CJC-1295 with DAC — long-acting GHRH analog with a Drug Affinity Complex

CJC-1295 with DAC is a growth hormone-releasing hormone (GHRH) analog built on the GRF(1-29) scaffold and extended with a Drug Affinity Complex (DAC): a chemical "anchor," developed by the Canadian company ConjuChem, that covalently attaches to the free thiol group of blood albumin and stretches the molecule's duration of action from minutes to days. It is precisely the presence of DAC that distinguishes this compound from "CJC-1295 without DAC" (also known as Mod GRF 1-29, a stabilized but still short-lived variant of the same scaffold) and makes it the subject of a separate body of research literature, including two published studies in humans. This page neutrally reports what the published work measured; it does not recommend use.

A note on format. Below is an extended reference overview of the published preclinical and clinical data on the structure, mechanism, pharmacokinetics, and study outcomes of this compound, with specific figures from the primary sources where they are reported. CJC-1295 with DAC is a compound for research use only (RUO); it has no approved indication for use in humans in any jurisdiction. This page contains no doses, protocols, or guidance on administration to humans. Dosing regimens are covered in a separate document (a general dosage table; general reference at /docs/peptide-dosage-chart).

Overview: where CJC-1295 with DAC fits in the growth hormone axis

Growth hormone (GH) secretion is governed by two opposing hypothalamic signals: GHRH-producing neurons stimulate somatotrophs in the anterior pituitary, while somatostatin-producing neurons inhibit them via the SSTR2/SSTR5 receptors; layered on top of this, the stomach's ghrelin system amplifies the size of each pulse through a separate receptor on the same cells. The result is not a constant output but a pulsatile secretion profile: brief, high-amplitude peaks against periods when GH is nearly undetectable in blood; the liver "integrates" this profile into a comparatively stable IGF-1 level ^[1]. GHRH acts through its own receptor, GHRHR, a class B (secretin-like) receptor coupled to the Gs protein, adenylate cyclase, cAMP, and PKA; it has been cloned and characterized as pituitary-specific ^[2]. CJC-1295 with DAC is an engineered analog designed not to replace the entire axis but to intervene at one specific node in it: to exert long, steady pressure on GHRHR specifically, without acting directly on the somatostatin or ghrelin branches of regulation.

This axis has its own negative-feedback loops: both GH and IGF-1 suppress further secretion: GH mainly by stimulating hypothalamic somatostatin (the short loop), IGF-1 directly at the pituitary and hypothalamus (the long loop). In other words, the effect of any single GHRH analog, including CJC-1295 with DAC, is capped from above by the system's own physiological brakes, not only by the substance's dose, worth keeping in mind when reading the specific figures below.

Mechanism of action

Historically, the problem of GHRH analogs' short lifespan has been addressed along two independent paths: protecting the peptide from degradation, and/or tethering it to something large and long-lived in the blood. CJC-1295 with DAC combines both approaches in sequence: first stabilizing the scaffold, then adding DAC.

Why native GHRH "lives" for minutes

Native GHRH(1-44) and its active N-terminal fragment GRF(1-29) (the same backbone used in sermorelin) degrade very rapidly in plasma. The main inactivation pathway is the enzyme dipeptidyl peptidase IV (DPP-IV), which cleaves the N-terminal Tyr1-Ala2 dipeptide, converting the active molecule into a truncated, essentially inactive GRH(3-44)-NH2 fragment; under experimental conditions this reaction is blocked by the competitive DPP-IV inhibitor diprotin A. A second, less significant pathway is trypsin-like cleavage around the 11-12 amino-acid residue ^[3]. Because of these two pathways, the native peptide's half-life is measured in minutes: in practice, maintaining a stably raised GH level with unmodified GHRH would require injecting it several times a day. Any long-acting GHRH analog, including CJC-1295, has to solve this degradation problem before duration of action even becomes relevant.

Two engineering changes: a stabilized scaffold plus DAC

CJC-1295 is built in two independent steps. First, the GRF(1-29) scaffold receives four amino acid substitutions: D-Ala at position 2, Gln at position 8, Ala at position 15, and Leu at position 27. D-Ala2 makes the molecule unrecognizable to DPP-IV (the enzyme recognizes only the L-configuration at this position), Gln8 removes a site prone to deamidation (replacing the unstable Asn), and the substitutions at positions 15 and 27 further reduce sensitivity to oxidation and non-enzymatic breakdown. Together, these four substitutions produce what is known as "CJC-1295 without DAC" (Mod GRF 1-29), a molecule already substantially more stable than the native peptide, but still short-lived (tens of minutes, not days), which is why the literature treats it as a separate compound.

The second step (the one that gives the compound its "with DAC" name) is the attachment, to the C-terminal lysine, of a maleimide derivative (the Drug Affinity Complex) capable of reacting covalently and selectively with the single free thiol group on the Cys34 residue of serum albumin. This technology (DAC/PC-DAC) belongs to ConjuChem and has been applied beyond GHRH analogs: the same chemistry underlies experimental conjugates of exenatide (PC-DAC:Exendin-4, also known as CJC-1134-PC) and insulin (PC-Insulin), meaning it is better understood as a platform technology for extending peptide duration of action than as a solution specific to the growth hormone axis ^[11]. By attaching to albumin, a protein with a very slow clearance of its own that recycles via the neonatal Fc receptor, the peptide effectively "rides along" on a carrier, escapes renal filtration through the increase in effective molecular size, and becomes less accessible to plasma proteases.

In the preclinical study that first identified and characterized this compound, three candidate maleimide derivatives of hGRF(1-29) were tested head-to-head in Sprague Dawley rats; CJC-1295 was selected as the lead candidate. Subcutaneous injection produced a 4-fold increase in the GH area under the curve over the first 2 hours compared with unconjugated hGRF(1-29) in the same study, and the immunoreactive conjugate was detectable in plasma as early as roughly 15 minutes post-injection, remained in circulation for more than 24 hours, and the compound itself was still measurable in plasma at 72 hours, orders of magnitude longer than the minutes-long "life" of the parent peptide ^[4].

Study data: what is preclinical and what is in humans

From here on it is worth distinguishing two levels of evidence: preclinical data in animals (a model system, controlled conditions, hormonal response as a surrogate endpoint) and early clinical data in humans (pharmacokinetics and pharmacodynamics, not clinical efficacy for any indication).

Preclinical data (rodents)

The primary characterization of CJC-1295 as a long-acting GRF analog was carried out in Sprague Dawley rats: subcutaneous injection was accompanied by covalent binding to albumin in vivo, activation of the anterior pituitary GRF receptor (confirmed in cultured pituitary cells), and a sustained rise in GH and IGF-1. In direct comparison with unconjugated hGRF(1-29), the conjugate produced a 4-fold larger GH area under the curve over the first 2 hours after administration, and the molecule itself remained detectable in plasma for more than 72 hours ^[4]. This is a preclinical level of evidence: an animal model and a hormonal response, not clinical endpoints; extrapolation to humans is complicated by cross-species differences in albumin kinetics, DPP-IV activity, and pituitary sensitivity, so these data should be read as a rationale for further studies in humans rather than as standalone proof of effect in people.

Data in humans (early phase 1/2)

Most importantly, real data on CJC-1295 with DAC in humans exist and have been published in a peer-reviewed journal. Teichman et al. (2006) conducted two randomized, double-blind, placebo-controlled dose-escalation studies lasting 28 and 49 days in healthy adults aged 21–61. The first used four ascending single subcutaneous doses (1 to 30 μg/kg); the second used two to three weekly or every-other-week doses of 30 or 60 μg/kg. Single administration raised mean GH concentrations dose-dependently by 2- to 10-fold for 6 days or longer, and IGF-1 levels rose 1.5- to 3-fold and remained high for 9–11 days; with repeated weekly or biweekly dosing, the raised IGF-1 level was sustained for up to 28 days. The estimated terminal half-life was 5.8–8.1 days. No serious adverse events were recorded; the compound was well tolerated, with transient injection-site reactions ^[5]. An important caveat: these are early phase 1/2 pharmacokinetic-pharmacodynamic data that confirm the mechanism and duration of action in humans at the level of hormonal markers. They are not a study of clinical efficacy for any indication (body composition, strength, sleep, and so on), and no such studies of the with-DAC version exist in the open literature.

Pulsatility is preserved

A separate study by the same group addressed the shape of secretion, not just its average level. Ionescu and Frohman (2006) gave healthy men aged 20–40 a single subcutaneous dose of 60 or 90 μg/kg and compared the nocturnal (12-hour) GH profile, sampled at 20-minute intervals, before and one week after injection. The frequency and amplitude of GH secretory peaks remained essentially unchanged. The axis's rhythm did not "smooth out" into a constant plateau. What changed the most instead was the basal, inter-peak GH level, which rose 7.5-fold (p<0.0001); the mean 24-hour integrated GH level rose by 46% (p<0.01), and IGF-1 by 45% (p<0.001); no statistically significant difference was found between the 60 and 90 μg/kg doses, suggesting a plateau effect within this range. Interestingly, the rise in IGF-1 did not correlate with any single parameter of pulsatile GH secretion. The authors suggested that it is the raised "floor" between peaks, rather than the height of the peaks themselves, that is the key driver of hepatic IGF-1 increase ^[6].

This phenomenon (preserved pulsatility despite sustained stimulation) has a longer history than CJC-1295 itself. As early as 1985, Vance et al. showed in six healthy men that even a continuous 24-hour intravenous infusion of native GRF(1-40) (2 ng/kg/min) does not "erase" the pulsatile GH profile: total secretion during the infusion was higher than on placebo (1576 vs. 634 μg, p=0.042), but the pulses still came in discrete waves, because GH pulses are governed not by the pulsatility of GHRH itself but by periodic waning of somatostatin's inhibitory tone ^[6]. The same protocol also uncovered a cautionary nuance: a supramaximal intravenous GRF bolus at the end of the infusion produced a weaker response than the same bolus given after placebo, an early hint of partial somatotroph desensitization. Later 14-day continuous GHRH infusions in healthy people and in a child with GH deficiency found no significant desensitization or depletion of hormone stores. The Ionescu and Frohman result for CJC-1295 ^[6] extends the same pattern (preserved pulsatility without obvious desensitization) to a compound with a fundamentally different exposure profile: not one driven by an infusion pump, but a sustained, multi-day exposure that cannot be "switched off" as quickly as an intravenous line.

Why CJC-1295 is studied alongside secretagogues

GHRH analogs such as CJC-1295 act on the GHRH receptor (GHRHR), a class B receptor coupled to the Gs protein, which raises intracellular cAMP and activates PKA ^[2]. A different class of GH stimulators, the ghrelin secretagogues (GHRP-6, GHRP-2, hexarelin, ipamorelin), acts on an entirely different receptor, GHS-R1a: a class A (rhodopsin-like) receptor coupled predominantly to the Gq protein and the phospholipase C/IP3/PKC/Ca²⁺ cascade. This receptor was identified and cloned as a distinct target in the pituitary and hypothalamus ^[7], and its endogenous ligand, ghrelin, an n-octanoylated 28-amino-acid stomach peptide, was discovered as a substance that releases growth hormone while also governing appetite and energy balance ^[8].

Because the two classes act through different receptors on the same somatotroph cell and trigger different intracellular cascades ("two different keys to two different locks"), preclinical and clinical work on combined administration of a GHRH analog and a secretagogue consistently records not an additive but a supra-additive (synergistic) GH release, larger than the arithmetic sum of each class's effects alone. This is a general physiological pattern of the axis, not a property specific to CJC-1295. It was reproduced for other GHRH-analog + GHS pairs long before long-acting analogs existed; the practical consequence for the literature is that CJC-1295 is almost always discussed alongside a member of the ghrelin class, not as a replacement for it. At the same time, the distinction is worth keeping in mind: ghrelin-class secretagogues, by acting on the same receptor as the endogenous orexigenic hormone, can additionally affect appetite, cortisol, and prolactin: effects that GHRH analogs relatively selective for the GH/IGF-1 axis, such as CJC-1295, have practically none of.

Pharmacokinetics and handling (research context)

The key pharmacokinetic feature of CJC-1295 with DAC is an estimated terminal half-life of 5.8–8.1 days in humans ^[5], orders of magnitude longer than that of native GHRH, and two orders of magnitude longer than tesamorelin, the only GHRH analog to reach approval, via a different chemical strategy (steric rather than albumin-based stabilization), which keeps a half-life on the order of tens of minutes ^[9][10]. This extension is achieved not by slowing the metabolism of the peptide itself but because, once covalently attached to albumin Cys34, the molecule's kinetics are effectively dictated by the kinetics of albumin, a protein that itself circulates for weeks thanks to recycling via the neonatal Fc receptor and is not filtered by the kidneys owing to its large size. The linkage is described as "reversible covalent": chemically strong within the pharmacologically relevant time window, but not absolutely irreversible on a longer timescale, which is what produces gradual release of free peptide rather than an abrupt loss of effect.

It is supplied as a lyophilized powder; physicochemically it is a standard peptide that, for analytical work, is reconstituted in a suitable solvent and stored cold, with the lyophilized form more stable than the reconstituted solution, a general property of practically all peptides in this class, including tesamorelin, for which the manufacturer separately developed formulations with a longer stability window for the reconstituted solution. What is stated here concerns solely the physicochemical properties of the substance under laboratory conditions and is not guidance on preparation, dosing, or administration to any person.

Research status and disclaimers

CJC-1295 was developed by the Canadian company ConjuChem Biotechnologies, which conducted the phase 1/2 studies described above and planned further development of the compound for GH deficiency, HIV-associated wasting, and visceral obesity. The clinical program was not carried through to approval: the company ran into financial difficulty and filed for bankruptcy in 2010, after which no one resumed development of CJC-1295 with DAC. By comparison, a different chemical strategy for extending GHRH's action, tesamorelin, went through a full phase 3 cycle over the same period (first 412 patients, then a pooled analysis of 806 patients with HIV-associated lipodystrophy) and received FDA approval in 2010 for reducing excess visceral fat ^[9][10], showing that regulatory approval of a long-acting GHRH analog is achievable in general, but that this path was not completed for the DAC variant specifically.

The regulatory status of CJC-1295 with DAC in humans is negative by default at present: the compound has no approved indication for human use in any jurisdiction. In the United States, CJC-1295 was also considered under a separate FDA process concerning "bulk" substances for pharmacy compounding (the bulks list under sections 503A/503B): as of 2023 the substance was placed in Category 2 of that list, the category of substances with significant potential safety risks whose compounding is temporarily not permitted. Materials from the public discussion of this nomination mentioned nonclinical toxicology signals and an unresolved question about cardiac safety, tied precisely to the fact that the clinical program of the 2000s was cut short. The nominator subsequently withdrew the application for CJC-1295's inclusion on the final list (September 2024), so as of the date of this review the substance appears on the official FDA list as "nominated but withdrawn", meaning it is not an approved substance for pharmacy compounding under this status either.

Therefore, despite compelling early pharmacokinetic data in humans ^[5][6], CJC-1295 with DAC remains a tool for studying the GHRH/GH/IGF-1 axis, not a therapy. Everything on this page is a neutral summary of published work and publicly available regulatory materials; it is not medical advice, a treatment recommendation, or an instruction for use in humans.

References

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2. Mayo KE. Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone. Molecular Endocrinology (1992). doi:10.1210/mend.6.10.1333056
3. Frohman LA, Downs TR, Heimer EP, Felix AM. Dipeptidylpeptidase IV and trypsin-like enzymatic degradation of human growth hormone-releasing hormone in plasma. Journal of Clinical Investigation (1989). doi:10.1172/JCI114049
4. Jetté L, Léger R, Thibaudeau K, Benquet C, et al. Human Growth Hormone-Releasing Factor (hGRF)1-29-Albumin Bioconjugates Activate the GRF Receptor on the Anterior Pituitary in Rats: Identification of CJC-1295 as a Long-Lasting GRF Analog. Endocrinology (2005). doi:10.1210/en.2004-1286
5. Teichman SL, Neale A, Lawrence B, Gagnon C, et al. Prolonged Stimulation of Growth Hormone (GH) and Insulin-Like Growth Factor I Secretion by CJC-1295, a Long-Acting Analog of GH-Releasing Hormone, in Healthy Adults. The Journal of Clinical Endocrinology & Metabolism (2006). doi:10.1210/jc.2005-1536
6. Ionescu M, Frohman LA. Pulsatile Secretion of Growth Hormone (GH) Persists during Continuous Stimulation by CJC-1295, a Long-Acting GH-Releasing Hormone Analog. The Journal of Clinical Endocrinology & Metabolism (2006). doi:10.1210/jc.2006-1702
7. Howard AD, Feighner SD, Cully DF, Arena JP, et al. A Receptor in Pituitary and Hypothalamus That Functions in Growth Hormone Release. Science (1996). doi:10.1126/science.273.5277.974
8. Kojima M, Hosoda H, Date Y, Nakazato M, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature (1999). doi:10.1038/45230
9. Vance ML, Kaiser DL, Evans WS, Furlanetto R, Vale W, Rivier J, Thorner MO. Pulsatile growth hormone secretion in normal man during a continuous 24-hour infusion of human growth hormone releasing factor (1-40). Evidence for intermittent somatostatin secretion. Journal of Clinical Investigation (1985). doi:10.1172/JCI111864
10. Falutz J, Allas S, Blot K, Potvin D, et al. Metabolic Effects of a Growth Hormone-Releasing Factor in Patients with HIV. The New England Journal of Medicine (2007). doi:10.1056/NEJMoa072375
11. Falutz J, Potvin D, Mamputu JC, Assaad H, et al. Effects of Tesamorelin (TH9507), a Growth Hormone-Releasing Factor Analog, in HIV-Infected Patients with Excess Abdominal Fat: a Pooled Analysis of Two Multicenter, Double-Blind Placebo-Controlled Phase 3 Trials with Safety Extension Data. The Journal of Clinical Endocrinology & Metabolism (2010). doi:10.1210/jc.2010-0490
12. ConjuChem Biotechnologies. Preformed Conjugate-Drug Affinity Complex (PC-DAC), platform technology overview. conjuchem.com/technology/pc-dac.html
13. U.S. Food and Drug Administration. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks (Category 2 and nominated-but-withdrawn lists, sections 503A/503B). fda.gov/drugs/human-drug-compounding/certain-bulk-drug-substances-use-compounding-may-present-significant-safety-risks