Summary
Two chemically distinct molecules circulate under one name. Both derive from human growth hormone-releasing hormone (GHRH, also called growth hormone-releasing factor, GRF) fragment 1-29, whose native sequence is the N-terminal 29 residues of mature somatoliberin 1. Both carry the same four substitutions relative to that sequence, D-alanine at position 2, glutamine at position 8, alanine at position 15 and leucine at position 27, with an amidated C-terminus 213. What separates them is a single appended group: CJC-1295 with DAC extends the peptide by a thirtieth C-terminal lysine whose side-chain nitrogen bears a 3-maleimidopropionamide group, the drug affinity complex, while the material described as CJC-1295 without DAC, or modified GRF(1-29), is the 29-residue tetrasubstituted peptide with no such group 452.
FDA treats the two as different active moieties and, with their acetate and trifluoroacetate salts, as five distinct bulk drug substances 2.
The chemistry of the drug affinity complex
The maleimide is the functional element. It reacts in vivo with the free thiol of cysteine-34 of serum albumin, forming a covalent bioconjugate rather than a reversible association 426. Two independent database records confirm the placement: the PubChem isomeric SMILES for CID 91971820 terminates in a lysine bearing a 3-(2,5-dioxopyrrol-1-yl)propanoylamino group, and the substance registry subunit record places the modification at residue 30 75. No disulfide bridge, glycosylation, pegylation or lipidation is described for either form in the sources retrieved 42.
The original characterisation established the mechanism experimentally. Three maleimido hGRF(1-29) derivatives conjugated ex vivo to human serum albumin showed enhanced in vitro stability against dipeptidyl peptidase-IV and released growth hormone from cultured rat pituitary cells; after a single subcutaneous administration in rats, the conjugate gave an approximately 4-fold increase in the growth hormone area under the curve over 2 hours compared with hGRF(1-29) and remained in plasma beyond 72 hours, with Western blotting showing immunoreactivity on the albumin band from 15 minutes and beyond 24 hours 4. FDA's summary of the same work adds that plasma growth hormone returned to baseline by 2 hours while drug remained detectable to 72 hours, and that the trifluoroacetate salt was used 2.
The choice of target for that chemistry is not incidental to this peptide family. Dipeptidyl peptidase IV cleaves GRF peptides including GRF(1-29)-NH2 at the 2-3 bond, and unmodified sermorelin, the plain amidated 1-29 fragment, was entirely degraded after four hours of incubation in human plasma at 37 °C 839. Albumin conjugation places the peptide on a carrier protein instead of leaving it free in plasma.
The pharmacokinetic consequence reported in the published human studies
Every published human pharmacokinetic figure for CJC-1295 belongs to the DAC form 10112. In healthy adults, a single subcutaneous administration produced dose-dependent increases in mean plasma growth hormone of 2- to 10-fold for six days or more, and in IGF-I of 1.5- to 3-fold for nine to eleven days, with an estimated half-life of 5.8 to 8.1 days 10. In the multiple-dose study the mean estimated half-life was 5.4 to 9.2 days and mean clearance 1.1 to 3.3 L/h, independent of body weight, with cumulative increases in maximum drug concentration and area under the curve on repeated administration 102.
A separate pharmacodynamic study examined whether continuous receptor stimulation abolished pulsatility. Overnight sampling one week after a single administration showed that growth hormone pulse frequency and magnitude were unaltered while trough growth hormone rose 7.5-fold, mean growth hormone rose 46% and IGF-I rose 44 to 45%, without exceeding the upper limit of normal in any subject; the IGF-I increases did not correlate with any growth hormone secretion parameter 112. A serum proteomic analysis of a subset of the same cohort found decreases in an apolipoprotein A1 isoform and a transthyretin isoform, and increases in beta-haemoglobin, a C-terminal albumin fragment and a mixed immunoglobulin and albumin fragment spot that varied linearly with IGF-I 12.
These are measurements of one conjugate in one programme, not a general property of albumin binding, and the programme ended. Adverse events in phase 1 were frequent: injection-site reactions in about 70% of single-administration recipients and in all multiple-administration recipients, transient urticarial rashes in almost 30%, and systemic vasodilatory reactions occurring only in treated subjects 102. In the phase 2 trial in HIV-associated visceral obesity, FDA reports that two hours after an eleventh weekly administration one subject developed chest discomfort with an electrocardiographically confirmed acute myocardial infarction and died about an hour later; the sponsor withdrew the DAC form from clinical trials in 2006 after that death, and the trial was terminated and never published 213.
The non-DAC tetrasubstituted GRF(1-29)
The non-DAC material is the whole of the tetrasubstituted GRF(1-29) amide with no further modification 23. It has been identified in an unknown pharmaceutical preparation as a 29-amino-acid peptide with a C-terminal amide function, and characterised in human plasma by immunoaffinity purification followed by liquid chromatography with high-resolution tandem mass spectrometry, with a monoisotopic mass of 3365.9 Da and the 5+ charge state at m/z 674 143.
Its pharmacology, however, is assigned by class alone. FDA states that neither the nominations it received nor its own literature search identified a study establishing whether CJC-1295 free base or CJC-1295 acetate is pharmacologically active, and no human or animal study of that form appears in the dossier 2. Without the maleimide there is no covalent albumin conjugation, so none of the pharmacokinetic findings above transfers to it 23.
Nomenclature confusion, and what it costs
FDA records at least nine names in use across the five CJC-1295-related substances and notes that the names of the DAC and non-DAC forms are routinely interchanged in the literature and in commerce, which it treats as a safety risk in itself 2. Four specific traps follow from that.
The identifiers do not separate cleanly. The only substance registry record, UNII 62RC32V9N7, is named simply CJC-1295 but its registered structure is the DAC molecule; FDA flags this as an error in the database, and no UNII exists for the non-DAC molecule 52. A certificate quoting that UNII for a non-DAC material is therefore internally inconsistent 52.
The CAS numbers are distinct but not reliably applied. The DAC free base carries 446262-90-4 and the non-DAC free base 446036-97-1, while a third number, 863288-34-0, appears on the PubChem record for the non-DAC peptide but is recorded by FDA as a deleted CAS number 57152.
PubChem's synonym lists mix the two. CID 56841945 has the 29-residue amide structure, but its synonym list mixes DAC and non-DAC names, and a stereochemistry-free record of the same connectivity, CID 91976842, carries both "CJC1295 Without DAC" and "CJC1295 With DAC" 1516.
The mass difference is the one unambiguous discriminator. The two free bases differ by about 279 g/mol, 3647.2 against 3367.9, which is the mass of the added maleimidopropionyl-lysine residue; the molecular formulae are C165H269N47O46 and C152H252N44O42 respectively 7152. Mass spectrometry therefore separates the two molecules where a name does not.
DAC form: rat and GHRH knockout mouse pharmacology, three phase 1 studies in healthy adults, and a phase 2 trial terminated in 2006 and never published 4101113. Non-DAC form: no human or animal study identified, and no study establishing pharmacological activity 2.
Open questions
Four points remain unresolved in the public record. No USP-NF, European Pharmacopoeia or Japanese Pharmacopoeia monograph, official reference standard or impurity specification exists for any CJC-1295-related substance, and FDA concluded that none of the five is well characterised 2. The substance registry's own property fields for UNII 62RC32V9N7, C155H258O42N44 and an estimated 3500 Da, disagree with both PubChem and FDA for the same molecule and appear to be wrong 572. For the DAC salts, FDA records no molecular weight, solubility, stability data or supplier at all, and notes the reported immunogenicity concern attached to the trifluoroacetate used in the original characterisation 24. And the published analytical work on the DAC form is limited: an LC-MS/MS confirmation method in equine plasma exploits the C-terminal maleimide precisely because it covalently binds plasma proteins, and a 2021 review covers detection methods for the synthetic GHRH analogues as a family 617.