Thread: Study of CJC 1295

Prolonged Stimulation of Growth Hormone and IGF-1 Secretion by CJC-1295, a Long-acting Analogue of Growth Hormone-Releasing Hormone, in Healthy Adults
Sam L. Teichman, Ann Neale, Betty Lawrence, Catherine Gagnon, Jean-Paul Castaigne, and Lawrence A. Frohman*

WinPharm Associates, San Ramon CA.; ConjuChem, Inc., Montréal, Québéc, Canada; Section of Endocrinology, Department of Medicine, University of Illinois at Chicago, Chicago IL

Context: Therapeutic use of growth hormone-releasing hormone (GHRH) to enhance GH secretion is limited by its short duration of action.

Objective: To examine the pharmacokinetic profile, pharmacodynamic effects, and safety of CJC-1295, a long-acting GHRH analog.

Design: Two randomized, placebo-controlled, double-blind, ascending dose trials with durations of 28 and 49 days.

Setting: Two investigational sites.

Participants: Healthy subjects, ages 21 to 61 yr.

Interventions: sc administration of CJC-1295 or placebo in one of 4 ascending single doses in the first study and in 2 - 3 weekly or biweekly doses in the second study.

Main Outcome Measures: Peak concentrations and area under the curve (AUC) of GH and IGF-1; standard pharmacokinetic parameters for CJC-1295.

Results: After a single injection of CJC-1295, there were dose-dependent increases in mean plasma GH concentrations by 2-10 fold for 6 days and in mean plasma IGF-1 concentrations by 1.5- to 3-fold for 9 - 11 days. The estimated half-life of CJC-1295 was 5.8 - 8.1 days. After multiple CJC-1295 doses, mean IGF-1 levels remained above baseline for up to 28 days. No serious adverse reactions were reported.

Conclusions: sc administration of CJC-1295 resulted in sustained, dose-dependent increases in GH and IGF-1 levels in healthy adults and was safe and relatively well-tolerated, particularly at doses of 30 µg/kg or 60 µg/kg. There was evidence of a cumulative effect after multiple doses. These data support the potential utility of CJC-1295 as a therapeutic agent.

Pulsatile Secretion of Growth Hormone (GH) Persists During Continuous Stimulation by CJC-1295, a Long-Acting GHRH Analog
Madalina Ionescu and Lawrence A. Frohman*
Section of Endocrinology, Metabolism, and Diabetes, University of Illinois at Chicago, Chicago, IL 60608


Context: Pulsatile GH secretion is considered important for many of the hormone's physiologic effects. Short-term GHRH infusions enhance GH pulsatility and increase IGF-1, but the short GHRH half-life limits its therapeutic use. A synthetic GHRH analog (CJC-1295) that binds permanently to endogenous albumin after injection (t1/2 = 8 d) stimulates GH and IGF-1 secretion in several animal species and in normal human subjects and enhances growth in rats.

Objective: To assess GH pulsatility after a single injection of CJC-1295 and determine which GH secretion parameters correlated to the increase in IGF-1 production.

Methods: GH pulsatility was assessed by 20-minute blood sampling during an overnight 12 h period in healthy 20-40 yr old men before and one week after injection of either 60 or 90 µg/kg CJC-1295.

Results: GH secretion was increased after CJC-1295 administration with preserved pulsatility. The frequency and magnitude of GH secretory pulses were unaltered. However, basal (trough) GH levels was markedly increased (7.5 fold; P < 0.0001) and contributed to an overall increase in GH secretion (mean GH levels: 46%; P < 0.01) and IGF-1 levels (45%; P < 0.001). No significant differences were observed between the responses to the two drug doses. The IGF-1 increases did not correlate with any parameters of GH secretion.

Conclusions: CJC-1295 increased trough and mean GH secretion and IGF-1 production with preserved GH pulsatility. The marked enhancement of trough GH levels by continuous GHRH stimulation implicates the importance of this effect on increasing IGF-1. Long-acting GHRH preparations may have clinical utility in patients with intact pituitary GH secretory capability.