New Data From Boehringer Ingelheim’s Ongoing Linagliptin Trial Programme Show Promising Safety and Efficacy Results

INGELHEIM, Germany - Results From Linagliptin Study in Type 2 Diabetes Patients Who Were Inadequately Controlled on Metformin Therapy Alone, Presented at Major Diabetes Meeting

Study results presented for the first time in the scientific sessions of this year’s American Diabetes Association Annual Meeting (ADA) show clinically relevant and statistically significant reductions in haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) levels when linagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, is given as add-on therapy in Type 2 diabetic patients inadequately controlled with metformin. Furthermore, these phase II study results show a placebo-like safety and tolerability profile under these therapeutic conditions. Notably, in the study no case of hypoglycaemia was recorded with linagliptin treatment.(1)

“To date, metformin is the most widely used oral therapy in Type 2 diabetes. However, many patients do not achieve adequate glycaemic control with metformin alone. As HbA1c and FPG levels are key diagnostic indicators for effective management of Type 2 diabetes, the significant efficacy results together with the favourable safety profile shown in this trial for the investigational drug linagliptin are very encouraging. Based on the results seen to date, we are very confident that linagliptin, if approved, can provide additional benefit to patients with Type 2 diabetes,” said Dr. Manfred Haehl, MD, Senior Vice-President Medicine at Boehringer Ingelheim headquarters. “Type 2 diabetes is a progressive chronic condition which frequently requires long-term treatment. Physicians treating patients with Type 2 diabetes need to have a range of treatment options including combination regimens so they can tailor the therapy to the individual patient’s need and response. We are now awaiting results from additional ongoing studies which will further assess the full potential of linagliptin for the treatment of Type 2 diabetes.”

Trial objective and results:

The aim of the 12-week, international, randomised, double-blind placebo-controlled study was to assess the safety and efficacy profile of linagliptin as add-on therapy in patients with Type 2 diabetes who were failing to achieve glycaemic control despite being treated with metformin. Primary endpoint was the change in HbA1c from baseline to week 12. Out of the 333 randomised patients, 268 patients received double-blind treatment with linagliptin or placebo. Three doses of linagliptin were investigated in this study: 1 mg, 5 mg and 10 mg. An open-label arm with 65 patients on glimepiride was added for descriptive control.

- The addition of linagliptin to metformin treatment for 12 weeks resulted in clinically relevant and statistically significant reductions in HbA1c and FPG levels (p-values of less than 0.05%). - All doses of linagliptin showed superior HbA1c reduction compared to metformin alone after treatment for 12 weeks (the placebo-corrected changes from baseline were -0.40% for the 1 mg dose, -0.73% for the 5 mg dose, and -0.67% for the 10 mg dose). Statistically significant reductions in mean HbA1c levels with linagliptin 5 mg and 10 mg compared with metformin alone (both p greater than 0.001) were observed already from week four onwards. - In addition, all linagliptin doses showed significant reductions in FPG levels compared with metformin alone (the placebo-corrected mean changes from baseline were -19.2 mg/dL for 1 mg, -34.7 mg/dL for 5 mg, and -29.0 mg/dL for 10 mg). - In the open-label comparator arm, the placebo-corrected mean change from baseline in HbA1c was -0.90%. - The predefined efficacy criterion of more than 80% DPP-4 inhibition in more than 80% of patients was reached with the 5 mg and 10 mg linagliptin doses, but not with the 1 mg dose, which fully supports the 5mg dose as optimal dosage. - HbA1c reductions of greater than or equal to 0.5% were achieved in 44% to 53% of patients on linagliptin, but only in 13% of the patients receiving metformin alone. - Linagliptin had a placebo-like safety/tolerability profile. The incidence of adverse events was similar in all treatment groups. No dose relationship of adverse event was observed - No cases of hypoglycaemia were recorded in the linagliptin groups, whereas three hypoglycaemic episodes were reported in the glimepiride group.

INGELHEIM, Germany, June 6 /PRNewswire/ –

Linagliptin is the most advanced compound for the treatment of Type 2 diabetes within Boehringer Ingelheim’s diabetes portfolio. Linagliptin belongs to the class of DPP-4 inhibitors and is being developed as an oral once-daily tablet. It is currently in phase III clinical development.

Please be advised: This release is from Boehringer Ingelheim Corporate Headquarters in Germany. Please be aware that there may be national differences between countries regarding specific medical information, including licensed uses. Please take account of this when referring to the information provided in this document. This press release is not intended for distribution within the U.S.A.

Notes to Editor:

About the Boehringer Ingelheim diabetes pipeline

Metabolism is one of Boehringer Ingelheim’s core R&D areas and diabetes is one of the indications at the centre of interest within the company’s global research network. As a result, Boehringer Ingelheim is pursuing various modes of action. The company’s most advanced compounds targeting Type 2 diabetes are linagliptin (planned trade name Ondero), an oral once-daily tablet which belongs to the novel class of dipeptidylpeptidase (DPP-4)inhibitors and is currently in Phase III development, and a compound in Phase II which belongs to another class of novel antidiabetics, the sodium-dependent glucosetransporter-2 (SGLT-2) inhibitors.

About Diabetes and Type 2 Diabetes

There are approximately 246 million people with diabetes in the adult population.(2a) The International Diabetes Federation estimates the number of people with diabetes will increase to 380 million people worldwide by 2025. (2a) Some 3.8 million men and women worldwide were estimated to have died from diabetes-related causes in the year 2007. This is more than 6% of the total world mortality.(2b)

Type 2 diabetes is the most common type of diabetes accounting for up to 95% of all diabetes cases in the developed world.(2a) Type 2 diabetes rates continue to increase and patients continue to be burdened by serious diabetes-related complications, (2a) also reflected in the fact that approximately 50% of people with diabetes die of cardiovascular disease, and more than 10% die of renal failure.(3) Traditional therapies have frequently failed to meet the demands of today’s Type 2 diabetes landscape and new, effective and tolerable treatments are required.

To address this unmet need, Boehringer Ingelheim is committed to researching and developing new compounds in this disease area.

HbA1c = The erythrocyte haemoglobin becomes irreversibly glycosylated in proportion to circulating glucose concentrations, and the resultant product is commonly referred to as haemoglobin A1c (HbA1c). Because of the half-life of the erythrocyte, the percentage of haemoglobin represented by HbA1c provides an index of the average plasma glucose concentration during the previous two to three months.(4)

FPG = Fasting plasma glucose is the level of glucose in blood after an overnight fast.(5)

About Boehringer Ingelheim

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 138 affiliates in 47 countries and 41,300 employees. Since it was founded in 1885, the independent, family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2008, Boehringer Ingelheim posted net sales of 11.6 billion euro while spending one fifth of net sales in its largest business segment Prescription Medicines on research and development.

References (1) DPP-4 inhibitor linagliptin improves glycaemic control in type 2 diabetes patients when added to ongoing metformin therapy. Poster No 535-P, presented at the 69th American Diabetes Association Scientific Sessions, 05-09 June 2009, New Orleans, U.S.A. (2) International Diabetes Federation. Diabetes Atlas. 3rd edn. Brussels: International Diabetes Federation, 2006 (a) Available at: www.eatlas.idf.org/index2983.html. Accessed on 28 April, 2009. (b) Available at www.eatlas.idf.org/index3669.html. Accessed on 28 April, 2009. (3) Morrish,N.J. et al.. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia.2001; 44 Suppl 2: S14-S21 (4) Woerle, H.J. et al. Diagnostic and Therapeutic Implications of Relationships Between Fasting, 2-Hour Postchallenge Plasma Glucose And Hemoglobin A1C Values. Arch Intern Med. 2004; 164:1627-1632. (5) American Diabetes Association. Diabetes Research. Available at: www.diabetes.org/diabetes-research/summaries/tirosh-plasma- glucose.jsp. Accessed on: 22 April 2009

INGELHEIM, Germany, June 6 /PRNewswire/ –

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Source: Boehringer Ingelheim GmbH

Contact: Ursula Bardon, Corporate Division Communications, Boehringer Ingelheim GmbH, 55216 Ingelheim/Germany, Phone: +49-6132-77-2622, Fax: +49-6132-72-2622, E-mail: press at boehringer-ingelheim.com