which FDA filed the 2014 GRAS notification without objection. The GRAS notification covers AOD-9604 as a food or dietary supplement ingredient and is distinct from any drug-approval pathway; FDA staff cited the absence of a drug approval and the limitation of the published human exposure data to oral and intravenous routes in the December 4, 2024 Pharmacy Compounding Advisory Committee briefing materials reviewing AOD-9604 for 503A bulks-list eligibility[9].

Anti-Doping Analytical Chemistry Research

AOD-9604 has been the subject of a sustained anti-doping analytical chemistry program in the World Anti-Doping Agency (WADA) accredited laboratory literature. Cox and colleagues at the Sports Medicine Research and Testing Laboratory reported detection assays and in-vitro metabolism studies of AOD-9604 in support of routine sports-drug testing programs[4]. Orlovius and colleagues at the Cologne WADA-accredited laboratory reported that AOD-9604 does not influence the WADA hGH isoform immunoassay used for differential detection of recombinant versus pituitary growth hormone[5].

This anti-doping analytical literature is the second-largest cluster of AOD-9604 publications after the Ng / Monash mechanism corpus and contains approximately five peer-reviewed papers (Cox 2015, Orlovius 2013, and Thevis / Schänzer review papers from 2014 and 2017). The methodological work was driven by the WADA Prohibited List classification of AOD-9604 under Category S2 (Peptide Hormones, Growth Factors, Related Substances, and Mimetics), with the substance prohibited at all times in all sports since 2011. WADA publicly clarified the S2 status to the Australian Sports Anti-Doping Authority on April 22, 2013, during the period when the Essendon Football Club supplements saga had raised the public profile of the substance. No Therapeutic Use Exemption pathway is available for AOD-9604 under current WADA rules.

Cosmeceutical Transdermal Formulation Research

AOD-9604 was licensed by Metabolic Pharmaceuticals (and its successor parent company Calzada Limited) to the Australian company Phosphagenics Limited in a 2009 collaborative research and option agreement for use in transdermal cosmeceutical anti-cellulite formulations. The peptide was incorporated into Phosphagenics's BodyShaper anti-cellulite cream using the company's TPM transdermal delivery platform technology.

Across this commercial-development program no peer-reviewed human efficacy trial of transdermal AOD-9604 was published. Phosphagenics subsequently dropped AOD-9604 from the BodyShaper formulation on stated cost and effectiveness grounds, and Phosphagenics Limited renamed to Avecho Biotechnology Limited in subsequent years with a pipeline pivot to cannabidiol soft-gel and other unrelated transdermal-delivery products[10]. AOD-9604 is no longer a marketed Avecho asset. The published primary literature does not establish human topical or transdermal efficacy for AOD-9604, and the FDA December 4, 2024 PCAC briefing materials cited the absence of published human exposure data on subcutaneous and topical administration routes as one factor in the negative bulks-list recommendation[9].

Replication and Clinical Status

The central methodology observation in the AOD-9604 literature is the Phase 2a-to-Phase 2b replication failure across the Metabolic Pharmaceuticals clinical program. The 12-week Phase 2a METAOD005 trial in approximately 300 obese adults reported a body-weight differential of 2.6 kg in the 1 mg oral arm versus 0.8 kg in the placebo arm, with statistical significance reported in selected dose-arm comparisons[3]. The subsequent 24-week Phase 2b METAOD006 OPTIONS trial in 536 obese adults at 16 Australian trial sites used three oral dosing arms (0.25, 0.5, and 1 milligram once-daily) bracketing the Phase 2a best-arm dose, was specifically designed to confirm the Phase 2a finding, and missed its weight-loss primary endpoint. Metabolic Pharmaceuticals announced on February 21, 2007 via the Australian Securities Exchange that the Phase 2b results did not support commercial viability for the obesity indication, and the obesity drug development program was formally terminated within weeks of the readout[11]. No Phase 3 trial of AOD-9604 has ever been conducted, registered, or published for any indication.

A second structural observation in the published literature is the route-of-administration gap. Every registered Metabolic Pharmaceuticals human trial used oral or intravenous administration. No registered human subcutaneous AOD-9604 trial has ever been conducted, and no registered human topical AOD-9604 trial has been published[3]. The FDA December 4, 2024 PCAC briefing language cited the absence of published human exposure data for the proposed subcutaneous and topical routes as one factor in the staff recommendation against 503A bulks-list inclusion. The committee voted against inclusion[9]. AOD-9604 had previously been placed in FDA 503A Category 2 (Do-Not-Compound) in October 2023, was removed from Category 2 via nominator withdrawal effective September 27, 2024, and was subsequently included in the April 22, 2026 12-peptide Category 2 reclassification cohort. AOD-9604 was not placed on the July 23-24, 2026 PCAC re-review docket alongside BPC-157, KPV, MOTS-c, and TB-500[12]. Australian regulatory status is Schedule 4 (Prescription Only Medicine) under the Poisons Standard, effective June 1, 2015, and the molecule is not on the Australian Register of Therapeutic Goods. WADA classification is S2, prohibited at all times in all sports since 2011, with no Therapeutic Use Exemption pathway available. The mechanism literature is characterized by approximately 100% concentration in the Ng / Monash originating laboratory; no independent academic group has published a peer-reviewed replication of the foundational beta-3-AR upregulation finding.

Reconstitution & Storage

Recommended Diluent
Bacteriostatic water (0.9% benzyl alcohol)
Storage (lyophilized)
-20°C, dry, dark, sealed amber vials with desiccant, 18-24 months
Storage (reconstituted)
2-8°C, use within 30 days
Shelf Life
18-24 months lyophilized

Research References

  1. [1] Ng FM, Sun J, Sharma L, Libinaka R, Jiang WJ, Gianello R. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Horm Res. 2000;53(6):274-278. PMID:11146367
  2. [2] Heffernan M, Summers RJ, Thorburn A, Ogru E, Gianello R, Jiang WJ, Ng FM. 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. Endocrinology. 2001;142(12):5182-5189. PMID:11713213
  3. [3] Stier H, Vos E, Kenley D. Safety and Tolerability of the Hexadecapeptide AOD9604 in Humans. J Endocrinol Metab. 2013;3(1-2):7-15.
  4. [4] Cox HD, Smeal SJ, Hughes CM, Cox JE, Eichner D. Detection and in vitro metabolism of AOD9604. Drug Test Anal. 2015;7(1):31-38. PMID:25208511
  5. [5] Orlovius AK, Thomas A, Schänzer W, Thevis M. AOD-9604 does not influence the WADA hGH isoform immunoassay. Drug Test Anal. 2013;5(11-12):850-852. PMID:24124033
  6. [6] Wilding J. AOD-9604 Metabolic. Curr Opin Investig Drugs. 2004;5(4):436-440. PMID:15134286
  7. [7] Kwon DR, Park GY. Effect of Intra-articular Injection of AOD9604 with or without Hyaluronic Acid in Rabbit Osteoarthritis Model. Ann Clin Lab Sci. 2015;45(4):426-432. PMID:26275694
  8. [8] Moré M, Vos E, Kenley D, Hashimoto T, Sakuma T. Safety and Metabolism of AOD9604, a Novel Nutraceutical Ingredient for Improved Metabolic Health. J Endocrinol Metab. 2014;4(4):93-105.
  9. [9] US Food and Drug Administration. Pharmacy Compounding Advisory Committee Meeting; AOD-9604 review of bulk drug substances nominated for 503A compounding. Briefing document and meeting transcript. December 4, 2024.
  10. [10] Lexology. AOD-9604: patents, peptides, performance and cellulite. Commentary on the Metabolic Pharmaceuticals to Calzada to Phosphagenics to Avecho Biotechnology corporate trajectory. 2017.
  11. [11] Metabolic Pharmaceuticals Limited. ASX announcement: Phase 2b OPTIONS results do not support commercial viability for obesity indication. Australian Securities Exchange. February 21, 2007.
  12. [12] Orrick, Herrington & Sutcliffe LLP. FDA Announces Removal of 12 Peptides from Category 2 and Schedules PCAC Meetings. Regulatory client alert. April 2026.
  13. [13] Thevis M, Schänzer W. Analytical approaches for the detection of emerging therapeutics and non-approved drugs in human doping controls. J Pharm Biomed Anal. 2014;101:66-83. PMID:24906629
  14. [14] Schänzer W, Thevis M. Human sports drug testing by mass spectrometry. Mass Spectrom Rev. 2017;36(1):16-46. PMID:26213263
  15. [15] Halford JC. Obesity drugs in clinical development. Curr Opin Investig Drugs. 2006;7(4):312-318. PMID:16625817
  16. [16] Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2003;25(8):641-686. PMID:14685303
  17. [17] Therapeutic Goods Administration (Australia). Final scheduling decision: AOD-9604 inclusion in Schedule 4 (Prescription Only Medicine) under the Poisons Standard, effective June 1, 2015. March 2015.
  18. [18] World Anti-Doping Agency. Statement on Substance AOD-9604: classification under Prohibited List Category S2 (Peptide Hormones, Growth Factors, Related Substances, and Mimetics). Clarification to ASADA. April 22, 2013.

Scientific Journal Author

Frank M. Ng, PhD

Department of Biochemistry and Molecular Biology, Monash University (Clayton, Victoria, Australia)

Landmark Publications

  • Ng FM, Sun J, Sharma L, Libinaka R, Jiang WJ, Gianello R. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Horm Res. 2000;53(6):274-278. (PMID 11146367)
  • Heffernan M, Summers RJ, Thorburn A, Ogru E, Gianello R, Jiang WJ, Ng FM. 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. Endocrinology. 2001;142(12):5182-5189. (PMID 11713213)
  • Ng FM, Bornstein J. Hyperglycemic action of synthetic C-terminal fragments of human growth hormone. Am J Physiol. 1978;234(5):E521-E526. (PMID 646430)

Dr. Ng is independently cited here as the originating researcher of AOD-9604 at the Department of Biochemistry and Molecular Biology at Monash University. There is no affiliation or commercial relationship between Dr. Ng, Monash University, or the historical commercial sponsors of the AOD-9604 program (Metabolic Pharmaceuticals Limited, Calzada Limited, Phosphagenics Limited, Avecho Biotechnology Limited) and Peerless Peptides.

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