The History of the Discovery of CJC-1295

CJC-1295 is often presented as a “new peptide,” although its history began almost half a century ago — with the search for a hypothalamic hormone that governs the production of growth hormone. The editorial team traced how the scientific discoveries of the 1980s, the pharmaceutical engineering of the 1990s–2000s and a failed clinical development shaped the substance that is discussed today on sports forums.

Background: the search for somatoliberin

Back in the 1960s endocrinologists assumed that the hypothalamus governs the secretion of growth hormone (GH) by means of two signals: a stimulating and an inhibiting one. The inhibiting signal — somatostatin — was identified in 1973 in the laboratory of Roger Guillemin. The stimulating factor, however, named somatoliberin, or growth hormone-releasing hormone (GHRH), long could not be isolated from hypothalamic tissue.

The problem lay in the minuscule concentration of the hormone: there is so little of it in the hypothalamus that classic purification methods did not yield a sufficient quantity to determine the amino acid sequence. The breakthrough came from an unexpected direction — from the clinic. Doctors described rare patients with acromegaly in whom the cause of the growth hormone excess was not a pituitary tumor but a tumor of the pancreas.

In 1982, independently of one another, two groups of researchers — Guillemin’s team and the group of J. Rivier and W. Vale together with M. Thorner — isolated from such tumors a peptide that powerfully stimulated GH secretion. The results were published by the journals Science and Nature. The tumors produced the hormone in quantities that were never present in the hypothalamus, and this finally made it possible to decipher its structure.

It turned out that human GHRH is a peptide of 44 amino acids. Soon another fundamental thing was clarified: for full biological activity the first 29 amino acids are sufficient. This shortened fragment, GHRH(1-29), became the basis for all subsequent analogs — from sermorelin to CJC-1295.

From the natural hormone to analogs

Natural GHRH has a serious pharmacological drawback: in the blood it lives only a few minutes. The enzyme dipeptidyl peptidase-4 (DPP-4) cleaves off the first two amino acids, after which the peptide loses its activity. In addition, the molecule is quickly destroyed by other proteases and renal clearance. For therapy this meant the need for frequent injections and an unpredictable effect.

The first drug based on GHRH was sermorelin — synthetic GHRH(1-29). In the US it was registered in the late 1990s for the diagnosis and treatment of GH deficiency in children. Sermorelin showed that the principle of stimulating one’s own pituitary works, but its short duration of action limited its clinical value. Later the manufacturer discontinued the drug, and today it has no valid FDA registration as a medicinal product.

In parallel, pharmacologists sought ways to make GHRH more stable. The main strategy was point substitutions of amino acids at the sites attacked by enzymes. Replacing L-alanine in the second position with D-alanine protected against DPP-4, while other substitutions reduced oxidation and breakdown. Thus appeared modified fragments that in the informal literature later received the name Mod GRF (1-29).

However, even the stabilized peptide was eliminated from the body within hours. A real change in duration of action required a fundamentally different approach — to tether the peptide to something that circulates in the blood for weeks. It was precisely this idea that was realized by the Canadian company ConjuChem.

DAC technology and the birth of CJC-1295

ConjuChem Biotechnologies of Montreal developed the Drug Affinity Complex (DAC) platform. Its essence is to attach to the peptide a chemically reactive linker which, after introduction into the body, covalently binds to the free thiol group of cysteine-34 of serum albumin. Albumin is the most abundant plasma protein, with a half-life of about three weeks, so the peptide effectively “rides” on it.

CJC-1295 is a modified GHRH(1-29) with four amino acid substitutions for resistance to enzymes and an additional lysine residue at the end of the molecule, to which a linker based on maleimidopropionic acid is attached. Thanks to this the peptide retained the ability to activate the GHRH receptor in the pituitary but circulated in the blood, bound to albumin, for much longer.

It is important to distinguish between two substances that on the informal market are often confused. “CJC-1295 with DAC” is the original ConjuChem molecule. “CJC-1295 without DAC” is effectively a modified GHRH(1-29) without the linker, that is, Mod GRF (1-29), with a short duration of action. The name of the second substance is a marketing phenomenon, not part of the official development history.

The DAC concept was not limited to a single peptide. ConjuChem applied a similar approach to other molecules as well, in particular to GLP-1 analogs for treating diabetes. The idea of prolonging the action of peptides through binding to albumin later became mainstream: other companies achieved this by other chemical means, for example with fatty acid chains in modern incretin drugs.

Clinical trials and their discontinuation

In 2006 the Journal of Clinical Endocrinology & Metabolism published two key articles. Teichman and colleagues described randomized placebo-controlled studies in healthy adults: a single subcutaneous injection of CJC-1295 dose-dependently increased the level of GH severalfold for six or more days, and the level of insulin-like growth factor-1 (IGF-1) — for a week and longer. The calculated half-life reached several days.

The second work, Ionescu and Frohman, answered an important physiological question: would constant stimulation of the receptor turn GH secretion into a level “background”? It turned out that the pulsatile character of secretion was preserved, and it was mainly the basal (inter-peak) secretion that increased. For endocrinologists this was an argument in favor of the GHRH analog acting “within the framework” of physiological regulation.

The next step was phase II studies, in particular in patients with HIV-associated lipodystrophy — a condition in which visceral fat accumulates. It was precisely in this niche that another GHRH analog — tesamorelin — later succeeded. However, in 2006, after the death of one of the participants in a CJC-1295 study, the company halted the trials. Public reports of the time stated that a connection between the event and the drug had not been established, but the program was never resumed.

Subsequently ConjuChem experienced financial difficulties and restructuring, and CJC-1295 never reached phase III. As a result, the drug has no registration from any major regulator — neither the FDA nor the EMA. The published data on it are limited to small early studies with a short observation period.

A second life outside medicine

Paradoxically, it was precisely after the halt of clinical development that CJC-1295 became known to the general public. From the late 2000s it began to be sold as a “research chemical” over the internet, and later it appeared in the offerings of so-called anti-aging clinics and sports communities. The name of the molecule, invented as an internal company code, turned into a gray-market trademark.

Sports regulators reacted fairly quickly. The World Anti-Doping Agency (WADA) classifies GHRH and its analogs in class S2 “Peptide hormones, growth factors, related substances and mimetics,” and CJC-1295 is directly mentioned in the Prohibited List as an example. The substance is banned for athletes at all times — both in-competition and out-of-competition.

In the US regulatory attention intensified in the 2020s: the FDA placed CJC-1295 on the list of substances for which there are significant safety concerns when used in pharmacy compounding. The reason is the lack of data on safety, immunogenicity and impurities. For the consumer this means that no one guarantees the quality and composition of products from unofficial sources.

The history of CJC-1295 well illustrates a general pattern: a molecule that has not completed the full clinical path does not become “safe” merely because it is easy to buy. The absence of registration means the absence of full data on long-term effects.

• Scientific value:CJC-1295 proved that prolonged stimulation of the GHRH receptor does not destroy the pulsatile secretion of GH.
• Technological value:the DAC platform became one of the early examples of prolonging the action of peptides through albumin.
• Clinical bottom line:the drug obtained no indications and no registration.
• Sports status:banned by WADA in class S2.

Editorial conclusions

CJC-1295 is the product of several successive stages of science: the discovery of GHRH in 1982, the understanding that the activity is concentrated in the first 29 amino acids, and attempts to prolong the peptide’s action through binding to albumin.

The early studies of 2006 showed a convincing pharmacological effect — a prolonged increase in GH and IGF-1 — but the clinical program stopped before data on long-term efficacy and safety were obtained.

The substance’s current popularity on the gray market is not backed by new clinical data: most of the arguments “in favor” rely on the same few publications from the mid-2000s.

To round out the picture, we recommend reading our articles “CJC-1295 and Cancer Risks: What Research Says,” “The History of the Discovery of Tesamorelin” and “Medical Use of CJC-1295: Official Indications.”

References

1. Guillemin R, Brazeau P, Böhlen P, et al. Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982;218(4572):585–587.
2. Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature. 1982;300(5889):276–278.
3. Teichman SL, Neale A, Lawrence B, et al. Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults. J Clin Endocrinol Metab. 2006;91(3):799–805.
4. Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. J Clin Endocrinol Metab. 2006;91(12):4792–4797.
5. World Anti-Doping Agency. The World Anti-Doping Code: International Standard. Prohibited List. Montreal: WADA; чинна редакція.
6. Melmed S, Auchus RJ, Goldfine AB, et al. (eds). Williams Textbook of Endocrinology. 14th ed. Elsevier; 2020.