TH9507: The Stabilized GHRH Analog in the Research Literature

Research-use-only context. This article summarizes published third-party scientific literature and laboratory practice. It is not medical advice, not a therapeutic or performance claim, and not a usage guide. US Prime Peptides products are supplied strictly for in vitro laboratory research and are not for human or veterinary use.

This article explains what TH9507 is chemically, why a single acyl group on its first residue changes how long it survives in plasma, what the receptor, animal and human-volunteer literature reports about growth hormone secretion in response to it, and how its approval by the FDA as Egrifta relates to a research vial of the same sequence.

TH9507 is full-length GHRH with an N-terminal hexenoyl cap

TH9507 is the complete 44-residue human growth hormone-releasing hormone, GHRH(1-44)-NH2, with a trans-3-hexenoyl group attached to the alpha-amine of tyrosine 1. Nothing else in the sequence is changed. The development code was TH9507, the formula is C221H366N72O67S, and the molecular weight is about 5,135.9 Da, which is 96 Da heavier than unmodified GHRH(1-44)-NH2 (about 5,039.7 Da); that 96 Da difference is the hexenoyl group and is the single most useful number on an identity check.

Ferdinandi and colleagues described the design logic in a 2007 Basic and Clinical Pharmacology and Toxicology paper: the analog was "minimally modified" so that it would resist dipeptidyl aminopeptidase IV, and in vitro the modification slowed degradation in rat, dog and human plasma relative to native hGRF(1-44)-NH2. The same paper reports that plasma growth hormone and IGF-1 rose in pigs, rats and dogs after repeated exposure, that the apparent elimination half-life in dogs was 21 to 45 minutes, and that findings in dogs after prolonged exposure were attributed to sustained supraphysiological growth hormone and IGF-1 rather than to the peptide itself.

The fragment and substitution strategies are covered in the sermorelin overview and the CJC-1295 overview; TH9507 is the one member of the family that keeps the entire native sequence.

Why an acyl cap defeats DPP-IV

Native GHRH is inactivated in plasma by dipeptidyl peptidase IV, which removes the first two residues, and an acyl group on the N-terminal amine stops that reaction. Frohman, Downs, Heimer and Felix showed in a 1989 Journal of Clinical Investigation paper that GHRH(1-44)-NH2 and its shorter fragments were all cleaved rapidly at the Ala2-Asp3 bond, that the reaction was blocked by the DPP-IV inhibitor diprotin A, and that the product GHRH(3-44)-NH2 was the main circulating form in a transgenic pig expressing the human hormone. Because the cryo-EM structure of the receptor shows the peptide's N-terminus in direct contact with the binding site, the clipped product is inactive.

DPP-IV requires a free, protonated N-terminal amine to position its substrate. Bongers and colleagues demonstrated the point in a 1992 Biochimica et Biophysica Acta paper on the enzyme's kinetics: analogs in which the N-terminal amine was removed (desamino-Tyr1) or methylated (N-methyl-Tyr1) were not cleaved at all, while the unmodified fragments were processed at about 5 micromoles per minute per milligram of enzyme. The trans-3-hexenoyl amide on TH9507 is the same principle applied with a six-carbon unsaturated acyl chain, chosen to keep the modification small enough not to disturb receptor contact.

What the cap does not do is make the peptide chemically inert. Campbell and colleagues, in a 1994 Peptides paper on the native 44-residue sequence, documented isomerization of asparagine 8 through an aminosuccinimide intermediate and oxidation of methionine 27 to the sulfoxide in aqueous solution. TH9507 retains both residues, so both reactions remain available once the powder is dissolved. Memdouh and colleagues, in a 2021 Drug Testing and Analysis paper, mapped the in vitro metabolites of TH9507 alongside sermorelin and CJC-1295, synthesizing nineteen of them as reference standards for a liquid chromatography-tandem mass spectrometry assay.

Receptor and secretion physiology in the cited models

TH9507 acts at the same receptor as the native hormone: the GHRH receptor, a class B G-protein-coupled receptor that Mayo cloned from rat pituitary in a 1992 Molecular Endocrinology paper and showed to be expressed predominantly in the anterior pituitary, where it couples to cAMP production. Zhou and colleagues resolved the human receptor bound to GHRH and the stimulatory G protein at 2.6 angstroms in a 2020 Nature Communications paper, finding that the peptide's alpha-helix contacts all three extracellular loops and every transmembrane helix except TM4, with the N-terminus engaging a broad set of specific interactions.

In animals, Ferdinandi's 2007 paper reported rises in circulating growth hormone and IGF-1 in pigs, rats and dogs. Jansen and colleagues, in a 2004 International Journal of Pharmaceutics paper, compared routes in beagle dogs and reported a terminal half-life of 39 minutes after intratracheal dry-powder delivery, with an absolute bioavailability of about 13 percent by that route.

In human volunteers, the clearest secretion-physiology data come from Stanley and colleagues' 2011 Journal of Clinical Endocrinology and Metabolism study of thirteen healthy men sampled overnight at frequent intervals before and after two weeks of exposure. Mean overnight growth hormone, pulse peak area and basal secretion all increased, and IGF-1 rose; the pulsatile pattern was augmented rather than replaced. Gonzalez-Sales and colleagues built population models from 38 and 41 phase I participants in two 2015 papers, in Clinical Pharmacokinetics and the Journal of Pharmacokinetics and Pharmacodynamics. TH9507's disposition fit a one-compartment model with a clearance of about 1,060 liters per hour and a volume of distribution of about 200 liters, and growth hormone was best described as released in a finite "episode" after each exposure, a model then used to predict the IGF-1 time course.

Development and approval: from TH9507 to Egrifta

TH9507 was developed by Theratechnologies of Montreal and is approved by the FDA as Egrifta. Tomlinson's 2006 Current Opinion in Investigational Drugs evaluation records the breadth of the original program, with phase III studies in HIV-associated lipodystrophy and phase II studies in several other conditions, and notes the licensing relationship with Valeant at the time. Grunfeld, Dritselis and Kirkpatrick summarized the outcome in a 2011 Nature Reviews Drug Discovery note: in November 2010, TH9507 (Egrifta; Theratechnologies/EMD Serono) was approved by the FDA for a single specified indication in adults with HIV-associated lipodystrophy. Later presentations of the drug have been marketed under the same brand.

A research vial labeled TH9507 is not Egrifta. It is not the approved finished product, it has not been manufactured or released under the approved application, and its certificate of analysis speaks only to the identity, purity and contaminant profile of the powder. The only published evidence about TH9507 in humans comes from the approved product's development program, and none of it transfers to a research-grade chemical. TH9507, like all GHRH analogs, is also listed under section S2 of the World Anti-Doping Agency Prohibited List, which is why the anti-doping detection work cited above exists.

What a certificate should show for TH9507

Identity by mass spectrometry is the line that distinguishes TH9507 from plain GHRH(1-44), and the certificate should state the observed mass against an expected value near 5,136 Da. On an electrospray instrument a 44-residue peptide with this many basic residues appears as a ladder of charge states, typically 4+ through 7+, and the deconvoluted mass should land within a few tenths of a dalton of the theoretical value; a result 96 Da light indicates the uncapped hormone, not the analog. The charge-state reasoning is explained in LC-MS identity confirmation.

Purity by HPLC should be reported as area percent with the chromatogram attached, and two known degradation products are worth looking for on it: the methionine 27 sulfoxide, 16 Da heavier and usually eluting slightly earlier, and the asparagine 8 isomer, which is isobaric within 1 Da and shows up as a shoulder rather than a separate mass. Net peptide content matters more for a 44-residue peptide than for a short one, because counter-ions and bound water make up a larger share of the lyophilized mass. Endotoxin by LAL, sterility and ICP-MS metals complete the panel. US Prime Peptides posts the lot-matched third-party certificate for TH9507 10 mg and TH9507 20 mg on each product page. For the two-component TH9507 / Ipamorelin 10 mg / 5 mg vial, the certificate must identify and quantify both peptides separately, a requirement explained in reading a blend certificate.

Frequently Asked Questions

What is TH9507?

TH9507 is the full 44-residue human growth hormone-releasing hormone with a trans-3-hexenoyl group on its N-terminal tyrosine. The cap makes it resistant to dipeptidyl peptidase IV, the plasma enzyme that inactivates native GHRH, and adds 96 Da to the molecular weight.

Is TH9507 approved by the FDA?

Yes. TH9507 is approved by the FDA as Egrifta, first approved in November 2010 for a specified indication in adults with HIV-associated lipodystrophy. A research vial of TH9507 is not Egrifta and is supplied only for laboratory use.

How is TH9507 different from sermorelin?

Sermorelin is the first 29 residues of GHRH with no other modification, while TH9507 keeps all 44 residues and adds an N-terminal acyl cap. Both act at the GHRH receptor, but unmodified sermorelin is cleaved by DPP-IV within minutes in plasma, whereas the cap on TH9507 blocks that cleavage.

What does the research literature on TH9507 actually measure?

The published work covers plasma stability and animal pharmacology (Ferdinandi 2007, Jansen 2004), growth hormone pulsatility in healthy volunteers (Stanley 2011), population pharmacokinetic models (Gonzalez-Sales 2015), the approval history (Grunfeld 2011) and anti-doping detection methods (Memdouh 2021). All human data come from the approved drug's development program, not from research-grade material.

Citations

1. Frohman LA, Downs TR, Heimer EP, Felix AM. Dipeptidylpeptidase IV and trypsin-like enzymatic degradation of human growth hormone-releasing hormone in plasma. J Clin Invest. 1989;83:1533-1540. PMID 2565342
2. Bongers J, Lambros T, Ahmad M, Heimer EP. Kinetics of dipeptidyl peptidase IV proteolysis of growth hormone-releasing factor and analogs. Biochim Biophys Acta. 1992;1122:147-153. PMID 1353684
3. Mayo KE. Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone. Mol Endocrinol. 1992;6:1734-1744. PMID 1333056
4. Campbell RM, Stricker P, Miller R, et al. Enhanced stability and potency of novel growth hormone-releasing factor (GRF) analogues derived from rodent and human GRF sequences. Peptides. 1994;15:489-495. PMID 7937325
5. Jansen M, Darby I, Abribat T, et al. Pulmonary delivery of TH9507, a growth hormone releasing factor analogue, in the dog. Int J Pharm. 2004;276:75-81. PMID 15113616
6. Tomlinson B. Drug evaluation: TH9507, a synthetic human growth hormone releasing factor. Curr Opin Investig Drugs. 2006;7:936-945. PMID 17086939
7. Ferdinandi ES, Brazeau P, High K, et al. Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue. Basic Clin Pharmacol Toxicol. 2007;100:49-58. PMID 17214611
8. Grunfeld C, Dritselis A, Kirkpatrick P. TH9507. Nat Rev Drug Discov. 2011;10:95-96. PMID 21283099
9. Stanley TL, Chen CY, Branch KL, et al. Effects of a growth hormone-releasing hormone analog on endogenous GH pulsatility and insulin sensitivity in healthy men. J Clin Endocrinol Metab. 2011;96:150-158. PMID 20943777
10. Gonzalez-Sales M, Barriere O, Tremblay PO, et al. Population pharmacokinetic analysis of TH9507 in HIV-infected patients and healthy subjects. Clin Pharmacokinet. 2015;54:285-294. PMID 25358450
11. Gonzalez-Sales M, Barriere O, Tremblay PO, et al. Population pharmacokinetic and pharmacodynamic analysis of TH9507 in HIV-infected patients and healthy subjects. J Pharmacokinet Pharmacodyn. 2015;42:287-299. PMID 25895899
12. Zhou F, Zhang H, Cong Z, et al. Structural basis for activation of the growth hormone-releasing hormone receptor. Nat Commun. 2020;11:5205. PMID 33060564
13. Memdouh S, Gavrilovic I, Ng K, et al. Advances in the detection of growth hormone releasing hormone synthetic analogs. Drug Test Anal. 2021;13:1871-1887. PMID 34665524

This article is for laboratory research reference only. US Prime Peptides products are supplied strictly for in vitro research. Not for human consumption.

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