Inside the body with CJC-1295

The DAC form carries a C-terminal Lys modified with a maleimidopropionamide group that reacts with the free thiol of Cys34 on serum albumin in vivo. In rats, CJC-1295 immunoreactivity appeared on the albumin band within 15 minutes and remained beyond 24 hours, and the peptide was detectable in plasma beyond 72 hours; albumin conjugates made in the laboratory were more stable against dipeptidyl peptidase-IV in vitro (Jette 2005). FDA notes that the reactive group could in principle also bind cysteine thiols on other proteins, but no such off-target binding has been established in humans.[src][src]

Teichman et al. estimated a half-life of 5.8-8.1 days after single subcutaneous injections in healthy adults, consistent with albumin-bound circulation. The authors framed this against the short duration of action of GHRH itself, which limits its therapeutic use. This was measured in people; the albumin-binding mechanism itself was demonstrated in rats and ex vivo.[src]

GHRH binds the GHRH receptor, a class B G-protein-coupled receptor on pituitary somatotrophs that couples to Gs and raises cyclic AMP. The cryo-EM structure of GHRH-bound GHRHR with Gs (PDB 7CZ5) shows how the natural 1-29 region is recognised. CJC-1295 is a GHRH(1-29) analogue; as a laboratory-made albumin conjugate it stimulated GH secretion from cultured rat anterior pituitary cells, and it raised GH after subcutaneous injection in rats (Jette 2005). The structure shown is of the natural hormone, not of CJC-1295, so receptor contacts for CJC-1295 are inferred.[src][src]

In healthy men aged 20-40 studied one week after a single injection, the frequency and size of GH secretory pulses were unchanged, while basal (trough) GH rose 7.5-fold (P < 0.0001), mean GH rose 46% and IGF-I rose 45% (Ionescu and Frohman 2006). After single injections in the ascending-dose trials, mean plasma GH rose 2- to 10-fold for 6 days or more (Teichman 2006). These are human data from small studies in healthy volunteers.[src][src]

After a single injection, mean plasma IGF-I rose 1.5- to 3-fold for 9-11 days, and after multiple injections it stayed above baseline for up to 28 days, suggesting a cumulative effect (Teichman 2006). In the later study, the IGF-I rise did not correlate with any measured pulse parameter of GH secretion, and the authors suggested the raised trough GH may matter most (Ionescu and Frohman 2006). A serum proteomics study in 11 healthy young men found several protein changes one week after injection, which the authors proposed as possible markers of GH/IGF-1 action (Sackmann-Sala 2009). Whether these hormone changes give any clinical benefit has not been shown.[src][src][src]

In GHRH-knockout mice treated for 5 weeks from age 1 week, once-daily CJC-1295 gave normal body weight and length; treatment every 48 or 72 hours gave partial correction. Femur and tibia length were normal with 24- and 48-hour injection intervals. Total pituitary RNA and GH mRNA increased and immunohistochemistry indicated somatotroph proliferation (Alba 2006). This is animal-only evidence. FDA also notes that transgenic mice overexpressing GHRH develop pituitary hyperplasia and tumours and that no carcinogenicity studies of CJC-1295 DAC were found, so this risk in people cannot be excluded.[src][src]

FDA states it has identified serious adverse events associated with CJC-1295 including increased heart rate and systemic vasodilatory reaction. Adverse events in the healthy-volunteer trials included vasodilatory reactions, transient dizziness, hypotension and increased heart rate. FDA also describes anecdotal reports (not a peer-reviewed publication) that in the ConjuChem phase 2 trial in HIV lipodystrophy one participant had chest discomfort after a weekly injection, was diagnosed with acute myocardial infarction and died; the attending physician's most likely explanation was asymptomatic coronary artery disease with plaque rupture. The trial was terminated and unpublished, and a causal link to CJC-1295 has been neither shown nor excluded.[src][src]