CJC-1295 DAC

CJC-1295 DAC Molecular Structure & Chemical Properties

CJC-1295 DAC peptide represents a significant advancement in growth hormone-releasing hormone (GHRH) analog research, developed in the mid-2000s by ConjuChem Biotechnologies to address the therapeutic limitations of native GHRH’s extremely short half-life. This synthetic peptide consists of a modified 29-amino acid GHRH sequence with four strategic amino acid substitutions to resist enzymatic degradation, coupled with a Drug Affinity Complex (DAC) that covalently binds to serum albumin. The DAC component – a maleimidopropionic acid derivative attached via lysine – extends the peptide’s biological half-life from minutes to approximately 6-8 days in human subjects, representing over a 1,000-fold increase in duration of action. This extended pharmacokinetic profile has made CJC-1295 DAC one of the most extensively studied long-acting GHRH analogs in preclinical and clinical research settings.

Chemical Structure

2D molecular structure (Source: PubChem)

Technical Specifications

The peptide’s structure contains four amino acid substitutions at positions 2, 8, 15, and 27 (D-Ala, Gln, Ala, Leu) compared to native GHRH, which dramatically improve resistance to proteolytic degradation. The C-terminal lysine residue is modified with N-epsilon-3-maleimidopropionamide, enabling selective covalent binding to cysteine-34 of serum albumin.

CJC-1295 DAC Mechanism of Action

CJC-1295 DAC exerts its biological effects through activation of the growth hormone-releasing hormone receptor (GHRHR) on somatotroph cells in the anterior pituitary gland, triggering a cascade of intracellular signaling events that result in growth hormone synthesis and secretion. Unlike native GHRH which rapidly degrades, the albumin-bound form of CJC-1295 DAC serves as a circulating reservoir, providing sustained GHRHR activation and prolonged growth hormone release over multiple days.

Primary Signaling Pathways

GHRH Receptor Activation and Growth Hormone Release

Research has demonstrated that CJC-1295 DAC binds selectively to GHRH receptors on anterior pituitary somatotrophs, activating adenylyl cyclase and increasing intracellular cyclic AMP (cAMP) levels. Studies in healthy adults showed that single subcutaneous administration resulted in 2- to 10-fold increases in plasma GH concentrations sustained for 6 days or longer. Key mechanistic features include:

• Selective GHRHR binding with preserved receptor specificity
• Dose-dependent growth hormone secretion response
• Maintained pulsatile GH release pattern despite extended half-life
• No significant elevation of prolactin, cortisol, or ACTH levels

The peptide’s ability to preserve physiologic GH pulsatility while extending duration of action represents a unique pharmacodynamic advantage over continuous GH infusion.

IGF-1 Stimulation and Downstream Signaling

CJC-1295 DAC-mediated GH release triggers hepatic production of insulin-like growth factor-1 (IGF-1), the primary mediator of GH’s anabolic effects. Clinical studies documented IGF-1 elevations of 1.5- to 3-fold above baseline persisting for 9-11 days following single administration. Downstream effects include:

• Activation of IGF-1 receptor tyrosine kinase signaling
• Stimulation of PI3K/Akt and MAPK/ERK pathways
• Enhanced protein synthesis in muscle and other tissues
• Modulation of glucose and lipid metabolism

Research in GHRH knockout mice demonstrated that CJC-1295 DAC could normalize IGF-1 levels and restore growth parameters, confirming its efficacy as a functional GHRH replacement.

Albumin Binding and Extended Pharmacokinetics

The Drug Affinity Complex (DAC) component enables CJC-1295 to form covalent bonds with serum albumin at cysteine-34 residues, creating a stable bioconjugate with dramatically extended circulation time. Pharmacokinetic studies revealed:

• Selective albumin binding without nonspecific protein interactions
• Protection from dipeptidyl peptidase-IV and other proteases
• Sustained therapeutic GH/IGF-1 elevation over 6-8 day intervals
• Potential for weekly or biweekly dosing regimens

This albumin-binding strategy represents an innovative approach to peptide half-life extension without altering the core pharmacological activity.

Somatotroph Cell Proliferation Effects

Animal research indicates that chronic CJC-1295 DAC administration may influence somatotroph cell populations in the pituitary. Studies in GHRH knockout mice showed increased total pituitary RNA and GH mRNA expression, suggesting proliferative effects on somatotroph cells. Findings include:

• Apparent increase in somatotroph cell number
• Enhanced GH mRNA transcription
• Normalized pituitary gland structure in GH-deficient models
• Frequency-dependent effects (daily dosing more effective than intermittent)

CJC-1295 DAC Research Applications & Key Findings

Growth Hormone Deficiency Research

Human Clinical Studies

The most comprehensive clinical investigation of CJC-1295 DAC consisted of two randomized, placebo-controlled, double-blind trials in healthy adults aged 21-61 years, published in 2006. These landmark studies established fundamental pharmacodynamic properties:

• Sustained GH elevation – Single doses produced 2- to 10-fold increases in plasma GH lasting 6+ days
• Prolonged IGF-1 response – IGF-1 levels increased 1.5- to 3-fold for 9-11 days
• Cumulative effects with repeat dosing – IGF-1 remained elevated for up to 28 days after multiple doses
• Dose-dependent responses – Effects scaled with doses from 30-60 mcg/kg
• Half-life of 5.8-8.1 days established through pharmacokinetic analysis

The studies concluded that CJC-1295 DAC was safe and relatively well tolerated, particularly at 30-60 mcg/kg doses, supporting potential therapeutic utility.

Preclinical Growth Normalization Studies

Research in GHRH knockout (GHRHKO) mice demonstrated CJC-1295 DAC’s ability to restore normal growth and body composition. Daily administration for 5 weeks produced:

• Complete growth normalization – Body weight, length, femur and tibia dimensions matched control animals
• Improved lean mass – Maintained normal muscle mass compared to untreated deficient mice
• Body composition benefits – Reduced fat accumulation compared to GH-deficient controls
• Dose frequency dependence – Daily dosing fully effective; every 48-72 hours produced partial normalization

Immunohistochemistry revealed that CJC-1295 DAC increased pituitary RNA and GH mRNA, suggesting somatotroph proliferation as a mechanism.

Metabolic and Body Composition Research

Lipid Metabolism Studies

CJC-1295 DAC was initially investigated for treatment of lipodystrophy in HIV/AIDS patients, with Phase II clinical trials initiated before termination. Preclinical research has explored metabolic effects:

• Growth hormone’s established lipolytic effects suggest potential for fat mass reduction
• Animal studies indicated possible improvements in body composition through increased lean mass and decreased adiposity
• GHRH knockout models showed prevention of obesity-related fat accumulation
• Mechanisms may involve enhanced lipolysis and increased metabolic rate through IGF-1 signaling

Protein Synthesis and Muscle Research

Studies examining anabolic effects in various models demonstrated:

• Enhanced protein synthesis mediated by IGF-1 receptor activation
• Muscle mass preservation in GH-deficient animal models
• Potential synergistic effects when combined with GHRP peptides like ipamorelin
• Myocellular mechanisms involving activation of mTOR and related growth pathways

Research suggests that the sustained IGF-1 elevation produced by CJC-1295 DAC may support anabolic processes over extended periods.

Sleep and Neurobehavioral Research

GHRH has documented roles in sleep regulation, and research has explored whether CJC-1295 DAC shares these properties:

• GHRH administration has been shown to enhance slow-wave sleep in clinical studies
• Animal models suggest GHRH analogs may support sleep quality and sleep architecture
• Potential effects on cognitive function through GH/IGF-1 axis modulation
• Theoretical applications in age-related sleep disturbances remain investigational

Cardiovascular and Aging Research

Preliminary investigations have examined potential effects on cardiovascular parameters:

• Growth hormone’s known effects on cardiac function suggest possible applications
• Proteomic analysis of human serum after CJC-1295 DAC showed alterations in apolipoprotein A1, transthyretin, and albumin isoforms
• One albumin/immunoglobulin fragment showed linear correlation with IGF-1 levels, suggesting potential biomarker applications
• Long-term cardiovascular safety remains incompletely characterized

CJC-1295 DAC Pharmacokinetics & Metabolism

Absorption & Distribution

CJC-1295 DAC exhibits unique pharmacokinetic properties due to its albumin-binding characteristics. Following subcutaneous administration in human clinical trials:

• Albumin bioconjugation occurs rapidly after injection, with the DAC moiety forming covalent bonds to cysteine-34 on serum albumin
• Systemic distribution follows albumin kinetics, with the peptide-albumin complex circulating throughout the vascular compartment
• Tissue penetration likely limited compared to smaller peptides due to albumin binding
• Volume of distribution approximates plasma volume given albumin restriction

Preclinical studies in rats, dogs, and pigs confirmed dose-dependent GH responses and sustained IGF-1 elevation across species, supporting translational potential.

Metabolism & Elimination

The metabolic fate of CJC-1295 DAC reflects its albumin-conjugated nature:

• Extended half-life of 5.8-8.1 days in humans, dramatically longer than native GHRH’s 7-minute half-life
• Albumin turnover rate likely determines overall elimination kinetics
• Proteolytic degradation significantly reduced due to structural modifications and albumin protection
• Dipeptidyl peptidase-IV resistance conferred by D-alanine substitution at position 2

The pharmacodynamic effects (elevated GH and IGF-1) persist beyond detectable plasma concentrations of intact peptide, suggesting continued bioactivity of the albumin-bound form or sustained receptor activation effects.

Excretion Pathways

Limited data exists on specific excretion pathways, but pharmacokinetic principles suggest:

• Renal elimination likely follows albumin catabolism and amino acid recycling
• Hepatic metabolism may contribute to peptide degradation
• No evidence of accumulation was observed in multiple-dose human trials
• IGF-1 elevation persisting 28 days after repeated dosing indicates prolonged biological effects exceeding drug presence

The disconnect between drug elimination and sustained pharmacodynamic response represents a unique feature of this albumin-bioconjugate approach.

CJC-1295 DAC Research Protocols & Administration

Dosing in Published Research

Human clinical trials and animal studies have established dose-response relationships:

• Human studies (adults): 30-60 mcg/kg subcutaneously produced optimal effects with acceptable tolerability
• Mouse studies: 2 mcg per dose administered daily, every 48 hours, or every 72 hours
• Rat studies: 1 mcg/kg subcutaneously demonstrated GH secretion and GHRH receptor activation
• Dose-dependent responses: Higher doses within safe ranges produced greater GH/IGF-1 elevations

Important: These are experimental doses used in controlled research studies and cannot be extrapolated to other species due to significant interspecies differences in GHRH receptor density, albumin binding characteristics, peptide metabolism rates, and GH secretion patterns. Pharmacokinetic and pharmacodynamic profiles vary substantially across species, making direct dose translation inappropriate.

Administration Routes in Research

CJC-1295 DAC has been investigated via multiple delivery methods:

• Subcutaneous injection – Primary route in human clinical trials; reliable systemic absorption with albumin binding
• Intraperitoneal injection – Used in rodent studies for GH secretion assessment
• Intravenous administration – Employed for pharmacokinetic characterization studies
• Dosing frequency – Once weekly or biweekly in human trials; daily to every-72-hours in animal models

The extended half-life enables significantly reduced injection frequency compared to native GHRH or non-DAC peptides.

Common Model Organisms

CJC-1295 DAC research has utilized diverse experimental systems:

• Humans – Phase I/II clinical trials in healthy adults aged 21-61; terminated Phase II trials in HIV-associated lipodystrophy
• Mice – GHRH knockout models demonstrating growth normalization and body composition effects
• Rats – GHRH receptor activation studies, GH secretion assays, pharmacokinetic investigations
• Dogs and pigs – Pharmacokinetic and pharmacodynamic studies confirming cross-species activity
• Cell culture – Rat anterior pituitary cells for in vitro GH secretion assays

Research Limitations & Regulatory Status

Critical Gaps in Current Evidence

Despite demonstrating promising pharmacological properties in early clinical studies, CJC-1295 DAC faces substantial limitations that have prevented further clinical development and therapeutic application.

Absence of Large-Scale Human Clinical Data

The most significant limitation is the termination of clinical development after Phase II trials:

• No completed Phase III efficacy trials – Long-term therapeutic benefits in target patient populations remain unestablished
• Limited safety database – Only two published human studies involving relatively small cohorts over 28-49 days
• Trial termination following patient death – Although the attending physician concluded the death was unrelated to CJC-1295 (attributed to asymptomatic coronary artery disease), development was discontinued as a precaution
• No pediatric studies – Safety and efficacy in growth hormone-deficient children uninvestigated
• Long-term safety unknown – Chronic use effects beyond several weeks remain completely uncharacterized

Mechanistic and Safety Uncertainties

Key questions remain unanswered regarding CJC-1295 DAC’s long-term effects:

• Cardiovascular safety concerns – The clinical trial death, while deemed unrelated, raised concerns about potential cardiovascular risks that were never fully investigated
• Somatotroph proliferation effects – Evidence of pituitary cell proliferation in mice raises questions about long-term pituitary changes in humans
• Cancer risk considerations – Effects on tumor growth or oncogenic potential through sustained IGF-1 elevation remain uninvestigated
• Chronic receptor activation consequences – Whether prolonged GHRHR stimulation leads to receptor desensitization or other adaptive changes is unknown
• Drug interaction potential – Effects of concomitant medications on albumin-bound CJC-1295 DAC are uncharacterized

Comparative Efficacy Questions

Important comparative research remains absent:

• Versus recombinant GH therapy – Direct head-to-head comparisons in GH-deficient populations never conducted
• Optimal dosing regimens – Whether weekly, biweekly, or other intervals provide optimal benefit-risk profiles undetermined
• Combination therapy potential – Synergistic or antagonistic effects with other growth factors unexplored in controlled trials

Regulatory & Competitive Sport Status

FDA Position

CJC-1295 DAC has not received regulatory approval for any indication:

• No FDA approval for therapeutic use in the United States
• Investigational New Drug status – Available only as a reference material for research purposes
• Not approved for compounding – Recent FDA actions have restricted compounding pharmacy access to unapproved growth hormone secretagogues
• Clinical development discontinued – No active therapeutic development programs exist
• No established medical use – Cannot be legally prescribed for any condition

The FDA’s position reflects the incomplete safety database and absence of completed efficacy trials.

WADA Prohibition

The World Anti-Doping Agency classifies CJC-1295 DAC as a prohibited substance:

• Listed under Section S2 – Growth Hormone and Growth Factors category of the Prohibited List
• Banned at all times – Prohibited both in-competition and out-of-competition for athletes
• No Therapeutic Use Exemptions available – No legitimate medical basis for TUEs given lack of approved indications
• Detection methods established – Anti-doping laboratories can identify CJC-1295 and metabolites in biological samples
• Applies to all WADA-compliant sports – Prohibited in Olympic, professional, and collegiate athletics

WADA’s prohibition reflects both performance-enhancing potential and lack of regulatory approval.

Research Classification: CJC-1295 DAC is available exclusively for laboratory research purposes under appropriate institutional oversight. It is not approved for human medical use, veterinary applications, or dietary supplement formulations. All research must comply with institutional review board protocols and applicable regulatory frameworks governing investigational compounds.

References

1. Teichman, S.L., Neale, A., Lawrence, B., Gagnon, C., Castaigne, J.P., & Frohman, L.A. (2006). 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. Journal of Clinical Endocrinology & Metabolism, 91(3), 799-805. PubMed
   
2. Alba, M., Fintini, D., Sagazio, A., Lawrence, B., Castaigne, J.P., Frohman, L.A., & Salvatori, R. (2006). Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse. American Journal of Physiology-Endocrinology and Metabolism, 291(6), E1290-E1294. PubMed
   
3. Jette, L., Leger, R., Thibaudeau, K., Benquet, C., Robitaille, M., Pellerin, I., Paradis, V., van Wyk, P., Pham, K., & Bridon, D.P. (2005). 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, 146(7), 3052-3058. PubMed
   
4. Ionescu, M., & Frohman, L.A. (2006). Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. Journal of Clinical Endocrinology & Metabolism, 91(12), 4792-4797. PubMed
   
5. Clemmons, D.R. (2007). Long-acting forms of growth hormone-releasing hormone and growth hormone: effects in normal volunteers and adults with growth hormone deficiency. Hormone Research, 68(Suppl 5), 178-181. PubMed
   
6. Sinha, D.K., Balasubramanian, A., Tatem, A.J., Rivera-Mirabal, J., Yu, J., Kovac, J., Pastuszak, A.W., & Lipshultz, L.I. (2020). Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Translational Andrology and Urology, 9(Suppl 2), S149-S159. PubMed
   
7. Henninge, J., Pepaj, M., Hullstein, I., & Hemmersbach, P. (2010). Identification of CJC-1295, a growth-hormone-releasing peptide, in an unknown pharmaceutical preparation. Drug Testing and Analysis, 2(11-12), 647-650. PubMed
   
8. Sigalos, J.T., Pastuszak, A.W., Khera, M., & Lipshultz, L.I. (2018). Growth hormone secretagogues in the treatment of testosterone deficiency: a systematic review and meta-analysis. Translational Andrology and Urology, 7(Suppl 3), S307-S318. PubMed
   
9. Khorram, O., Laughlin, G.A., & Yen, S.S. (1997). Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women. Journal of Clinical Endocrinology & Metabolism, 82(5), 1472-1479. PubMed
   
10. Veldhuis, J.D., Keenan, D.M., & Pincus, S.M. (2008). Motivations and methods for analyzing pulsatile hormone secretion. Endocrine Reviews, 29(7), 823-864. PubMed
    

All references open in new window. These citations are provided for educational and research purposes only. This information is not intended to diagnose, treat, cure, or prevent any disease. CJC-1295 DAC is intended for laboratory research use only.