CJC-1295 and Ipamorelin — two different ways to reach growth hormone

CJC-1295 and Ipamorelin are discussed together so consistently that the pairing can look like a single subject. It is not. The two peptides reach growth hormone through separate receptors, were characterised eight years apart by different groups for different reasons, and have been carried to very different stages of human study.

CJC-1295 is an analogue of growth hormone-releasing hormone. Jetté and colleagues identified it in 2005 as a tetrasubstituted form of human GRF(1-29) carrying an added N-epsilon-3-maleimidopropionamide derivative of lysine at the C terminus, and reported that hGRF(1-29)-albumin bioconjugates of this kind activate the GRF receptor on the anterior pituitary in rats (1).

Ipamorelin is a pentapeptide, Aib-His-D-2-Nal-D-Phe-Lys-NH2, described by Raun and colleagues in 1998. Profiling it against GHRP and GHRH antagonists placed its action at what those authors called a GHRP-like receptor rather than the GHRH receptor (2) — the target the later trial literature names when it describes ipamorelin as a ghrelin-receptor agonist (3).

Neither compound holds a marketing authorisation anywhere. Everything below describes what a published study measured in its own subjects — cultured cells, rats, swine or human volunteers — and none of it is a protocol for anyone to follow.

Growth hormone release from the anterior pituitary can be driven through two distinct receptors, and the distinction is the whole reason these two compounds are ever mentioned in the same sentence. One is the receptor for growth hormone-releasing hormone. The other is the receptor for the growth hormone secretagogues — the one activated by ghrelin and by the synthetic peptides built to imitate it.

The clearest evidence that these are separate routes arrived before either compound existed. Bowers and colleagues gave 18 normal men a synthetic hexapeptide secretagogue at 0.1, 0.3 and 1.0 µg/kg by intravenous bolus and compared it with GHRH-(1-44)-NH2 at 1.0 µg/kg. Mean peak serum GH was 1.2 ± 0.3 µg/L after placebo, and 7.6 ± 2.5, 16.5 ± 4.1 and 68.7 ± 15.5 µg/L across the three secretagogue doses (5).

The result that mattered was what happened when the two were given together: submaximal secretagogue doses plus GHRH stimulated GH release synergistically, which the authors read as evidence that the two act independently (5). Two inputs converging on one cell, rather than two ways of pressing the same switch.

That is a statement about pathway architecture, published in 1990, using GHRP-6 rather than ipamorelin and native GHRH rather than any analogue of it. It is why the literature pairs a GHRH analogue with a secretagogue at all. It is not a result about CJC-1295 and Ipamorelin, which that study predates by more than a decade, and no trial cited here tested the two of them together.

The most consequential thing to know about CJC-1295 is that two different materials circulate under the name. The difference is a drug affinity complex — DAC — and it changes how long the peptide lasts by roughly three orders of magnitude.

Jetté and colleagues built the compound around exactly that mechanism. Three maleimido derivatives of human GRF(1-29) were synthesised and bioconjugated to human serum albumin; the reactive group attaches to the free thiol on Cys34 of serum albumin, which the authors describe as a useful tool for extending plasma half-life. CJC-1295 was still present in plasma beyond 72 hours, and a Western blot of plasma from an injected rat found its immunoreactive species sitting on the serum albumin band, appearing after 15 minutes and still in circulation beyond 24 hours (1).

In healthy adults, Teichman and colleagues estimated the half-life of that conjugate at 5.8 to 8.1 days (4). Ionescu and Frohman, working with the same compound, put it more bluntly still: a GHRH analogue that binds permanently to endogenous albumin after injection, half-life 8 days (7).

For scale, consider what the design exists to outlast. Frohman and colleagues measured the half-life of GRH(1-44)-NH2 at 6.8 minutes after intravenous injection in normal subjects, and named the mechanism — a plasma dipeptidylaminopeptidase that cleaves the peptide to GRH(3-44)-NH2, a product with less than a thousandth of the parent's biological activity (8). Teichman and colleagues open their paper on the same premise: therapeutic use of GHRH is limited by its short duration of action (4).

Material described as CJC-1295 without DAC is the peptide without the linker that makes any of the above possible — in effect modified GRF(1-29), with nothing to bind it to albumin. Every published pharmacokinetic figure quoted for CJC-1295 belongs to the conjugate. No peer-reviewed pharmacokinetic study of a non-DAC preparation was located in preparing this post, so no half-life is published here for it.

Ipamorelin is described almost everywhere as selective. The claim is real, it comes from the characterisation paper, and it is narrower than the way it is usually repeated.

Raun and colleagues measured GH release across three systems. In primary rat pituitary cells, ipamorelin released GH with a potency and efficacy similar to GHRP-6 — EC50 1.3 ± 0.4 nmol/l and Emax 85 ± 5%, against 2.2 ± 0.3 nmol/l and 100% for GHRP-6. In pentobarbital-anaesthetised rats, its ED50 was 80 ± 42 nmol/kg against 115 ± 36 nmol/kg for GHRP-6. In conscious swine, ED50 was 2.3 ± 0.03 nmol/kg with an Emax of 65 ± 0.2 ng GH/ml plasma, close to GHRP-6 at 3.9 ± 1.4 nmol/kg and 74 ± 7 ng/ml; GHRP-2 was more potent but less efficacious, at 0.6 nmol/kg and 56 ± 6 ng/ml (2).

The selectivity work itself was done in swine, and this is the part most often reported loosely. None of the secretagogues tested — ipamorelin, GHRP-6 or GHRP-2 — changed plasma FSH, LH, prolactin or TSH. What separated them was the adrenal axis: GHRP-6 and GHRP-2 both raised ACTH and cortisol, while ipamorelin did not, at levels the authors found no different from those following GHRH stimulation, and still not at doses more than 200-fold above its own ED50 for GH release (2).

So prolactin is not what that swine study discriminated on; ACTH and cortisol are. Prolactin does appear in the human record, but from a different paper: among Bowers and colleagues' 18 men, serum prolactin and cortisol rose about two-fold above basal, and only at the highest hexapeptide dose of 1.0 µg/kg (5). Two studies, two species, two different secretagogues — and no human measurement of ipamorelin against this endpoint in either of them.

Both compounds have human data. Neither has a completed development programme, and the two records stop at different points and for different reasons.

For CJC-1295, the published human work is two studies from 2006. Teichman and colleagues ran two randomised, placebo-controlled, double-blind ascending-dose trials, of 28 and 49 days, at two investigational sites, in healthy subjects aged 21 to 61. After a single injection, mean plasma GH rose 2- to 10-fold for six days or more and mean plasma IGF-I rose 1.5- to 3-fold for nine to eleven days; after multiple doses, mean IGF-I stayed above baseline for up to 28 days. The estimated half-life was 5.8 to 8.1 days, and no serious adverse reactions were reported (4).

Ionescu and Frohman then asked a narrower question — whether continuous stimulation flattens the natural pulse. Sampling blood every 20 minutes across a 12-hour overnight period in healthy men aged 20 to 40, before and one week after a single 60 or 90 µg/kg injection, they found pulse frequency and magnitude unaltered while trough GH rose 7.5-fold (P < 0.0001), mean GH by 46% (P < 0.01) and IGF-I by 45% (P < 0.001) (7). These are trial design details, reported because the results cannot be read without them.

For ipamorelin, the human record begins with pharmacokinetics. Gobburu and colleagues studied five 15-minute infusion rates, from 4.21 to 140.45 nmol/kg, with eight healthy male subjects at each dose level, and reported dose-proportional kinetics, a terminal half-life of two hours, clearance of 0.078 L/h/kg and a single episode of GH release peaking at 0.67 hours before declining to negligible concentrations at every dose (6).

It was then taken into an indication that has nothing to do with growth. Helsinn Therapeutics developed ipamorelin for postoperative ileus, on the reasoning that ghrelin-receptor stimulation has promotility effects in the gastrointestinal tract. The phase 2 proof-of-concept trial, registered as NCT00672074 and run from April 2008 to December 2009, enrolled 117 patients undergoing small and large bowel resection, of whom 114 formed the safety and modified intent-to-treat populations, and gave 0.03 mg/kg intravenously twice daily from postoperative day 1 to day 7 or hospital discharge. Median time to first tolerated solid meal was 25.3 hours on ipamorelin against 32.6 hours on placebo, a difference that did not reach significance at p = 0.15. The authors concluded that the regimen was well tolerated and that there were no significant differences between ipamorelin and placebo in the key and secondary efficacy analyses (3).

That is the sum of it. For CJC-1295, two 2006 studies of GH and IGF-I in healthy volunteers. For ipamorelin, a 1999 pharmacokinetic study and one phase 2 trial in a gut indication whose key endpoint was not met. Reporting both plainly is more informative than any account of the mechanism.