Phase 3a Liraglutide 3 mg Trial Demonstrated Significant Weight Loss and Improved Cardiovascular Risk Factors in Adults With Obesity and Type 2 Diabetes Compared With Placebo

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Jun 21, 2014, 02:00 ET

CHICAGO, June 21, 2014 /PRNewswire/ --

Today, new data from the phase 3a SCALE™ Diabetes trial were presented at the International Congress of Endocrinology (ICE) and the Endocrine Society's meeting (ENDO), investigating the effect of liraglutide 3 mg in adults with obesity and type 2 diabetes or who were overweight with type 2 diabetes. Data demonstrated that at 56 weeks, in addition to clinically meaningful weight loss, treatment with liraglutide 3 mg provided statistically significantly greater improvements in risk factors for cardiovascular (CV) disease, compared with placebo, in combination with diet and physical activity.

All treatment groups followed a reduced-calorie diet and increased physical activity programme. At 56 weeks of treatment, the SCALE™ Diabetes trial demonstrated that adults treated with liraglutide 3 mg achieved significantly greater mean weight loss of 5.9% compared with 2.0% with placebo (P<0.0001). The 3.0 mg dose also produced more weight loss than liraglutide 1.8 mg (4.6%, P=0.0024). Waist circumference was also significantly reduced with both liraglutide 3 mg (-6.0 cm) and liraglutide 1.8 mg(-4.9 cm), compared with placebo (-2.8 cm, P≤0.0004).^[¹^]

"Cardiovascular disease is a major concern in people with obesity and type 2 diabetes," said Dr. Ralph DeFronzo, Deputy Director of the Texas Diabetes Institute, San Antonio and a SCALE™ Diabetes trial investigator. "The results from the SCALE™ Diabetes trial indicate that treatment with liraglutide 3 mg may lead to improvements across a number of cardiovascular disease risk factors, including cholesterol and blood pressure, which may be especially important for this patient population."

A moderate weight loss of 5% to 10% has been shown to reduce risk factors for CV disease in people with obesity.^[²^]^,^[³^] In the SCALE™ Diabetes trial, liraglutide 3 mg and 1.8 mg significantly reduced systolic blood pressure by 3.0 and 3.1 mm Hg, respectively, compared with 0.4 mm Hg with placebo (P<0.05). No significant difference between treatments was observed in diastolic blood pressure. Compared with baseline, liraglutide 3 mg significantly improved total cholesterol (-4%) and fasting lipid levels, including very low density lipoproteins, high density lipoproteins and triglycerides (-13%, +3% and -14%, respectively, P<0.05). Liraglutide 1.8 mg had no significant effect on cholesterol or lipid levels.

Liraglutide 3 mg and 1.8 mg significantly improved levels of the inflammatory marker C-reactive protein (CRP) by -27% and -25% compared with placebo (P≤0.0002). CRP is elevated in people with obesity and is a good predictor of CV disease.^[⁴^] Compared with placebo, liraglutide 3 mg additionally improved CV risk factors, including the blood clot risk factor plasminogen activator inhibitor-1 (-24%, P=0.0004) and the urinary albumin/creatinine ratio (-20%, P=0.0086),which is a common marker for chronic kidney disease.^[⁵^]

The most frequently reported side effects were gastrointestinal disorders (driven by nausea and diarrhoea), and occurred in 65% of people treated with liraglutide 3 mg compared with 56% with liraglutide 1.8 mg and 39% with placebo. The most common adverse events occurring in more than 5% of people treated with liraglutide 3 mg included hypoglycaemia, decreased appetite, abdominal distension, abdominal pain, dyspepsia, flatulence, vomiting, constipation, nasopharyngitis (usually referred to as the common cold), upper respiratory tract infection, influenza, back pain, musculoskeletal pain, arthralgia, headache, dizziness, fatigue, and increased lipase. The most frequent side effects leading to withdrawal from the liraglutide 3 mg treatment group were gastrointestinal disorders (5.7%).^[¹^]

In December 2013, based on the results of the SCALE™ clinical development programme, Novo Nordisk submitted a New Drug Application and a Marketing Authorisation Application to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), respectively, for liraglutide 3 mg for chronic weight management in adults who have obesity (BMI ≥30 kg/m^[²^]), or are overweight (BMI ≥27 kg/m^[²^]) with comorbidities, as an adjunct to a reduced-calorie diet and increased physical activity.^[¹^] These applications are under review.

Liraglutide is currently available in the U.S. at a lower dose (1.2 mg and 1.8 mg) under the brand name Victoza^® (liraglutide [rDNA origin] injection) for treatment of adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve blood glucose control. Victoza^® is not approved for weight management.^[⁶^]

FDA guidance recommends that any investigational product being developed for weight management should be investigated in people with type 2 diabetes, as overweight and obese patients with type 2 diabetes often respond less favourably to weight-management medications.^[⁷^] The FDA requested the inclusion of liraglutide 1.8 mg (Victoza^®) in the SCALE™ Diabetes study to bridge to the safety and efficacy data for Victoza^® in the treatment of adults with type 2 diabetes.

About liraglutide 3 mg

Liraglutide 3 mg is a once-daily glucagon-like peptide-1 (GLP-1) analogue with 97% similarity to naturally occurring human GLP-1,^[⁸^] a hormone that is released in response to food intake. Like human GLP-1, liraglutide 3 mg regulates appetite and food intake by decreasing hunger and increasing feelings of fullness and satiety after eating.^[⁹^]^,^[ ¹⁰^] The dual actions of liraglutide 3 mg on both appetite and blood glucose regulation (for adults with pre-diabetes or type 2 diabetes) hold therapeutic potential for adults with obesity, both those with and without type 2 diabetes.

Liraglutide 3 mg is an investigational product and is not approved by the FDA or EMA.

About SCALE™ Diabetes

SCALE™ Diabetes^[¹¹^] is a multinational 56-week, randomised, placebo-controlled, double-blind phase 3a clinical trial involving 846 adults with obesity or who are overweight and have type 2 diabetes. It was designed to demonstrate clinically meaningful weight loss with liraglutide 3 mg in this population. It is one of four trials in the SCALE™ clinical development programme, which encompassed more than 5,000 participants who are obese with or without comorbidities or overweight with comorbidities.

About Victoza^® (liraglutide [rDNA origin] injection)

Victoza^® is a human glucagon-like peptide-1 (GLP-1) analog that was approved by the U.S. Food and Drug Administration on January 25, 2010, as an adjunct to diet and exercise to improve blood sugar control in adults with type 2 diabetes.

As of January 2014, Victoza^® has been commercially launched in 68 countries globally including the U.S., Canada, Japan, U.K., Germany, France, Italy, Denmark, Hungary, Russia, India, Brazil, Mexico, Argentina, Malaysia, and China, as well as a number of other countries, and will be available in other markets throughout 2014.

Indications and Usage:

Victoza^® (liraglutide [rDNA origin] injection) is an injectable prescription medicine that may improve blood sugar (glucose) in adults with type 2 diabetes when used along with diet and exercise.

Victoza^® is not recommended as the first medication to treat diabetes. Victoza^® has not been studied in patients with history of inflammation of the pancreas (pancreatitis). Victoza^® is not a substitute for insulin and has not been studied in combination with prandial (mealtime) insulin. Victoza^® is not for people with type 1 diabetes or people with diabetic ketoacidosis. It is not known if Victoza^® is safe and effective in children. Victoza^® is not recommended for use in children.

Important Safety Information:

In animal studies, Victoza^® caused thyroid tumors-including thyroid cancer-in some rats and mice. It is not known whether Victoza^® causes thyroid tumors or a type of thyroid cancer called medullary thyroid cancer (MTC) in people, which may be fatal if not detected and treated early. Do not use Victoza^® if you or any

Important Safety Information (cont'd):

of your family members have a history of MTC or if you have Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). While taking Victoza^® (liraglutide [rDNA origin] injection), tell your doctor if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer.

Do not use Victoza^® if you are allergic to liraglutide or any of the ingredients in Victoza^®. Serious allergic reactions can happen with Victoza^®. If symptoms of serious allergic reactions occur, stop taking Victoza^® and seek medical attention. Pancreatitis may be severe and lead to death. Before taking Victoza^®, tell your doctor if you have had pancreatitis, gallstones, a history of alcoholism, or high blood triglyceride levels since these medical conditions make you more likely to get pancreatitis.

Stop taking Victoza^® and call your doctor right away if you have pain in your stomach area that is severe and will not go away, occurs with or without vomiting, or is felt going from your stomach area through to your back. These may be symptoms of pancreatitis.

Before using Victoza^®, tell your doctor about all the medicines you take, especially sulfonylurea medicines or insulin, as taking them with Victoza^® may affect how each medicine works. If you use Victoza^® with insulin, you may give both injections in the same body area (for example, your stomach area), but not right next to each other.

Also tell your doctor if you have severe stomach problems such as slowed emptying of your stomach (gastroparesis) or problems with digesting food; have or have had kidney or liver problems; have any other medical conditions; or are pregnant or plan to become pregnant. Tell your doctor if you are breastfeeding or plan to breastfeed. It is unknown if Victoza^® will harm your unborn baby or if Victoza^® passes into your breast milk.

Your risk for getting hypoglycaemia, or low blood sugar, is higher if you take Victoza^® with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. The dose of your sulfonylurea medicine or insulin may need to be lowered while taking Victoza^®.

Victoza^® may cause nausea, vomiting, or diarrhea leading to dehydration, which may cause kidney failure. This can happen in people who have never had kidney problems before. Drinking plenty of fluids may reduce your chance of dehydration.

The most common side effects with Victoza^® include headache, nausea, and diarrhea. Nausea is most common when first starting Victoza^®, but decreases over time in most people. Immune system related reactions, including hives, were more common in people treated with Victoza^® compared to people treated with other diabetes drugs in medical studies.

Please click here for Prescribing Information and Medication Guide.

About Novo Nordisk

Headquartered in Denmark, Novo Nordisk is a global healthcare company with 90 years of innovation and leadership in diabetes care. The company also has leading positions within haemophilia care, growth hormone therapy and hormone replacement therapy. Novo Nordisk employs approximately 40,000 employees in 75 countries, and markets its products in more than 180 countries. For more information, visit novonordisk.com.

References

1. Data on file. Novo Nordisk Inc; Plainsboro, NJ.

2. Dengo AL, Dennis EA, Orr JS, et al. Arterial destiffening with weight loss in overweight and obese middle-aged and older adults. Hypertension. 2010;55(4):855-861.

3. Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr. 1992;56:320-328.

4. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA. 1999;282(22):2131-2135.

5. Eddy AA, Fogo AB. Plasminogen activator inhibitor-1 in chronic kidney disease: evidence and mechanisms of action. J Am Soc Nephrol. 2006;17:2999-3012.

6. Victoza [package insert]. Plainsboro, NJ: Novo Nordisk Inc; 2013.

7. FDA. Guidance for Industry Developing Products for Weight Management. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071612.pdf. Published 2007. Accessed May 8, 2014.

8. Knudsen LB, Nielsen PF, Huusfeldt PO, et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem. 2000;43(9):1664-1669.

9. Flint A, Raben A, Ersbøll AK, Holst JJ, Astrup A. The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes. 2001;25(6):781-792.

10. van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. [published online ahead of print October 1, 2013]. Int J Obes. doi:10.1038/ijo.2013.162.

11. SCALE™ Diabetes ClinicalTrials.gov study registration: NCT01272232.

SOURCE Novo Nordisk