Albugon and CJC-1131/1134 are GLP-1-albumin proteins which exploit the long circulating half life of albumin to extend the short duration of action of native GLP-1. Whereas CJC-1131 is a human GLP-1 analogue that forms a covalent bond with human serum albumin following subcutaneous injection of the free CJC-1131 peptide in vivo, CJC1134 is Exendin-4 conjugated to albumin. Albugon is a recombinant GLP-1-albumin protein produced ex vivo prior to administration of the much larger single recombinant protein in vivo. See the August 24 2005 Conjuchem Press Release for details.
The mechanisms of CJC1134 action on the pancreas, gut and CNS have been examined in preclinical studies in WT and Glp1r-/- mice. Although high molecular weight CJC1134 does not appear to rapidly traverse the blood brain barrier and directly engage central GLP-1 receptors, peripheral administration of CJC1134 rapidly activates c-FOS in multiple regions of the CNS. Moreover, CJC1134 promotes satiety and inhibits gastric emptying in a GLP-1R-dependent manner, and chronic administration is associated with weight loss in mice. Hence, these findings provide further evidence supporting the importance of ascending GLP-1R-dependent neural signals for transmission of responses controlling satiety and gut motility in vivo. See An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis Gastroenterology 2008, do1:10.1053/j.gastro.2008.01.017
Preliminary Clinical Data for CJC-1134 was provided in a Press Release on April 26 2006, describing improved tolerability and promising efficacy in an escalating dose Phase 1B study in human subjects with Type 2 diabetes.
A repeat dose study of CJC1134 was reported, in preliminary form, in a March 26 2007 Press Release. Patients with Type 2 Diabetes on metformin received 3 doses of the drug, over a 4 week period, and all 3 treatment arms, 1-3 mg once weekly, reported a significant reduction in fasting glucose. Similarly HbA1c improved in all three treatment groups with median HbA1c decreasing 0.5%, 0.8%, and 0.6% in the 1 mg, 2 mg, and 3 mg groups at the end of the five-week period, and decreasing 0.7%, 0.6%, and 0.7% at day 49, and decreasing 0.7%, 0.8%, and 0.9% at the end of the study period (day 63).
Albugon, a recombinant-GLP-1 protein, lowers blood glucose and enhances insulin secretion in mice, and stimulates GLP-1R-dependent cAMP accumulation in cells expressing the GLP-1 receptor. Remarkably, Albugon also activates c-fos expression in multiple regions of the central nervous system, inhibits gastric emptying and inhibits food intake in mice following both icv and peripheral administration. For an overview of the data, see A Recombinant Human Glucagon-Like Peptide (GLP)-1-Albumin Protein (Albugon) Mimics Peptidergic Activation of GLP-1 Receptor-Dependent Pathways Coupled With Satiety, Gastrointestinal Motility, and Glucose Homeostasis. Diabetes. 2004 Sep;53(9):2492-500.
On October 26 2004, GlaxoSmithKline and Human Genome Sciences announced a co-development deal for Albugon, as described in the Press Release.
CJC-1131 is a human GLP-1 analogue, modified to be resistant to DPP-4, with a reactive chemical linker at the carboxy terminal end of the molecule which permits covalent coupling to albumin (Cys 34 residue) following administration in vivo. This drug is no longer under active clinical development. As albumin exhibits a long circulating half life in vivo, the underlying premise is that albumin-conjugated drugs should exhibit prolonged action, and delayed clearance, consistent with the known turnover of albumin in human subjects, which is estimated to exhibit a t1/2 of about 15-19 days.
Although CJC-1131 linked to albumin exhibits a decreased binding affinity at the GLP-1 receptor, it still retains the ability to bind and activate the GLP-1 receptor both in vitro and in vivo, and studies in normal and diabetic rodents demonstrate that CJC-1131 exhibits the full spectrum of GLP-1-dependent activities, including glucose control, stimulation of insulin secretion and insulin biosynthesis, regulation of food intake and body weight, and stimulation of islet neogenesis and expansion of islet mass, as illustrated in Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo. Diabetes. 2003 Mar;52(3):751-9.
CJC-1131 was originally developed by Conjuchem Inc, and more information about the drug affinity complex (DAC) technology and the molecule may be found at www.conjuchem.com
To review the preliminary human clinical trial data achieved in the first 4 weeks of the Phase 2 trial with CJC-1131, see the April 12 2004 Press Release from Conjuchem.
The Phase 2 study was carried out to determine the optimal dosing regimen and frequency of drug administration in patients with Type 2 diabetes.
Patients included in the study had an entry HbA1c level greater than 7.5%, and most patients were on one or two oral anti-diabetic medications. The trial enrolled 206 patients, whose oral anti-diabetic medications were withdrawn up to 15 days prior to receiving DAC(TM):GLP-1. The male to female ratio was 69 to 31, the mean age for the study population was 56±10 years and the mean duration of disease was 5.0±2.9 years. The mean HbA1c level at the time of inclusion in the study was 8.45±0.9% with an average basal fasting glucose level of 11.9±3.0 mmol/l.
Patients were washed out of previous drug, treated for one month with daily doses of CJC-1131 to the maximum tolerated dose, then randomized to receive drug either once a day (OD), three times a week (EOD), twice a week (TW), once a week (OW)) or a no treatment control cohort (NT). During the 56-day maintenance phase, patient dosages were individually adjusted with the objective of maintaining stable plasma concentrations.
Nausea and vomiting was dose-limiting in all cohorts, and prevented patients in the less frequent administration regimens from receiving target drug doses, with patients in the once a week cohort only able to attain, on average, approximately 35% of the target dosing levels. Nevertheless, all patients achieved significant improvements in glycemic control, with the best results observed in the once daily dosing cohort. To review the data, see the July 14 2004 Press Release.
Conjuchem also initiated a separate Phase 2 study of CJC-1131 as an add on therapy in diabetic patients previously treated with metformin, as described in a separate Metformin Study May 26 2004 Press Release.
The results of this double blind study, described in a Press Release dated Dec 15 2004, demonstrated that once daily CJC-1131, when added to existing metformin treatment, produced a significant reduction in HbA1c of ~ 1%, together with weight loss of about 2.5 kg, in a 12 week study of patients with type 2 diabetes. Patient characteristics included a pre-treatment BMI of about 32, HbA1c of 7.93% and mean duration of diabetes just over 7 years. The drop out rate, due to nausea, lack of efficacy, and other factors, was about 24% in patients treated with CJC-1131 who received mean daily doses in single injections of either 2.1 (low dose) or 2.6 (high dose) ug/kg per day.