CJC-1295

1. 01Bloodstream

   Sticking to a blood protein

   The long-lasting version of CJC-1295 has a small chemical hook on its tail. After it enters the blood, the hook grabs onto albumin, the most common protein in blood. This stops the body from clearing it away quickly.

   For experts

   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]

2. 02Bloodstream

   Staying in the blood for about a week

   Because it is attached to albumin, CJC-1295 stays around for days instead of minutes. In healthy adults its half-life was estimated at roughly six to eight days. Natural GHRH is cleared from the body much faster, which limits its use as a drug.

   For experts

   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]

3. 03Brain

   Switching on the GHRH receptor in the pituitary

   The pituitary is a pea-sized gland at the base of the brain. Its growth hormone cells have a receptor that the natural hormone GHRH fits. CJC-1295 is a modified copy of GHRH built to fit the same receptor and give the same signal.

   For experts

   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]

4. 04Brain

   More growth hormone, with its natural rhythm kept

   Growth hormone normally comes out in bursts. In healthy young men, CJC-1295 kept the bursts but raised the low points between them, so overall growth hormone went up.

   For experts

   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]

5. 05Liver

   A rise in IGF-1, a growth hormone messenger

   Growth hormone tells the body, especially the liver, to make another hormone called IGF-1. In healthy adults, IGF-1 stayed higher for more than a week after one injection.

   For experts

   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]

6. 06Bone

   Growth effects, shown in mice only

   In mice that cannot make their own GHRH and stay small, daily CJC-1295 brought body size and bone length up to normal. This is animal-only evidence. It does not show the same would happen in people.

   For experts

   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]

7. 07Heart

   Heart-rate and blood-vessel effects seen in safety reports

   In safety reports, FDA lists a faster heart rate and widening of blood vessels as serious side effects linked to CJC-1295. A 2006 trial in people with HIV was stopped, and unofficial reports say one participant died of a heart attack during it. The attending physician blamed existing heart disease, and the data were never published.

   For experts

   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]

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