CJC-1295 peptide: from a ConjuChem bench to two human trials

CJC-1295 in five numbers

• 30residues: GHRH(1-29) plus one lysine
• 4substitutions against enzymatic cleavage
• 5.8 to 8.1 dhalf-life in healthy adults
• 2 to 10×mean GH after one dose, for 6 days or more
• 1.5 to 3×IGF-1 after one dose, for 9 to 11 days

All five come from two papers, one in Endocrinology in 2005 and one in the Journal of Clinical Endocrinology and Metabolism in 2006 [Jetté et al., 2005] [Teichman et al., 2006]. The rest of the page is the story around them.

From a ConjuChem bench in Montreal

The starting material is the 1-29 fragment of human growth-hormone-releasing hormone, identified in 1982 as the shortest piece of the 44-residue hormone that retains full activity [Rivier et al., 1982]. Its problem as a drug was always duration: the fragment is cut by dipeptidyl peptidase IV within minutes. ConjuChem's approach, described by Jetté and colleagues in 2005, was to make the peptide hitch a ride on the most abundant and longest-lived protein in blood. Serum albumin has one free thiol, cysteine 34; a maleimide group placed on a peptide reacts with it spontaneously after injection.

The team synthesised three maleimido derivatives of a tetrasubstituted hGRF(1-29), conjugated each to human serum albumin, confirmed that the conjugates resisted dipeptidyl peptidase IV and still released GH from cultured rat pituitary cells, and injected them into rats. The best of the three, a version carrying an N-epsilon-3-maleimidopropionamide derivative of lysine at the C-terminus, produced four times the GH area under the curve of unmodified hGRF(1-29) over two hours, was still detectable in plasma beyond 72 hours, and appeared on Western blots riding on the albumin band from 15 minutes after injection. They named it CJC-1295 [Jetté et al., 2005].

The four substitutions (D-Ala2, Gln8, Ala15, Leu27) are the same ones that define the linker-free peptide sold as Mod GRF 1-29; their purpose and history are in Mod GRF 1-29. The linker is what "DAC" refers to, and its consequences are set out in DAC versus no DAC.

The first human trial: a week from one injection

Teichman and colleagues ran two randomized, placebo-controlled, double-blind, ascending-dose studies in healthy adults aged 21 to 61, at two sites, lasting 28 and 49 days. In the first, subjects received one of four ascending single subcutaneous doses or placebo; in the second, two or three doses a week or two weeks apart. After a single injection, mean plasma GH rose 2 to 10-fold depending on dose and stayed elevated for 6 days or more; mean IGF-1 rose 1.5 to 3-fold and stayed elevated for 9 to 11 days.

After multiple doses, IGF-1 remained above baseline for up to 28 days. The estimated half-life was 5.8 to 8.1 days. No serious adverse reactions were reported, and the authors concluded that the peptide was safe and relatively well tolerated, "particularly at doses of 30 or 60 µg/kg", with evidence of a cumulative effect after multiple doses [Teichman et al., 2006].

The second: does a week-long signal flatten the pulses?

The physiological worry about a GHRH analogue that never goes away was that it would turn the pulsatile GH pattern into a plateau. Ionescu and Frohman answered it with the most direct experiment possible: healthy men aged 20 to 40 had blood drawn every 20 minutes for 12 hours overnight, received one injection of 60 or 90 µg/kg, and repeated the sampling night one week later. The pulses came back unchanged in frequency and in magnitude.

What changed was the baseline between them, 7.5-fold higher (P < 0.0001), and that raised trough accounted for a 46 % increase in mean GH and a 45 % increase in IGF-1. The two doses gave the same response, and the IGF-1 increase did not correlate with any single GH parameter [Ionescu et al., 2006]. Serum from 11 healthy young men, examined by two-dimensional electrophoresis before and one week after a CJC-1295 injection, showed the protein fingerprint of a raised GH/IGF-1 axis: an apolipoprotein A1 isoform and a transthyretin isoform down, beta-hemoglobin and albumin fragments up [Sackmann-Sala et al., 2009].

What the mice added

One animal study belongs in the story because it tested the peptide where it would matter most: in mice with no GHRH gene at all. Alba and colleagues gave 1-week-old GHRH-knockout mice 2 µg of CJC-1295 every 24, 48 or 72 hours for 5 weeks. Daily dosing normalised body weight and length; every-48-hour and every-72-hour dosing improved them without full normalisation; femur and tibia length were normal with daily and 48-hour dosing; relative lean and subcutaneous fat mass were normal in all treated groups.

The pituitaries of treated animals contained more total RNA and more GH mRNA, and immunohistochemistry showed more somatotroph cells, which the authors read as proliferation [Alba et al., 2006]. A mouse clears the albumin conjugate faster than a person, so the interval that worked in mice is not a human interval; the finding that matters is that a GHRH analogue given once a day could replace the missing hormone entirely.

The phase 2 that stopped

ConjuChem's clinical target was the same one tesamorelin later succeeded with: the visceral fat that accumulates in HIV patients on antiretroviral therapy. Trial GH100-013 (NCT00267527) was registered in December 2005 as a multicentre, randomized, placebo-controlled, double-blind phase 2 study of 120 patients receiving low-dose CJC-1295, high-dose CJC-1295 or placebo for 12 weeks with 6 weeks of follow-up.

Its status on the registry is "terminated", with a completion date of September 2006 and no results posted [ConjuChem, 2005]. No later trial of CJC-1295 has been registered. The public record does not give the reason for the termination, and this site does not speculate. Tesamorelin, a different GHRH analogue, went on to a 412-patient trial and an approval; the contrast is drawn in CJC-1295 ipamorelin versus tesamorelin.

Afterlife under two names

A peptide that stops in phase 2 usually disappears. CJC-1295 did not, because its published human data were unusually clean and its synthesis is not difficult. It reappeared in the research-chemical market in two forms: the original albumin-binding molecule, sold as CJC-1295 DAC, and the linker-free intermediate, sold as CJC-1295 no DAC or Mod GRF 1-29, usually blended with ipamorelin. Neither is an approved drug.

The FDA's 2023 compounding decision placed ipamorelin acetate in category 2 and lists the CJC-1295 nomination among those later withdrawn [U.S., 2023]; the WADA Prohibited List names CJC-1295 among GHRH analogues in class S2 [World, 2026]. What the trials recorded by way of adverse events is on the CJC-1295 side effects page, and the doses used are in the dosage guide.

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