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Lyxumia® Combined With Insulin Demonstrates Significant HbA1C Reductions And Improvements In Post-Prandial Glucose In Type 2 Diabetes

Phase III GetGoal studies support the need to improve PPG control, independent of FPG levels 1,2,3,4

Sanofi announced on Monday that once-daily Lyxumia® () achieved the primary efficacy endpoint of significantly reducing HbA1c in combination with Lantus® (), with an associated significant reduction in post-prandial glucose (PPG), in patients with uncontrolled (T2DM) on oral anti-diabetics (OADs). 1

Positive results from the GetGoal Duo1 study, presented at the (ADA) meeting, showed that HbA1c decreased on average from 8.60% to 7.60% during the run-in period with insulin glargine. 1 The addition of lixisenatide led to a further significant HbA1c decrease to 6.96% after 24 weeks, compared to 7.3% in patients receiving placebo (p<0.0001). A significantly higher percentage of patients achieved target HbA1c of <7.0% with lixisenatide, compared to placebo (56.3% vs. 38.5%, respectively, p=0.0001). Results also showed a beneficial effect on body weight. 1

In order to achieve complete glycaemic control in T2DM, both fasting plasma glucose (FPG) and PPG components need to be addressed.5 PPG is the term used to define plasma glucose concentrations after eating. A patient’s PPG profile is determined by carbohydrate absorption, insulin and glucagon secretion, and their co-ordinated effects on glucose metabolism in the liver and peripheral tissues.

With traditional treatment regimens focusing on FPG control, approximately 40% of patients currently treated with basal insulin+OADs are not achieving target HbA1c, despite optimised FPG control. This can be due to inadequately controlled PPG. The role of PPG in overall HbA1c control is therefore increasingly recognised. 5 A wider choice of therapies to target PPG would support patients in achieving better control of their condition.

”This is a useful step towards meeting the demand for a combination therapy to address the needs of some uncontrolled Type 2 diabetes patients who fail to meet HbA1c targets despite controlled fasting plasma glucose,” said Dr. Martin Hadley Brown, Chair of the Primary Care Diabetes Society and GP from Norfolk. “These results suggest that once-daily lixisenatide in combination with Lantus® could be an innovative therapeutic option by addressing post-prandial glucose levels in a simple and convenient once-daily regimen which reduces the chance of weight gain.”

This randomised, double-blind, placebo-controlled study included a 12-week run-in period with insulin glargine initiated and titrated to reach a target fasting plasma glucose of 80-100 mg/dL (4.44-5.56 mmol/l) followed by a 24-week randomised period where 446 patients with HbA1c ≥7% – despite controlled fasting plasma glucose – received either lixisenatide once-daily or placebo while insulin glargine and metformin were continued. 1

Consistent with the GLP-1 class, the most common adverse events were nausea and vomiting. Fifty (22.4%) lixisenatide-treated patients and 30 (13.5%) patients in the placebo group reported symptomatic hypoglycaemic events as defined in the protocol during the on-treatment period. 1

Also presented at ADA were results from the GetGoal-L study, which showed that lixisenatide added to a variety of non-optimised basal insulin ± metformin, also significantly reduced HbA1c, PPG and body weight vs placebo. 2 This 24-week randomised, double-blind multicentre, placebo-controlled study concluded that lixisenatide achieved its primary efficacy endpoint of significantly reducing HbA1c vs. placebo (p=0.0002). Full results will be published in a peer review journal later this year. 2 The GetGoal programme also undertook an elderly subanalysis which found that the efficacy and safety profile of lixisenatide is similar regardless of age, with comparable decreases in HbA1C, adverse event rates and the incidence of hypoglycaemia. 3 “It is refreshing to see that this trial reflected real life, with patients over the age of 70 included in the randomisation. These results show that this product appears to be equally effective and equally safe in the elderly as in the general adult population on basal insulins who have raised HbA1c levels, but with FPG at goal,” commented Dr Richard Brice, a GP from Eastern and Coastal Kent PCT.

In addition, results of the GetGoal-P study were presented at the meeting, which showed that lixisenatide provides significantly greater reductions in HbA1C compared with placebo in patients with T2DM insufficiently controlled on pioglitazone ± metformin. 4

On November 16th, 2011 the European Medicines Agency (EMA) accepted Sanofi’s marketing authorisation application filed for Lyxumia® (lixisenatide). Submission for regulatory approval of lixisenatide in the U.S. is expected in Q4 2012.

About Lyxumia® (lixisenatide)

Lixisenatide*, a glucagon-like peptide-1 agonist (GLP-1), is in development for the treatment of patients with Type 2 diabetes mellitus (T2DM).1 Lixisenatide was in-licensed from Zealand Pharma A/S (Copenhagen, Denmark), www.zealandpharma.com. Lyxumia® is the intended trademark of lixisenatide. Lixisenatide is not currently approved or licensed anywhere in the world.

* To date, GetGoal-X, GetGoal-L,2 GetGoal-L Asia, GetGoal-Mono, GetGoal-S, GetGoal-F1 and GetGoal Duo 11 (also known as EFC10781*) have reported positive top-line results supporting potential efficacy and safety for lixisenatide.

GLP-1 is a naturally-occurring peptide that is released within minutes of eating a meal. It is known to suppress glucagon secretion from pancreatic alpha cells and stimulate insulin secretion by pancreatic beta cells. GLP-1 receptor agonists are in development as an add-on treatment for T2DM and their use is endorsed by the European Association for the Study of Diabetes, the American Diabetes Association, the American Association of Clinical Endocrinologists and the American College of Endocrinology.

About the GetGoal clinical trial programme

The GetGoal phase III clinical programme provides data for lixisenatide in adults with T2DM treated monotherapy, with various oral anti-diabetic agents or in combination with basal insulin. The GetGoal programme started in May 2008 and has enrolled more than 4,500 patients.

Source

1 Rosenstock J. et al. Efficacy and Safety of Once-Daily Lixisenatide Added on to Titrated Glargine plus Oral Agents in Type 2 Diabetes: GetGoal-Duo 1 Study. Abstract presented at the 2012 72nd Scientific Session at the American Diabetes Association Meeting, Philadelphia, USA. Oral 062-OR

2 Riddle M. et al. Efficacy and Safety of Once-Daily Lixisenatide in Type 2 Diabetes Insufficiently Controlled with Basal Insulin ± Metformin: GetGoal-L Study. Abstract presented at the 2012 72nd Scientific Session at the American Diabetes Association Meeting, Philadelphia, USA. Poster 983-P

3 Racchach D et al. Efficacy and Safety of Lixisenatide in Elderly (~65 yr) and Very Elderly (~75 yr) Patients with Type 2 Diabetes: An Analysis from the GetGoal Phase 3 Program. Abstract presented at the 2012 72nd Scientific Session at the American Diabetes Association Meeting, Philadelphia, USA. Poster 972-P

4 Pinget M. et al. Efficacy and Safety of Lixisenatide Once Daily versus Placebo in Patients with Type 2 Diabetes Insufficiently Controlled on Pioglitazone (GetGoal-P). Abstract presented at the 2012 72nd Scientific Session at the American Diabetes Association Meeting, Philadelphia, USA. Poster 1010-P

5 Riddle M. et al. Contributions of Basal and Postprandial Hyperglycemia Over a Wide Range of A1C Levels Before and After Treatment Intensification in Type 2 Diabetes. Diabetes Care, 2011; 34: 2508-2514

6 Colclough,H et al. Levels of FPG and HbA1c control and the relationship to BMI in T2D patients treated with basal insulin and OAD therapy. Abstract presented at the 2012 72nd Scientific Session at the American Diabetes Association Meeting, Philadelphia, USA. Abstract 2416-PO, 01-D Clinical Therapeutics/New Technology – Pharmacologic Treatment of Diabetes or its Complications

7 Rosenstock J. et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in patients with T2DM insufficiently controlled on metformin (GetGoal-X). Poster 786 presented at EASD 2011

8 Seino Y. et al. Randomized, double-blind, placebo-controlled trial of the once daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes, Obesity and Metabolism 2012 [Epub abstract ahead of print available online: http://onlinelibrary.wiley.com/doi/10.1111/j.1463-1326.2012.01618.x/abstract. Last accessed May 2012]

9 Fonseca V.et al. Efficacy and Safety of the Once-Daily GLP-1 Receptor Agonist Lixisenatide in Monotherapy: A randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono). Diabetes Care 2012. [Epub abstract ahead of print available online: http://www.ncbi.nlm.nih.gov/pubmed/22432104. Last accessed May 2012]

10 Ratner R. et al. Efficacy and safety of lixisenatide once daily versus placebo in patients with T2DM insufficiently controlled on sulfonylurea ± metformin (GetGoal-S). Poster 785 presented at EASD 2011

11 Bolli G. et al. Efficacy and safety of lixisenatide once-daily versus placebo in pati ents with T2DM insufficiently controlled on metformin (GetGoal-F1). Poster 784 presented at EASD 2011

12 Pinkney J. et al. Selecting GLP-1 agonists in the management of type 2 diabetes: differential pharmacology and therapeutic benefits of liraglutide and exenatide. Therapeutics and Clinical Risk Management 2010; 6:401–411

13 Reid T. Choosing GLP-1 Receptor Agonists or DPP-4 Inhibitors: Weighing the Clinical Trial Evidence. Clinical Diabetes 2012; 30 (1): 3-12