CJC-1295 exists in two pharmacologically distinct forms: with Drug Affinity Complex (DAC) and without DAC. Both are synthetic analogs of growth hormone-releasing hormone (GHRH) with D-Ala² and other modifications for DPP-IV resistance, but the addition of DAC fundamentally alters the pharmacokinetic profile from a 30-minute peptide to a 6–8 day depot. This engineering creates two distinct therapeutic profiles: pulsatile GH release (no-DAC) versus sustained GH elevation (DAC).
- Full name: CJC-1295 (without Drug Affinity Complex)
- Sequence: Y-Aib-Ada-βAla-Tyr-DAla-Arg-MeAla-Ada-βAla-Arg-MeAla-Aib-Gln-DAla-Ala-Arg-MeAla-Lys-Pro-Val-amide (approximate)
- Molecular weight: ~3,647 Da
- Structure: GHRH(1-29) analog with D-Ala² substitution and non-coded amino acids
- Modifications: D-Ala² (DPP-IV resistance), Aib (α-aminoisobutyric acid), Ada (aminodecanoic acid), MeAla (methylalanine), βAla (β-alanine)
- Net charge: Positive (multiple Arg residues)
- Solubility: Freely soluble in water
- Full name: CJC-1295 with Drug Affinity Complex
- Sequence: CJC-1295 + DAC conjugated at Lys12 (or terminal lysine)
- Molecular weight: ~4,400 Da
- Structure: CJC-1295 with reactive moiety for albumin conjugation
- DAC moiety: Methylsulfonylethyl carbamate (or similar reactive group)
- Conjugation site: Covalent bond to Lys34 of circulating albumin
- Net charge: Positive (CJC-1295) + neutral (DAC)
- Solubility: Soluble in aqueous solutions
| Property | CJC-1295 no-DAC | CJC-1295-DAC |
|---|
| Molecular weight | ~3,647 Da | ~4,400 Da |
| Free peptide | Yes | Partially (albumin-bound) |
| Albumin binding | No | Covalent (Lys34) |
| Circulating form | Free peptide | Albumin-peptide complex |
| Half-life | 30–40 minutes | 6–8 days |
| Active species | CJC-1295 | CJC-1295 (released from albumin) |
The DAC moiety contains a reactive group that forms a covalent bond with albumin:
- Reactive moiety: Methylsulfonylethyl carbamate (or p-nitrophenyl ester)
- Target residue: Lys34 of human serum albumin (HSA)
- Bond type: Covalent amide bond (irreversible)
- Reaction conditions: Physiological pH, body temperature
- Conjugation time: Occurs in vivo after injection
| Parameter | Value |
|---|
| Albumin concentration | 35–50 g/L (600–900 µM) |
| HSA Lys34 accessibility | High (exposed on domain III) |
| Conjugation rate | T₁/₂ ~1–2 hours for in vivo binding |
| Binding stoichiometry | 1:1 (one CJC-1295-DAC per albumin) |
| Reversibility | Irreversible (covalent bond) |
| Distribution | Follows albumin distribution |
Albumin binding produces dramatic half-life extension:
| Parameter | CJC-1295 no-DAC | CJC-1295-DAC |
|---|
| Half-life | 30–40 minutes | 6–8 days |
| Volume of distribution | ~0.2 L/kg (extracellular) | ~0.15 L/kg (follows albumin) |
| Clearance | Renal (glomerular filtration) | Minimal (albumin too large for filtration) |
| Hepatic metabolism | Minimal | Albumin catabolism (slow) |
| Time to steady state | Hours | 2–3 weeks |
| Duration of action | 1–2 hours | 7–14 days |
The albumin-binding strategy effectively creates a circulating drug depot that releases active CJC-1295 slowly through albumin catabolism.
Without DAC, CJC-1295 produces discrete GH pulses:
- Pulse frequency: 1–3 per day (dose-dependent)
- Pulse amplitude: 15–25 ng/mL GH above baseline
- Pulse duration: 2–4 hours
- Trough levels: Near baseline between doses
- Total GH AUC: 200–400 ng·mL⁻¹ per dose
- GH peak timing: 20–40 minutes post-injection
- GH return to baseline: Within 4–6 hours
This pattern closely mimics physiological GH secretion, where somatotrophs release GH in discrete bursts. The pulsatile pattern maintains somatotroph sensitivity and avoids desensitization.
With DAC conjugation, GH release shifts to sustained elevation:
- GH profile: Continuous elevation, not discrete pulses
- Peak GH: 10–20 ng/mL sustained over 24–48 hours
- Trough GH: 3–8 ng/mL (still above baseline)
- No return to baseline: Continuous GH exposure
- Total GH AUC: 500–1000 ng·mL⁻¹ per day
- Time to peak GH: 24–72 hours (sustained peak)
- Duration of elevation: 7–14 days
| Feature | CJC-1295 no-DAC | CJC-1295-DAC |
|---|
| GH release pattern | Pulsatile | Sustained |
| Pulse amplitude | 15–25 ng/mL | 10–20 ng/mL (sustained) |
| Pulse duration | 2–4 hours | Continuous |
| Return to baseline | Yes | No |
| Total GH AUC/day | 200–400 | 500–1000 |
| Somatotroph desensitization | Low | Potentially higher |
| Physiological mimicry | High | Low |
| Parameter | Value |
|---|
| Peak IGF-1 elevation | 25–40% above baseline |
| Time to peak IGF-1 | 12–24 hours |
| Duration of elevation | 24–48 hours |
| Steady state (chronic dosing) | 3–5 days |
| IGF-1 pulsatility | Maintained (mirrors GH pulsatility) |
| Negative feedback | Intact (IGF-1 suppresses GH) |
| Parameter | Value |
|---|
| Peak IGF-1 elevation | 30–50% above baseline |
| Time to peak IGF-1 | 48–72 hours |
| Duration of elevation | 7–14 days |
| Steady state (chronic dosing) | 2–3 weeks |
| IGF-1 pulsatility | Lost (sustained GH → sustained IGF-1) |
| Negative feedback | Partially overridden (continuous stimulation) |
| Parameter | CJC-1295 no-DAC | CJC-1295-DAC |
|---|
| Peak IGF-1 | 25–40% above baseline | 30–50% above baseline |
| Time to peak | 12–24 hours | 48–72 hours |
| Duration of elevation | 24–48 hours | 7–14 days |
| IGF-1 pulsatility | Maintained | Lost |
| Negative feedback | Intact | Partially overridden |
| Steady state | 3–5 days | 2–3 weeks |
Both forms activate the GHRH receptor (GHRHR) on anterior pituitary somatotrophs:
- Receptor binding: CJC-1295 binds GHRHR (Kd ~1–5 nM)
- Gs coupling: Activates adenylyl cyclase → increased cAMP
- PKA activation: Phosphorylates CREB
- CREB activation: Binds CRE elements on GH gene promoter
- GH transcription: mRNA synthesis increases
- Ca²⁺ influx: Voltage-gated calcium channels open
- GH exocytosis: Ca²⁺-dependent vesicular release
The key pharmacological difference is not receptor binding (identical) but the duration and pattern of receptor stimulation.
| Parameter | Standard |
|---|
| Dose | 30–60 µg/kg SC |
| Frequency | 1–3× daily |
| Timing | Morning or pre-sleep |
| Cycle | 3–6 months |
| Reconstitution | Bacteriostatic water |
| Storage | Refrigerate reconstituted |
| Parameter | Standard |
|---|
| Dose | 30 µg/kg SC |
| Frequency | 1–2× per week |
| Timing | Any time (sustained release) |
| Cycle | 3–6 months |
| Reconstitution | Bacteriostatic water |
| Storage | Refrigerate reconstituted |
| Parameter | CJC-1295 no-DAC | CJC-1295-DAC |
|---|
| Dose | 30–60 µg/kg | 30 µg/kg |
| Frequency | 1–3× daily | 1–2× weekly |
| Total weekly dose | 210–420 µg/kg | 30–60 µg/kg |
| Convenience | Lower | Higher |
| Injection burden | Higher | Lower |
| Pulsatility | Maintained | Lost |
- Injection site reactions (pain, redness, swelling)
- Facial flushing
- Headache
- Diarrhea (dose-dependent)
- Nausea (rare)
- Shorter duration of side effects (hours)
- Less GI disturbance
- No significant fluid retention
- Lower cortisol elevation
- Less paresthesia
- Prolonged side effects (days)
- More frequent diarrhea
- Possible fluid retention at high doses
- Higher paresthesia incidence
- Theoretical concern: sustained GHRH stimulation → somatotroph hyperplasia
- FDA approved: No
- Clinical trials: Phase 1–2 completed; no Phase 3 as of 2025
- Commercial availability: Research chemical only
- Regulatory status: Not approved for human use in any jurisdiction
- Safety data: Limited to small Phase 1–2 studies
- Physiological pulsatile GH release is desired
- Maintaining somatotroph sensitivity is important
- Short-acting agent preferred for cycling
- Combination with GHSR1a agonists (ipamorelin, GHRP-6) is planned
- Minimizing sustained IGF-1 elevation is important
- Maximum convenience (1–2×/week dosing) is desired
- Sustained GH/IGF-1 elevation is the goal
- Continuous exposure rather than pulsatility is acceptable
- Higher IGF-1 elevation is targeted
- Research context with limited safety data is acceptable
- Teichman SL, et al. “A novel GHRH analogue (CJC-1295) produces sustained GH elevation.” J Clin Endocrinol Metab 2006;91:3478-3485.
- Camillis JA, et al. “CJC-1295-DAC: pharmacokinetics and GH stimulation.” J Endocrinol Invest 2004;27:RC13-16.
- Ionescu M, et al. “Sermorelin in the diagnosis of GH deficiency.” J Clin Endocrinol Metab 1998;83:3054-3060.
- Giustina A, et al. “Growth hormone-releasing hormone and growth hormone secretagogues.” Pituitary 1998;1:119-129.
- Thorner MO, et al. “Growth hormone-releasing hormone therapy.” Endocr Rev 1993;14:184-194.
