Research Dossier on CJC-1295 with DAC

(Growth Hormone Secretagogue)

Classification & Molecular Identity

Amino acid sequence, molecular weight, structural motifs

CJC-1295 with DAC (also referred to as DAC:GRF) is a synthetic analog of human growth hormone-releasing hormone (GHRH) based on the 1–29 N-terminal fragment of GHRH (also known as GRF(1-29)), which contains the essential pharmacophore for pituitary GHRH receptor (GHRHR) activation. To increase metabolic stability and dramatically extend systemic exposure, the peptide incorporates (i) strategic amino-acid substitutions within the GRF(1-29) backbone to resist enzymatic cleavage (e.g., dipeptidyl-peptidase-IV at the Tyr¹–Ala² bond), and (ii) a Drug Affinity Complex (DAC) moiety—classically a maleimidopropionic group positioned on a lysine side chain—designed to form a selective thiosuccinimide linkage with Cys34 of circulating human serum albumin (HSA) in vivo. The covalent albumin conjugation underlies the long effective half-life of the construct. [Endocrinology 2005; Jetté et al.] PubMed+1

Reported analytical identifications of CJC-1295 in seized preparations and anti-doping contexts confirm the modified GRF(1-29) core and DAC maleimide chemistry used to couple the analog to albumin, supporting the above structural description. [Drug Test Anal 2010; Henninge et al.; Drug Test Anal 2021; Memdouh et al.] PubMed+1

Because the clinically used formulation is a mixture of free peptide that rapidly bioconjugates to endogenous albumin, the exact molecular mass in circulation corresponds to an albumin-peptide conjugate (~66–67 kDa) rather than the unconjugated ~3 kDa peptide alone. The pharmacologically active entity at steady state is thus largely albumin-bound DAC:GRF. [Endocrinology 2005; Jetté et al.; albumin maleimide reviews] PubMed+2PMC+2

Discovery history (lab, year, species)

CJC-1295 originated at ConjuChem Biotechnologies (Montréal) in the early-to-mid-2000s as part of a platform to extend peptide half-life via albumin conjugation. Proof-of-concept studies demonstrated in vivo albumin bioconjugation after subcutaneous dosing in rats, with persistent GH responses and protection against DPP-IV cleavage; this culminated in the identification of CJC-1295 as a long-acting GRF analog. [Endocrinology 2005; Jetté et al.] PubMed

Subsequently, randomized, placebo-controlled, ascending-dose Phase 1 studies in healthy adults characterized the pharmacokinetics (PK) and pharmacodynamics (PD), showing sustained, dose-dependent increases in GH and IGF-1after single or multiple subcutaneous administrations. [J Clin Endocrinol Metab (JCEM) 2006; Teichman et al.] PubMed+1

Endogenous vs synthetic origin

CJC-1295 is fully synthetic. Its target (GHRHR) and downstream axis (GH–IGF-1) are endogenous. The DAC uses maleimide–thiol conjugation chemistry that selectively couples to albumin’s Cys34 in vivo, a widely exploited approach for exposure extension. [Feng et al. 2018; Kang et al. 2021] PMC+1

Homologs, analogs, derivatives

• Sermorelin (GRF(1-29)): the unmodified 29-mer reference agonist; short half-life due to rapid proteolysis/renal clearance.

• Tesamorelin: a stabilized GHRH analog (not DAC-conjugated) with distinct clinical program in HIV-associated visceral adiposity. [N Engl J Med 2007; Falutz et al.] PubMed

• Modified GRF(1-29) (“CJC-1295 without DAC”): backbone-stabilized analog lacking albumin-reactive maleimide; far shorter half-life than DAC:GRF. Analytical anti-doping studies distinguish these entities. [Drug Test Anal 2010, 2021] PubMed+1

Historical Development & Research Trajectory

Key milestones in discovery and study

• 2005 – Rat work establishes albumin bioconjugation and identifies CJC-1295 as a long-lasting GRF analog. [Endocrinology 2005] PubMed

• 2006 – Phase 1 RCTs in healthy adults: subcutaneous CJC-1295 produces sustained, dose-dependent elevations of GH and IGF-1, with evidence of cumulative effects after multiple doses. [JCEM 2006] PubMed

• 2006 – GH pulsatility preserved despite elevated trough GH—an important physiological observation for long-acting GHRH agonism. [Ionescu et al., 2006] PubMed

• 2006–2007 – Program expands to HIV-associated lipodystrophy; Phase 2 RCT halted after a patient death, with sponsor-reported investigation attributing a likely unrelated cardiovascular cause; nonetheless the program was curtailed. [ClinicalTrials.gov NCT00267527; company/specialist reports] ClinicalTrials.gov+2BioSpace+2

• 2009–2011 – Proteomic/transcriptomic work explores systemic signatures of GH/IGF-1 axis activation after CJC-1295 exposure. [Growth Horm IGF Res 2009; Ding et al. 2011 follow-ups] PubMed+2PMC+2

Paradigm shifts and controversies

• Shift: From direct GH administration to endogenous GH axis stimulation with longer-acting GHRH agonists, attempting to preserve physiologic pulsatility and reduce supraphysiologic peaks. [Ionescu 2006; GH/IGF-1 reviews] PubMed+1

• Controversy: Program discontinuation after the HIV lipodystrophy trial stoppage generated caution despite non-definitive causality. Independent replication in large, modern trials is limited. [NCT00267527; news reports contemporaneous to the halt] ClinicalTrials.gov+1

Evolution of scientific interest

Interest migrated toward exposure-extension chemistries (albumin conjugation, Fc fusion), next-generation GHRH analogs, and GH secretagogues more broadly—while CJC-1295 itself remains a widely studied reference for DAC-albumin conjugation and long-acting GHRH agonism. [Feng 2018; Kang 2021; domain reviews] PMC+1

Mechanisms of Action

Primary and secondary receptor interactions

CJC-1295 is a GHRH receptor (GHRHR) agonist at pituitary somatotrophs, promoting Gs-coupled adenylyl cyclase activation, cAMP elevation, PKA signaling, and GH synthesis and pulsatile release. The DAC moiety itself is not a pharmacophore; its role is kinetic (albumin binding), thereby sustaining receptor exposure. [Endocrinology 2005; JCEM 2006; GH/IGF-1 axis reviews] PubMed+2PubMed+2

Intracellular signaling pathways

• GHRHR→Gs→AC→cAMP→PKA→CREB: transcriptional up-regulation of GH gene; facilitation of regulated exocytosis.

• Downstream hepatic: GH→IGF-1 (via JAK2–STAT5 in hepatocytes), increasing systemic IGF-1 and binding proteins. [Blum 2018 review; Sackmann-Sala 2009 profile changes] PMC+1

CNS vs peripheral effects

CJC-1295’s primary site is the anterior pituitary (CNS-adjacent, but outside the classic BBB). Peripheral effects are mediated by GH/IGF-1 axis activation (e.g., hepatic IGF-1). No unique central nervous system receptor action distinct from GHRHR has been established. Unknown whether albumin-conjugate meaningfully crosses BBB; pharmacology is consistent with peripheral stimulation of the somatotropic axis. (Unknown/Not established for direct CNS penetration.) [Axis reviews] PMC

Hormonal, metabolic, immune interactions

Activation of GH/IGF-1 can modulate lipid turnover, protein synthesis, and glucose homeostasis system-wide. Proteomic studies in normal adults exposed to CJC-1295 demonstrate serum protein profile shifts consistent with GH/IGF-1 activation. [Growth Horm IGF Res 2009; Ding 2011] PubMed+1

Evidence grading (A–C)

• A (replicated clinical PD): Sustained GH and IGF-1 elevations with preserved pulsatility in healthy adults; multiple RCTs/PK-PD characterizations. [JCEM 2006; Ionescu 2006] PubMed+1

• B (limited translational/indication data): Early exploration in HIV-associated visceral adiposity; program halted; limited outcome readouts available. [NCT00267527] ClinicalTrials.gov

• C (hypothesis): Potential disease-specific benefits relative to daily short-acting GHRH analogs due to kinetic differences; requires modern confirmatory trials. (Hypothesis; Not established.)

Pharmacokinetics & Stability

ADME profile

• Absorption: After subcutaneous administration, CJC-1295 (free peptide) rapidly undergoes in vivo albumin bioconjugation, effectively converting the dose into an albumin-peptide conjugate with prolonged circulation. [Endocrinology 2005] PubMed

• Distribution: The albumin conjugate confines distribution to plasma and interstitial compartments, typical of albumin-bound macromolecules; receptor access at the pituitary remains pharmacologically adequate. (Mechanistic inference consistent with albumin carriers.) [Feng 2018; Kang 2021] PMC+1

• Metabolism: Enzymatic cleavage of peptide bonds occurs more slowly when albumin-conjugated; maleimide–thiol adducts can undergo ring-opening/hydrolysis yet remain stable for days in vivo. [Feng 2018] PMC

• Excretion: Albumin-bound conjugates are not filtered by glomeruli; ultimate clearance likely via reticuloendothelial/proteolytic turnover of albumin. (Generalizable property of albumin conjugates.) [Kang 2021 review] PMC

Plasma half-life & degradation pathways

In healthy adult RCTs, effective terminal half-life estimates of CJC-1295 with DAC are on the order of several days, with IGF-1 elevations persisting 1–2 weeks after a single dose. [JCEM 2006] PubMed
Specific half-life numbers vary by assay/model; albumin turnover (~15–20 days) sets an upper bound, whereas functional PD half-life for GH/IGF-1 response typically registers ~6–8 days in clinical descriptions. (Range synthesized from JCEM PK-PD outcomes and general albumin kinetics.) [JCEM 2006; albumin conjugation literature] PubMed+1

Stability in vitro & in vivo

• In vitro: The DAC strategy confers DPP-IV resistance to the N-terminus and reduces proteolysis; albumin conjugation prevents rapid renal filtration. [Endocrinology 2005] PubMed

• In vivo: Serum stability of the albumin conjugate supports once-weekly or longer PD effects in research settings; GH pulsatility is preserved despite elevated baseline GH. [Ionescu 2006] PubMed

Storage/reconstitution considerations

Not established in peer-reviewed PK-stability monographs beyond general peptide handling; albumin-conjugation occurs in vivo, so reconstitution chemistry focuses on peptide integrity pre-dose. (Data gap.)

Preclinical Evidence

Animal and in vitro studies

• Rat anterior pituitary & receptor assays: Albumin-conjugated hGRF(1-29) retained receptor activation and in vitro bioactivity; in vivo dosing generated robust GH secretion. [Endocrinology 2005] PubMed

• Bioconjugation principle: The maleimide strategy targeted HSA Cys34 to yield long-lived conjugates, a platform later generalized to other peptides and small molecules. [Feng 2018; Kang 2021] PMC+1

Dose ranges tested (animals)

Preclinical work often expressed doses in µg·kg⁻¹; albumin conjugation shifted dose-response curves by increasing apparent potency through residence time (exact equivalences vary by species and are not standardized). (Data summarized from Endocrinology 2005 and platform reviews.) PubMed+1

Comparative efficacy/safety

In receptor and pituitary cell systems, DAC-conjugated constructs retained agonism and outlasted unmodified GRF(1-29) or non-DAC-stabilized analogs in both stability and in vivo GH response windows. [Endocrinology 2005] PubMed

Limitations

• Species translation from rodent albumin to human albumin (binding kinetics) may differ.

• Few head-to-head animal studies directly compare DAC:GRF to tesamorelin or other long-acting approaches. (Data gap.)

Human Clinical Evidence

Phase I trials (healthy adults)

Two randomized, placebo-controlled, double-blind, ascending-dose studies (28 and 49 days) evaluated single and multiple subcutaneous doses of CJC-1295 in healthy adults. Findings:

• Sustained, dose-dependent increases in mean and trough GH and IGF-1; cumulative effect after multiple weekly doses.

• Pulsatile GH secretion was preserved (evaluated in a separate mechanistic study).

• Adverse events were generally mild to moderate; local injection reactions and transient systemic symptoms were reported.
  Investigational doses reported included 30–60 µg·kg⁻¹ (investigational dose used in study Teichman 2006). [JCEM 2006; Ionescu 2006] PubMed+1

Phase II exploration (HIV-associated visceral adiposity)

A Phase II, randomized, placebo-controlled trial (NCT00267527) aimed to assess efficacy, PK, safety, and tolerability of CJC-1295 in HIV-associated visceral adiposity (lipodystrophy). The study was halted after a patient death; sponsor statements suggested a likely unrelated cardiovascular event, but dosing was discontinued as a precaution and further development in this indication did not proceed. (Investigational doses were protocol-specified; see ClinicalTrials.gov.) [NCT00267527; contemporaneous reports] ClinicalTrials.gov+1

Other human readouts

• Serum proteomics demonstrate systemic signatures of GH/IGF-1 axis activation one week after CJC-1295 exposure in healthy adults (n=11). (Investigational single dose used in study Sackmann-Sala 2009). [Growth Horm IGF Res 2009; PMCID] PubMed+1

Safety signals/adverse events

Across early studies, adverse events included injection-site reactions, flu-like symptoms, headache, nausea, urticaria; serious adverse events were rare in healthy adult studies. The Phase II trial halt highlights the need for robust, modern safety datasets to contextualize risk in disease populations. [JCEM 2006; FDA presentation summarizing historical AE patterns; NCT00267527] PubMed+2Regulations.gov+2

ClinicalTrials.gov IDs

• NCT00267527 – “A Study to Evaluate CJC-1295 in HIV Patients With Visceral Adiposity.” (Status: halted; see registry record for details.) ClinicalTrials.gov

Comparative Context

Related peptides / approaches

• Sermorelin (GRF(1-29)): short-acting, requires frequent administration; baseline for receptor pharmacology.

• Tesamorelin: stabilized GHRH analog with demonstrated efficacy in HIV-associated visceral adiposity in large RCTs; not DAC-conjugated (distinct PK profile). [N Engl J Med 2007] PubMed

• Ghrelin mimetics (GHSR agonists): act upstream via ghrelin receptor; mechanistically distinct from GHRH analogs. [Sinha 2020 review] PMC

Advantages/disadvantages (research perspective)

• Advantages: Prolonged exposure via albumin conjugation; preservation of GH pulsatility; predictable axis activation measurable by IGF-1. [Ionescu 2006; JCEM 2006] PubMed+1

• Disadvantages: Legacy development halt limits contemporary clinical datasets; albumin conjugates can have complex biotransformations; program lacks recent Phase II/III outcomes. [NCT00267527; conjugation reviews] ClinicalTrials.gov+1

Research category placement

Long-acting GHRH receptor agonist utilizing in vivo albumin bioconjugation to extend half-life (a founding example of DAC chemistry in peptide therapeutics). [Endocrinology 2005; Feng 2018] PubMed+1

Research Highlights

• Landmark clinical PD: Sustained, dose-dependent GH and IGF-1 elevations with weekly dosing windows in healthy adults. [JCEM 2006] PubMed

• Physiology preserved: GH pulsatility maintained despite higher troughs under continuous GHRH stimulation—relevant for physiologic signaling. [Ionescu 2006] PubMed

• Platform proof: In vivo albumin conjugation established a generalizable half-life extension strategy for peptides. [Endocrinology 2005; Feng 2018] PubMed+1

Conflicting evidence / uncertainties:

• The clinical development halt prevents robust conclusions on disease outcomes; Unknown long-term safety profile under chronic exposure; Not established comparative efficacy vs. modern alternatives. [NCT00267527] ClinicalTrials.gov

Potential Research Applications

The following are research domains suggested by axis pharmacology and early clinical PD. They do notconstitute clinical claims.

• Endocrine physiology: Controlled activation of GH–IGF-1 for mechanistic studies of protein synthesis, lipolysis, and bone turnover. [Blum 2018 review] PMC

• Pharmacokinetic engineering: Albumin conjugation as a model system for exposure extension across peptide classes. [Feng 2018; Kang 2021] PMC+1

• Proteomics/transcriptomics: Mapping biomarker signatures of GH/IGF-1 activation. [Sackmann-Sala 2009; Ding 2011] PubMed+1

• Comparative endocrinology: Evaluating GHRH agonists vs. GHSR agonists (ghrelin mimetics) for differential systemic effects. [Sinha 2020] PMC

Safety & Toxicology

Preclinical / mechanistic considerations

• Albumin conjugates typically avoid rapid renal filtration, shifting clearance to albumin turnover; this may reduce peak–trough variability but also prolong systemic exposure after dose cessation. [Kang 2021] PMC

• Maleimide adduct stability is generally favorable; potential for retro-Michael reactions is context-dependent but minimized by in vivo ring-opening/hydrolysis stabilization. [Feng 2018] PMC

Clinical safety observations (early studies)

• In healthy adult RCTs, injection-site reactions, flu-like symptoms, headache, nausea, urticaria were described; serious AEs were uncommon. (Investigational doses used in study Teichman 2006.) [JCEM 2006; FDA compilation] PubMed+1

Data gaps

• Chronic exposure safety in diverse populations: Unknown.

• Cardiometabolic outcomes under prolonged axis activation: Not established.

• Immunogenicity specific to albumin conjugation for this scaffold: Not established.

Limitations & Controversies

• Program discontinuation after an SAE in Phase II (HIV lipodystrophy) limits the evidence base for indications. Causality for the death was assessed as likely unrelated, yet the trial was halted. [NCT00267527; contemporaneous reports] ClinicalTrials.gov+1

• Comparative effectiveness vs. tesamorelin or other modern agents has not been rigorously established in contemporary RCTs. (Not established.)

• Analytical detection in anti-doping has focused on distinguishing CJC-1295 DAC vs. non-DAC analogs, underscoring circulating heterogeneity (free vs. albumin-bound). [Henninge 2010; Knoop 2016; Memdouh 2021] PubMed+2PMC+2

Future Directions

• Modernized clinical programs with adaptive designs to clarify exposure–response, benefit–risk, and biomarker-guided stratification. (Currently not registered for new late-phase trials; Unknown roadmap.)

• Medicinal chemistry: Alternative albumin-binding handles or site-specific conjugation to fine-tune conjugate homogeneity and PK profiles. [Kang 2021; general albumin-binding literature] PMC

• Comparative physiology: Head-to-head GHRH vs. GHSR agonism in systems biology frameworks to resolve axis-specific proteomic signatures. [Sinha 2020; Ding 2011] PMC+1

References (peer-reviewed or ClinicalTrials.gov)

1. Jetté L, 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;146(7):3052-3058. PMID: 15817669. PubMed+1

2. Teichman SL, et al. Prolonged stimulation of GH and IGF-I secretion by CJC-1295, a long-acting analog of GHRH, in healthy adults. J Clin Endocrinol Metab. 2006;91(3):799-805. PMID: 16352683. PubMed+1

3. Ionescu M, et al. Pulsatile secretion of GH persists during continuous stimulation by CJC-1295; increased trough GH with preserved pulsatility. J Clin Endocrinol Metab. 2006;91(12):4792-4797. PMID: 17018654. PubMed

4. Sackmann-Sala L, et al. Activation of the GH/IGF-1 axis by CJC-1295 results in serum protein profile changes in normal adult subjects. Growth Horm IGF Res. 2009;19(6):471-477. PMID: 19386527; PMCID: PMC2787983. PubMed+1

5. Henninge J, et al. Identification of CJC-1295 in an unknown pharmaceutical preparation. Drug Test Anal.2010;2(11-12):647-650. PMID: 21204297. PubMed

6. Memdouh S, et al. Advances in detection of GHRH synthetic analogs (sermorelin, tesamorelin, CJC-1295 ± DAC). Drug Test Anal. 2021;13(11-12):1803-1818. DOI: 10.1002/dta.3183. Analytical Science Journals

7. Feng J, et al. Maleimidopropionic-acid–conjugated peptide platform for prolonged half-life and in-vivo efficacy; discussion of albumin Cys34 conjugation chemistry. Theranostics. 2018;8(19):5121-5138. PMCID: PMC5928873. PMC

8. Kang MS, et al. Recent developments in chemical conjugation strategies (including albumin coupling) for biotherapeutics. Int J Mol Sci. 2021;22(21):11804. PMCID: PMC8549674. PMC

9. ClinicalTrials.gov. A Study to Evaluate CJC-1295 in HIV Patients With Visceral Adiposity. NCT00267527. (Accessed Sep 2025). ClinicalTrials.gov

10. Blum WF, et al. The GH–IGF-I axis in physiology and disease: foundational context for axis modulation. Horm Res Paediatr. 2018;89(6):284-296. PMCID: PMC5987361. PMC

11. Ding J, et al. NOVEL serum protein biomarkers indicative of GH action; contextualizes proteomic shifts after CJC-1295. J Proteome Res. 2011;10(8):3430-3439. PMCID: PMC3517138. PMC

12. Sinha DK, et al. Beyond the androgen receptor: the role of GH/IGF-1 and secretagogues in anabolism—background review. Transl Androl Urol. 2020;9(Suppl 2):S125-S140. PMCID: PMC7108996. PMC

Note on investigational amounts:
• 30–60 µg·kg⁻¹ (subcutaneous) — investigational doses used in Teichman 2006 (healthy adults) with sustained GH/IGF-1 elevations. PubMed
• Protocol-specified dosing in NCT00267527 (HIV lipodystrophy) — investigational; study halted. ClinicalTrials.gov

⚠️ Disclaimer (mandatory)

This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.