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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
Context: Therapeutic use of GHRH to enhance GH secretion is limited by its short duration of action.
Objective: The objective of this study was to examine the pharmacokinetic profile, pharmacodynamic effects, and safety of CJC-1295, a long-acting GHRH analog.
Design: The study design was two randomized, placebo-controlled, double-blind, ascending dose trials with durations of 28 and 49 d.
Setting: The study was performed at two investigational sites.
Participants: Healthy subjects, ages 21–61 yr, were studied.
Interventions: CJC-1295 or placebo was administered sc in one of four ascending single doses in the first study and in two or three weekly or biweekly doses in the second study.
Main Outcome Measures: The main outcome measures were peak concentrations and area under the curve of GH and IGF-I; standard pharmacokinetic parameters were used for CJC-1295.
Results: After a single injection of CJC-1295, there were dose-dependent increases in mean plasma GH concentrations by 2- to 10-fold for 6 d or more and in mean plasma IGF-I concentrations by 1.5- to 3-fold for 9–11 d. The estimated half-life of CJC-1295 was 5.8–8.1 d. After multiple CJC-1295 doses, mean IGF-I levels remained above baseline for up to 28 d. No serious adverse reactions were reported.
Conclusions: Subcutaneous administration of CJC-1295 resulted in sustained, dose-dependent increases in GH and IGF-I levels in healthy adults and was safe and relatively well tolerated, particularly at doses of 30 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.
THE USE OF GH for the treatment of children with impaired linear growth has been accepted as an important therapeutic modality for more than 50 yr (1). An unlimited supply of the hormone, made possible by the availability of recombinant GH in the 1980s, permitted expansion of the target population to include GH-deficient adults. Most adults receiving GH today have primary pituitary disease with impaired GH secretory capacity. However, most children being treated with GH have no evidence of pituitary disease and are believed to have an impaired hypothalamic signaling mechanism due to a GHRH neurosecretory dysfunction. GH has also been used for therapy of disorders in children and adults in which pituitary function is either intact or only slightly impaired, such as chronic renal failure and Turner syndrome (in children) and HIV-related wasting and lipodystrophy and burn therapy (in adults).
In patients with intact pituitary function, there has been interest in the use of GHRH rather than GH in the hope of producing a more physiological pattern of tissue exposure to GH than occurs by a single daily injection of the hormone. In fact, several studies in both children and adults have suggested that comparable or near-comparable results can be achieved with GHRH therapy (2, 3, 4).
A major limitation in the use of GHRH for therapy, however, is its short half-life. Native GHRH, a 44-amino acid peptide, has a half-life of 7 min (5), which is even shorter than that of GH (12 min) (6), necessitating daily or even more frequent injections. Polyethylene glycol-conjugated GHRH has been studied in an effort to overcome this limitation (7).
A synthetically modified form of GHRH has been linked to a reactive chemical that enables binding to endogenous serum albumin after sc administration. The chemical structure of this compound, drug affinity complex-GH-releasing factor (DAC-GRF; CJC-1295, ConjuChem, Inc., Montréal, Canada) is shown in Fig. 1. The core therapeutic moiety is GHRH-(1–29)NH2, which contains the full biological activity of GHRH-(1–44)NH2 modified by substitution of four amino acids that serve to render the compound more resistant to proteolytic cleavage (herein called GRF). GRF is linked by the amino acid, lysine, to a reactive chemical [maleimidoproprionic acid (MPA)] that binds to unpaired thiol (sulfhydryl) groups. The predominant free thiol group available for binding after parenteral administration is the single unpaired cysteine (cysteine 34) in serum albumin. At least 90% of CJC-1295 binds covalently to albumin in this fashion, with trace amounts found bound to fibrinogen and IgG. No other chemical species have been found bound to DAC-GRF after administration (data on file, ConjuChem, Inc.). This binding extends the half-life of the active pharmacophore, resulting in a markedly prolonged duration of action in several animal species (8). Moreover, studies in both dogs and pigs indicate that physiological GH secretion is maintained, and IGF-I levels are enhanced for several days after a single administration.
We assessed the safety, tolerability, pharmacokinetic profile, and effect of CJC-1295 on circulating concentrations of GH and IGF-I in two randomized, placebo-controlled, double-blind, dose-escalating studies in healthy adult subjects.
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Context: Therapeutic use of GHRH to enhance GH secretion is limited by its short duration of action.
Objective: The objective of this study was to examine the pharmacokinetic profile, pharmacodynamic effects, and safety of CJC-1295, a long-acting GHRH analog.
Design: The study design was two randomized, placebo-controlled, double-blind, ascending dose trials with durations of 28 and 49 d.
Setting: The study was performed at two investigational sites.
Participants: Healthy subjects, ages 21–61 yr, were studied.
Interventions: CJC-1295 or placebo was administered sc in one of four ascending single doses in the first study and in two or three weekly or biweekly doses in the second study.
Main Outcome Measures: The main outcome measures were peak concentrations and area under the curve of GH and IGF-I; standard pharmacokinetic parameters were used for CJC-1295.
Results: After a single injection of CJC-1295, there were dose-dependent increases in mean plasma GH concentrations by 2- to 10-fold for 6 d or more and in mean plasma IGF-I concentrations by 1.5- to 3-fold for 9–11 d. The estimated half-life of CJC-1295 was 5.8–8.1 d. After multiple CJC-1295 doses, mean IGF-I levels remained above baseline for up to 28 d. No serious adverse reactions were reported.
Conclusions: Subcutaneous administration of CJC-1295 resulted in sustained, dose-dependent increases in GH and IGF-I levels in healthy adults and was safe and relatively well tolerated, particularly at doses of 30 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.
THE USE OF GH for the treatment of children with impaired linear growth has been accepted as an important therapeutic modality for more than 50 yr (1). An unlimited supply of the hormone, made possible by the availability of recombinant GH in the 1980s, permitted expansion of the target population to include GH-deficient adults. Most adults receiving GH today have primary pituitary disease with impaired GH secretory capacity. However, most children being treated with GH have no evidence of pituitary disease and are believed to have an impaired hypothalamic signaling mechanism due to a GHRH neurosecretory dysfunction. GH has also been used for therapy of disorders in children and adults in which pituitary function is either intact or only slightly impaired, such as chronic renal failure and Turner syndrome (in children) and HIV-related wasting and lipodystrophy and burn therapy (in adults).
In patients with intact pituitary function, there has been interest in the use of GHRH rather than GH in the hope of producing a more physiological pattern of tissue exposure to GH than occurs by a single daily injection of the hormone. In fact, several studies in both children and adults have suggested that comparable or near-comparable results can be achieved with GHRH therapy (2, 3, 4).
A major limitation in the use of GHRH for therapy, however, is its short half-life. Native GHRH, a 44-amino acid peptide, has a half-life of 7 min (5), which is even shorter than that of GH (12 min) (6), necessitating daily or even more frequent injections. Polyethylene glycol-conjugated GHRH has been studied in an effort to overcome this limitation (7).
A synthetically modified form of GHRH has been linked to a reactive chemical that enables binding to endogenous serum albumin after sc administration. The chemical structure of this compound, drug affinity complex-GH-releasing factor (DAC-GRF; CJC-1295, ConjuChem, Inc., Montréal, Canada) is shown in Fig. 1. The core therapeutic moiety is GHRH-(1–29)NH2, which contains the full biological activity of GHRH-(1–44)NH2 modified by substitution of four amino acids that serve to render the compound more resistant to proteolytic cleavage (herein called GRF). GRF is linked by the amino acid, lysine, to a reactive chemical [maleimidoproprionic acid (MPA)] that binds to unpaired thiol (sulfhydryl) groups. The predominant free thiol group available for binding after parenteral administration is the single unpaired cysteine (cysteine 34) in serum albumin. At least 90% of CJC-1295 binds covalently to albumin in this fashion, with trace amounts found bound to fibrinogen and IgG. No other chemical species have been found bound to DAC-GRF after administration (data on file, ConjuChem, Inc.). This binding extends the half-life of the active pharmacophore, resulting in a markedly prolonged duration of action in several animal species (8). Moreover, studies in both dogs and pigs indicate that physiological GH secretion is maintained, and IGF-I levels are enhanced for several days after a single administration.
We assessed the safety, tolerability, pharmacokinetic profile, and effect of CJC-1295 on circulating concentrations of GH and IGF-I in two randomized, placebo-controlled, double-blind, dose-escalating studies in healthy adult subjects.
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