CJC-1295 DAC (5mg)

CJC-1295 with DAC (5mg): A Long-Acting Growth Hormone-Releasing Hormone (GHRH) Analogue Conjugated with a Drug Affinity Complex (DAC) That Covalently Binds Serum Albumin, Extending Plasma Half-Life to 6-8 Days and Producing Sustained Pulsatile Growth Hormone Release with Once- or Twice-Weekly Dosing — Distinct from Short-Acting GHRH Analogues (Mod-GRF 1-29) and Growth Hormone Secretagogues (GHRP-2, GHRP-6, Ipamorelin) That Require Daily or Multiple-Daily Administration

CJC-1295 with DAC (Drug Affinity Complex) represents a significant pharmacological advancement in the field of growth hormone-releasing hormone (GHRH) analogues, addressing one of the primary limitations of native GHRH and its short-acting analogues: an extremely short plasma half-life that necessitates frequent dosing. Native GHRH is a 44-amino-acid peptide hormone secreted by the hypothalamus that stimulates growth hormone (GH) synthesis and release from anterior pituitary somatotroph cells through activation of the GHRH receptor (GHRHR), a class B G-protein-coupled receptor. However, native GHRH is rapidly degraded by peptidases (particularly dipeptidyl peptidase IV [DPP-IV] and neutral endopeptidase) and cleared renally, resulting in a plasma half-life of only 7-10 minutes in humans. The first-generation GHRH analogue, Mod-GRF 1-29 (also known as CJC-1295 without DAC), addressed this through structural modifications — including substitution of the second amino acid (alanine→D-alanine) to confer DPP-IV resistance, and modifications at positions 8, 15, and 27 to enhance metabolic stability — extending the half-life to approximately 30 minutes. While this represented a substantial improvement, Mod-GRF 1-29 still requires daily or multiple-daily administration to sustain therapeutic GH levels. CJC-1295 with DAC takes a fundamentally different approach to half-life extension: rather than relying solely on metabolic stabilization, it employs a Drug Affinity Complex — a reactive maleimido-propionic acid group that, after subcutaneous injection, spontaneously forms a covalent thioether bond with the free thiol group of cysteine-34 on serum albumin. Because albumin has a circulating half-life of approximately 19 days, the CJC-1295-albumin conjugate is effectively shielded from renal clearance and proteolytic degradation, extending the functional half-life of CJC-1295 DAC to 5.8-8.1 days in humans — roughly 100-fold longer than Mod-GRF 1-29 and nearly 1000-fold longer than native GHRH. This extraordinary half-life extension allows for once-weekly or even twice-weekly dosing, dramatically improving convenience and adherence compared to daily GHRH analogue or GHRP administration^{[1][2][3][4][5][6][7][8][9][10]}.

Mechanism of Action: Albumin Conjugation and Sustained GHRH Receptor Activation

The mechanism of CJC-1295 DAC can be understood at two interconnected levels: the molecular mechanism of albumin conjugation that confers long-acting pharmacokinetics, and the physiological mechanism of GHRH receptor activation that produces sustained growth hormone release. At the molecular level, the DAC moiety consists of a maleimido-propionic acid group attached to the lysine side chain at position 12 of the CJC-1295 peptide. After subcutaneous injection, the peptide diffuses into the bloodstream, where the reactive maleimide group undergoes a spontaneous Michael addition with the free thiol (-SH) group of cysteine-34 on human serum albumin — the most abundant plasma protein, present at concentrations of approximately 35-50 g/L. This covalent thioether bond forms rapidly (within minutes to hours) and is essentially irreversible under physiological conditions. Once conjugated to albumin, CJC-1295 benefits from all of the pharmacokinetic properties of albumin itself: a large molecular size (~66.5 kDa for albumin alone, ~71 kDa for the conjugate) that prevents glomerular filtration, protection from proteolytic degradation due to the steric shielding provided by the albumin molecule, and a circulating half-life that matches that of albumin (~19 days). The estimated functional half-life of CJC-1295 DAC in humans is 5.8-8.1 days — somewhat shorter than albumin itself because the peptide may be slowly cleaved from albumin or the conjugate may be cleared through non-renal pathways, but still dramatically longer than any unmodified GHRH analogue. At the physiological level, while circulating as an albumin conjugate, CJC-1295 retains its ability to bind and activate the GHRH receptor on anterior pituitary somatotroph cells. The GHRHR is a class B GPCR that preferentially couples to Gs proteins, triggering adenylyl cyclase activation and subsequent cyclic AMP (cAMP) accumulation. This second messenger cascade activates protein kinase A (PKA), which phosphorylates transcription factors including CREB (cAMP response element-binding protein), ultimately promoting both GH synthesis (through increased transcription of the GH gene) and exocytotic GH release (through calcium-dependent vesicle fusion). A critical feature of CJC-1295 DAC is that it preserves the pulsatile pattern of GH release — rather than producing constant, non-physiological GH elevation, the sustained receptor activation maintains the natural ultradian rhythm of GH secretion, with pulses occurring approximately every 3-4 hours. This pulsatile pattern is considered important because it more closely mimics physiological GH secretion and may reduce the risk of desensitization or down-regulation of the GHRH receptor that can occur with constant receptor stimulation. The downstream effects of sustained GH elevation include increased hepatic and peripheral production of insulin-like growth factor 1 (IGF-1), which mediates many of the anabolic effects of GH, including increased protein synthesis, muscle growth, bone remodeling, fat metabolism (lipolysis), and cellular repair and regeneration^{[1][2][3][4][5][6][7][8][9][10]}.

Clinical and Preclinical Evidence

The clinical development of CJC-1295 DAC has been extensively studied in healthy adults and patient populations, with the landmark Phase 1 trial published in the Journal of Clinical Endocrinology & Metabolism in 2006 (PMID 16505145) establishing the pharmacokinetic and pharmacodynamic profile that forms the basis for its research use. In this randomized, double-blind, placebo-controlled, single-dose escalation study, 74 healthy adults aged 21-61 received subcutaneous injections of CJC-1295 at doses ranging from 30 to 250 mcg/kg, or placebo. The results were remarkable: after a single injection, mean plasma GH concentrations increased in a dose-dependent manner by 2- to 10-fold over baseline, with elevations persisting for 6 days or more. Mean plasma IGF-1 concentrations increased by 1.5- to 3-fold over baseline, with elevations sustained for 9-11 days after a single dose — a duration that far exceeds anything achievable with daily GHRH analogue or GHRP administration. The estimated half-life of CJC-1295 was 5.8-8.1 days, confirming the successful albumin conjugation strategy. In multiple-dose studies, twice-weekly administration of CJC-1295 produced sustained elevations in both GH and IGF-1 throughout the dosing period, with mean IGF-1 levels increasing by approximately 2-3 fold and remaining within or above the physiological range for young adults. Importantly, the pulsatile pattern of GH secretion was preserved, with identifiable GH pulses occurring at regular intervals rather than the flat, non-physiological elevation seen with continuous GH infusion or constant receptor activation. In preclinical studies in GHRH knockout mice (a model of isolated GHRH deficiency), once-daily administration of CJC-1295 normalized growth over a 5-week treatment period, demonstrating that the sustained GHRH receptor activation produced by CJC-1295 is sufficient to support normal somatic growth in the absence of endogenous GHRH. The safety profile of CJC-1295 DAC in clinical trials has been generally favorable, with the most common adverse events being injection site reactions (redness, swelling, pain), transient headaches, and mild flushing — typically mild and self-limiting. There have been theoretical concerns about potential effects on glucose metabolism (because GH can be diabetogenic at high doses), but clinical studies have generally shown minimal or no significant effects on fasting glucose or insulin sensitivity at the doses studied. It is important to note that CJC-1295 DAC is not approved for any clinical indication by the FDA or other regulatory agencies — it is available only as a research-grade peptide for laboratory and investigational use. The research community has employed CJC-1295 DAC in a wide range of preclinical and clinical investigations, including studies of growth hormone physiology, aging and longevity (because GH and IGF-1 decline with age), body composition and muscle wasting, bone health, wound healing, and cognitive function. The once- or twice-weekly dosing schedule makes CJC-1295 DAC particularly convenient for research protocols that require sustained GH elevation without the burden of daily injections^{[1][2][3][4][5][6][7][8][9][10]}.

• Unmatched half-life extension: CJC-1295 DAC's 5.8-8.1 day half-life is approximately 100-fold longer than Mod-GRF 1-29 (~30 min) and nearly 1000-fold longer than native GHRH (7-10 min), enabling once- or twice-weekly dosing rather than daily or multiple-daily administration — a convenience advantage that is unmatched among GHRH analogues and GHRPs.
• Preserved pulsatile GH secretion: Unlike continuous GH infusion or constant receptor activation that can produce flat, non-physiological GH levels and potential receptor desensitization, CJC-1295 DAC maintains the natural ultradian rhythm of GH secretion with pulses occurring approximately every 3-4 hours — a feature that may be important for physiological efficacy and long-term safety.
• Sustained IGF-1 elevation: A single dose of CJC-1295 DAC produces IGF-1 elevations of 1.5-3 fold that persist for 9-11 days — substantially longer than any daily GHRH analogue or GHRP, which typically produce IGF-1 elevations lasting only hours to one day at most.
• Albumin conjugation technology: The DAC maleimide group spontaneously forms a covalent thioether bond with cysteine-34 on serum albumin, leveraging albumin's 19-day half-life, large size (~66.5 kDa, preventing renal clearance), and steric protection from proteolytic degradation — a well-established drug delivery technology also used in approved therapies like liraglutide (albumin-binding) and certolizumab pegol (PEGylation).
• Dose-dependent GH response: Clinical studies demonstrate clear dose-response relationships across the 30-250 mcg/kg range, with GH elevations of 2-10 fold and IGF-1 elevations of 1.5-3 fold — allowing for titration to desired GH/IGF-1 levels in research protocols.
• Favorable safety profile: Clinical trials have shown CJC-1295 DAC to be generally well-tolerated, with most adverse events being mild and self-limiting (injection site reactions, transient headaches, mild flushing); no serious adverse events related to the study drug were reported in the Phase 1 program, and effects on glucose metabolism were minimal at therapeutic doses.

References

1. Jaffe CA, 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. J Clin Endocrinol Metab. 2006;91(3):799-805. PMID: 16505145. (Landmark Phase 1 trial; 74 healthy adults; single doses 30-250 mcg/kg; GH increased 2-10× for ≥6 days; IGF-1 increased 1.5-3× for 9-11 days; half-life 5.8-8.1 days)
2. Synergen Peptides. CJC-1295 with DAC – A Long-Acting GHRH Analogue for Sustained Growth Hormone Release. synergenpeptides.com. 2026. (29-amino-acid GHRH analogue modified with DAC; binds reversibly to serum albumin; sustained receptor activation; prolonged pulsatile GH release with weekly/bi-weekly dosing; stimulates IGF-1 production; anabolic processes)
3. PeptideJournal. CJC-1295 with DAC: Extended-Release Research. peptidejournal.org. 2025. (After SC injection, reactive maleimido group forms covalent thioether bond with cysteine-34 on serum albumin; spontaneous, no enzymatic catalyst, essentially irreversible; albumin-bound CJC-1295 circulates with effective half-life matching albumin ~6-8 days; remains biologically active while bound)
4. CJC-1295.com. Key Clinical Studies on CJC-1295. cjc-1295.com. 2026. (Pharmacokinetic studies: with DAC half-life 6-8 days; non-DAC form ~30 min; these differences drive practical dosing choices; foundational clinical work in healthy adults demonstrated dose-dependent GH and IGF-1 elevations sustained for days)
5. American Physiological Society. Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse. Am J Physiol Endocrinol Metab. 2007;292(3):E861-E867. PMID: 17003230. (CJC-1295 selectively and covalently binds endogenous albumin after injection, extending half-life; GHRHKO mice treated for 5 weeks with 2 mcg CJC-1295 at 24/48/72h intervals; normalized somatic growth in absence of endogenous GHRH)
6. RethinkPeptides. CJC-1295 and IGF-1: What the Research Shows About Elevation. rethinkpeptides.com. 2026. (After SC injection, reactive group covalently and irreversibly binds to cysteine-34 on serum albumin; albumin circulating half-life ~19 days; CJC-1295-albumin conjugate persists in bloodstream for days, continuously stimulating GHRH receptors on pituitary somatotroph cells; estimated half-life in humans 5.8-8.1 days)
7. Peptides Institute. CJC-1295 DAC. peptidesinstitute.org. 2026. (Once injected SC, DAC moiety undergoes bioconjugation with endogenous albumin through maleimide-thiol linkage; albumin half-life ~19 days; conjugated peptide shielded from renal clearance and proteolytic degradation; functional half-life extended to 6-8 days in humans; marked contrast to short-acting GHRH analogues)
8. Delta Peptides. CJC-1295. deltapeptides.com. 2025. (CJC-1295 binds GHRHR extracellular domain with high affinity [Kd ~2-5 nM], inducing conformational changes through transmembrane domains to activate intracellular G proteins; receptor preferentially couples to Gs, triggering adenylyl cyclase activation and cAMP accumulation; activates PKA, phosphorylates CREB, ultimately promoting GH synthesis and exocytotic release)
9. Spartan Peptides. CJC-1295: The Complete 2026 Research Guide to Growth Hormone Secretagogues. spartanpeptides.com. 2026. (Dose range studied: 30, 60, 125, 250 mcg/kg SC single injection in healthy adults aged 21-61; GH response: mean GH levels increased 2-10× over baseline at 2-6 hours post-injection, persisting in elevated state for approximately 6 days; IGF-1 response: serum IGF-1 increased 1.5-3× over baseline with elevations sustained for 9-11 days)
10. Broglio F, et al. Growth hormone-releasing hormone and growth hormone secretagogues: from basic science to clinical applications. Eur J Endocrinol. 2007;156(Suppl 1):S39-S46. (Review of GHRH physiology and GHRH analogue development; native GHRH half-life 7-10 min due to DPP-IV degradation and renal clearance; structural modifications at positions 2, 8, 15, 27 confer metabolic stability; albumin conjugation represents most advanced half-life extension strategy)