Studies Highlight the Potential of Liraglutide, Novo Nordisk's Investigational GLP-1 Analogue.

MUNICH, Germany -- Novo Nordisk (NYSE:NVO):

Long-Acting Analogue Offers Improved Blood Glucose Control, Weight Control and Low Risk of Hypoglycaemia, in a Once-Daily Treatment

Studies presented today at the 40th Annual Meeting of the European Association for the Study of Diabetes (EASD) underline the potential benefits of liraglutide, Novo Nordisk's investigational drug as a novel treatment for type 2 diabetes.

One study in patients showed that liraglutide, used alone or in combination with metformin, improves glycaemic control (fasting serum glucose (FSG)) compared to using metformin alone. In combination with metformin, liraglutide improved both glycaemic control (fasting serum glucose and HbA1c) and weight control when compared to glimepiride with metformin.(1)

Another study in animals showed that liraglutide demonstrated decreased food intake and weight loss compared with another investigational drug (LAF237).(2)

"These new findings add to the growing body of data supporting the potential of liraglutide as a promising and valuable therapy for treating type 2 diabetes," said Professor Michael Nauck, Diabeteszentrum, Bad Lauterberg, Germany, who presented these latest clinical data on liraglutide.

He explained that the treatment of type 2 diabetes is complicated by the need to treat frequent co-morbid conditions such as obesity, but that none of the currently available medications result in weight loss.

Studies and findings

A randomised, double-blind clinical trial in 144 subjects with type 2 diabetes,(1) examined the effects on glycaemic control and body weight of liraglutide alone or in combination with metformin compared with metformin alone or in combination with glimepiride. The results were as follows:

--After five weeks, the treatment comparisons showed that liraglutide, used alone, resulted in a significant reduction in FSG (-1.37mM). The baseline FSG in the liraglutide group was 13.3 mmol/L.

--In combination with metformin, liraglutide demonstrated improved glycaemic and weight control compared with glimepiride. The liraglutide + metformin group had a 1.25 mM greater decrease in FSG (the baseline FSG in the liraglutide + metformin group was 13.2 mmol/L).

--The liraglutide + metformin group lost 2.9 kg (3.2% body weight) more than the glimepiride + metformin group.

--With baseline values being similar, the liraglutide + metformin group was the only to have a mean decrease in HbA1c larger than 1% points (-1.1, 95% CI: -1.3; -0.8%) after 5 weeks. The difference between liraglutide monotherapy and metformin monotherapy was -0.2 (95% CI: -0.6; 0.2%). Between the two combination treatments, liraglutide + metformin and metformin + glimepiride, the difference was -0.3 (95% CI: -0.6; 0.1%). The difference between liraglutide + metformin and metformin monotherapy was -0.82 (95% CI: -1.2; -0.4).

Thus, in addition to better glycaemic control, weight loss was observed in the liraglutide + metformin group (2.4%) but not in the glimepiride + metformin group where weight gain was seen (+0.9%) compared to baseline. There were no biochemically confirmed episodes of hypoglycaemia with liraglutide treatment (alone or in combination with metformin).

Gastrointestinal side effects, although reported frequently, were mild to moderate and transient in nature. The most common gastrointestinal side effect was nausea, resulting in the withdrawal of 3 out of 72 subjects exposed to liraglutide or liraglutide in combination with metformin.

A preclinical study(2) compared the effects of liraglutide with the investigational drug LAF237 in diet-induced obese rats, fed with chow and candy to mimic the excessive food intake associated with human obesity. The presented data suggest that there are significant pharmacodynamic differences between the two drugs; whereas liraglutide is a long-acting analogue of native GLP-1, LAF237 is a DPP-IV inhibitor. DPP-IV inhibitors work by rescuing endogenous peptides normally metabolised by DPP-IV, including but not limited to GLP-1.

Thus, liraglutide gives rise to chronically elevated GLP-1 levels, whereas LAF237 gives rise to increased postprandial levels of endogenous GLP-1 and other peptide hormones. By the end of the 12-week study, liraglutide-treated rats significantly decreased their intake of candy and their body weight to the level of the lean control group. In contrast, LAF237-treated rats did not decrease their calorie intake, gained weight, and were significantly heavier than the lean control group.

Liraglutide - novel and broad action

Glucagon-Like Peptide-1 (GLP-1) demonstrates a number of potential benefits for type 2 diabetes, but in its natural state is rapidly broken down in the body and thus is not practical as a therapeutic agent. Liraglutide has already completed phase 2 clinical trials and is a once-daily long-acting analogue(3) of this naturally occurring hormone.

Liraglutide may present therapeutic benefits for type 2 diabetes because it:

--Acts in a glucose-dependent manner, meaning that it will stimulate insulin secretion and inhibit glucagon secretion only when blood glucose levels are higher than normal.(6), (7)

--Has a low risk of hypoglycaemia as observed in clinical studies to date.(4), (5)

--Improves markers of beta-cell function in patients. In a 1-week trial in 13 patients, liraglutide treatment improved all parameters in standard beta-cell function tests (IVGTT, arginine stimulation, and hyperglycaemic clamp) and, in a single-dose trial in 10 patients, beta-cell sensitivity to glucose was restored (ISR in response to graded glucose infusion).(6), (7)

--Has the potential for beta-cell regeneration as seen in animal studies.(8), (9), (10), (11)

--Controls body weight. In a 12-week trial, liraglutide and glimepiride offered similar glycaemic control but liraglutide was associated with a significant weight reduction compared with glimepiride treatment.(4)

--Is associated with mild to moderate and transient GI side effects as seen in two 12-week trials exposing more than 300 patients to liraglutide.(4), (5)

--Is suitable for once-daily administration. A short-term trial demonstrated that once-daily dosing of liraglutide significantly improves the 24-hour blood glucose profile(6) and all results in patients referenced above were obtained with once-daily dosing.

Novo Nordisk expects to initiate phase 3 clinical trials by the end of 2004.

Novo Nordisk is a healthcare company and a world leader in diabetes care. The company has the broadest diabetes product portfolio in the industry, including the most advanced products within the area of insulin delivery systems. In addition, Novo Nordisk has a leading position within areas such as haemostasis management, growth hormone therapy and hormone replacement therapy. Novo Nordisk manufactures and markets pharmaceutical products and services that make a significant difference to patients, the medical profession and society.

With headquarters in Denmark, Novo Nordisk employs approximately 18,800 full-time employees in 69 countries, and markets its products in 179 countries. Novo Nordisk's B shares are listed on the stock exchanges in Copenhagen and London. Its ADRs are listed on the New York Stock Exchange under the symbol 'NVO'. For more information, visit novonordisk.com.

References

(1) Nauck MA et al. Liraglutide significantly improves glycemic control and reduces body weight compared with glimepiride as add-on to metformin in type 2 diabetes. Poster presentation number 778, category PS-67: GLP-1 analogues, presented at: 40th annual meeting of the European Association for the Study of Diabetes (EASD), Munich, Germany, 5-9 September 2004.

(2) Knudsen LB et al. Liraglutide, a long-acting GLP-1 derivative, reduces body weight and food intake in obese candy fed rats while the DPP-IV inhibitor LAF237 does not. Poster presentation number 777, category PS-67: GLP-1 analogues, presented at: 40th annual meeting of the European Association for the Study of Diabetes (EASD), Munich, Germany, 5-9 September 2004.

(3) Knudsen LB, et al. GLP-1 derivatives as novel compounds for the treatment of type 2 diabetes: selection of NN2211 for clinical development. Drugs of the Future 2001; 26(7):677-685.

(4) Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR. Improved glycaemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analogue liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care 2004; 27(6):1335-1342.

(5) Saad et al. The effect of NN2211, a long-acting GLP-1 derivative, on glycaemic control and body weight in obese patients with Type 2 diabetes. Diabetologia 2002; 45(Suppl 2)A44. Presented at: European Association for the Study of Diabetes annual meeting, Budapest, Hungary, September 2002.

(6) Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, et al. One week's treatment with the long-acting GLP-1 derivative, liraglutide (NN2211), markedly improves 24-h glycaemia, a- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 2004; 53:1187-1194.

(7) Chang AM, Jakobsen G, Sturis J, Smith MJ, Bloem CJ, Galecki A, Halter JB. The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes 2003; 52:1786-1791.

(8) Sturis J, Gotfredsen CF, Romer J, Rolin B, Ribel U, Brand CL, et al. GLP-1 derivative liraglutide in rats with beta-cell deficiencies influence of metabolic state on beta-cell mass dynamics. Br J Pharmacol 2003; 140:123-132.

(9) Rolin B, Larsen MO, Gotfredsen CF, Deacon CF, Carr RD, Wilken M, Knudsen LB. The long-acting GLP-1 derivative, NN2211, ameliorates glycaemia and increases beta-cell mass in diabetic mice. Am J Physiol Endocrin Metab 2002; 283:E745-E752.

(10) Bregenholt S et al. The GLP-1 analogue, NN2211, inhibits free fatty acid-induced apoptosis in primary rat b-cells. Diabetologia 2001; 44(S1):A19.

(11) Bregenholt S et al. The GLP-1 derivative NN2211 inhibits cytokine-induced apoptosis in primary rat b-cells. Diabetes 2001; 50(S2):A31.

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