Boehringer Ingelheim Presents New Phase III Data Evaluating Linagliptin In People With Type 2 Diabetes

Pharmacokinetic data also announced investigating linagliptin in renally impaired study participants

Ridgefield, CT /PRNewswire/ - New Phase III data found that investigational linagliptin therapy resulted in significant reductions in blood sugar as measured by hemoglobin A1c (HbA1c) when compared to placebo, both when added to sulfonylurea (SU) in inadequately controlled type 2 diabetes (T2D) patients,(1) and when administered as monotherapy in T2D patients for whom metformin is inappropriate.(2) In addition, new pharmacokinetic (PK) data demonstrate that decreases in renal function had minor effect on the elimination of linagliptin.(3) These findings support the study conclusion that a dose adjustment may not be required in T2D patients with varying degrees of renal impairment (RI) when treated with linagliptin.(3) Boehringer Ingelheim Pharmaceuticals, Inc. is investigating the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin as an oral once-daily tablet, as monotherapy and combination therapy, to treat T2D. The data are being presented this week at the 46th Annual Meeting of the European Association for the Study of Diabetes (EASD) in Stockholm, Sweden.

PK study shows minor effect on excretion in T2D patients with RI
Results from this PK study show that minor changes were observed in linagliptin exposure in study participants with RI (a 1.4-fold increase in exposure at steady state in T2D patients with severe RI compared with T2D patients with normal renal function).(3) As a result of these findings, the study authors suggest that no dose adjustment is required in T2D patients with varying degrees of RI when treated with linagliptin.(3)

RI refers to varying degrees of kidney damage, or chronic kidney disease (CKD), and can range from mild to severe.(4) About a third of people with diabetes develop CKD.(4)

"These results are consistent with existing data showing that linagliptin has a primarily non-renal route of excretion," said Dr. Tu Nguyen, executive director & medical leader, medical affairs, metabolic medicine, Boehringer Ingelheim Pharmaceuticals, Inc. "The data provide more information about linagliptin clearance in people with type 2 diabetes and varying degrees of renal impairment."

Linagliptin demonstrates significant reductions in HbA1c in T2D patients for whom metformin therapy is inappropriate
In this Phase III study, statistically significant differences in HbA1c between linagliptin and placebo could be seen at week six, and at week 18 the placebo adjusted mean difference was –0.57 percent (p<0.0001).(2) Among patients who began the trial with an HbA1c of greater than or equal to 7.0 percent, 23.5 percent taking linagliptin achieved HbA1c <7.0 percent, compared to 11.8 percent taking placebo.(2) Linagliptin-treated patients also saw statistically significant reductions in fasting plasma glucose (FPG) levels compared to placebo (adjusted mean difference from baseline –20.5 mg/dl; p=0.0002).(2) The most commonly reported adverse events (AEs) in the linagliptin arm were general disorders and administration site conditions (2.6 percent), metabolism and nutrition disorders (2.6 percent), gastrointestinal disorders (1.3 percent) and nervous system disorders (1.3 percent in linagliptin group, 1.3 percent in placebo group).(2)

Linagliptin as add-on therapy to an SU in inadequately controlled T2D patients
In another Phase III study presented at EASD, treatment with linagliptin resulted in significant reductions in HbA1c from baseline (mean placebo adjusted HbA1c reduction –0.47 percent; p<0.0001).(1) The most commonly reported AEs in the linagliptin arm were metabolism and nutrition disorders (4.3 percent in linagliptin group, 8.3 percent in placebo group), nervous system disorders (1.9 percent) and general disorders and administration site conditions (1.2 percent).(1)

Safety data and additional information about the studies

• In the PK study, linagliptin was investigated in people with mild RI (CrCl 51-80 ml/min, n=6), moderate RI (CrCl 31-50 ml/min, n=6), severe RI (CrCl less than or equal to 30ml/min, n=6), end-stage renal disease (n=6) and in healthy volunteers (CrCl> 80 ml/min, n=6).(3) Linagliptin's PK was also compared in people with T2D and severe RI (n=10) and in people with T2D with normal renal function (n=11).(3)
  • Study participants received 5 mg linagliptin once-daily as single dose (severe RI and end-stage renal disease groups) or for 7 days (healthy volunteers, mild or moderate RI) or for 10 days (patients with T2D).(3) Plasma and urine concentrations of linagliptin, inhibition of plasma DPP-4, and plasma protein binding were determined.(3)
  • The primary analysis was the comparison of linagliptin exposure in steady state (subjects with mild or moderate RI vs. healthy volunteers and T2D patients with severe RI vs. normal renal function) or after single-dose (subjects with severe RI/end-stage renal disease vs. healthy volunteers).(3)
  • There were no reported serious AEs, AEs of severe intensity or AEs leading to discontinuation of study medication.(3)
  • Drug-related AEs were headache, diarrhea, and fatigue, all of which were considered mild.(3)
• The Phase III trial that assessed linagliptin (5 mg once-daily) as monotherapy in patients for whom metformin therapy is inappropriate, was a multi-center, 18-week, randomized, double-blind, placebo-controlled, parallel group study (followed by an ongoing 34-week double-blind extension period in which placebo was switched to glimepiride).(2)
  • Hyperglycemic T2D patients who were treatment-naive or pre-treated with one oral antidiabetic agent were randomized to linagliptin (n=151) or placebo (n=76) followed a 2-week placebo run-in (previously treated patients went without medication for four weeks prior to this).(2)
  • The primary endpoint for the trial was the change in HbA1c from baseline after 18 weeks of treatment, evaluated with an analysis of covariance (ANCOVA) adjusted for prior oral antidiabetic agents, baseline HbA1c and reason for metformin ineligibility.(2)
  • The incidence of reported AEs was 48.7 percent placebo vs. 40.4 percent linagliptin.(2) The proportion of patients experiencing greater than or equal to 1 AE classified as drug-related within the linagliptin and placebo groups was 6.6 percent and 1.3 percent, respectively.(2)
  • Hypoglycemia occurred in two patients (1.3 percent) in the linagliptin group and none in the placebo group and there were no severe cases in either group.(2)
  • There was no significant weight change observed between groups.(2)
• The Phase III trial that evaluated linagliptin as add-on to SU in patients with T2D and insufficient glycemic control was an 18-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study.(1)
  • Before being randomized to linagliptin (5 mg once-daily) (n=161), or placebo (n=84), all participants had a 2-week placebo run-in.(1)
  • The primary endpoint for the trial was the change in HbA1c from baseline after 18 weeks of treatment evaluated with an analysis of covariance (ANCOVA) adjusted for treatment, prior oral antidiabetic agents and baseline HbA1c.(1)
  • The frequency of reported AEs was 42.2 percent in the linagliptin group and 42.9 percent in the placebo group.(1)
    • Of these AEs, 13/161 (8.1 percent) and 8/84 (9.5 percent) in the linagliptin and placebo groups, respectively, were considered drug-related by the investigator.(1)
    • AEs of severe intensity were reported for 4 participants (2.5 percent) in the linagliptin group and none in the placebo group; all other AEs were of mild or moderate intensity.(1)
    • None of the severe AEs were considered as drug-related.(1)
  • Investigator-defined cases of hypoglycemia occurred in 5.6 percent and 4.8 percent of participants in the linagliptin and placebo groups, respectively.(1)
  • No significant changes in body weight or waist circumference were observed in the two groups.(1)

About diabetes
Approximately 27 million Americans(5) and 285 million people worldwide have diabetes.(5) Type 2 diabetes is the most common type, accounting for more than 90 percent of all diabetes cases in the developed world.(6) Each year, more than 231,000 people in North America(5) and more than 3.96 million people worldwide die from diabetes and its complications(5) – a number which is expected to increase by more than 50 percent over the next decade.(6) Diabetes is a chronic disease that occurs when the body either does not properly produce, or use the hormone, insulin.(7)

About Boehringer Ingelheim and diabetes
Metabolism is one of Boehringer Ingelheim's core R&D areas and diabetes is one of the indications at the center of interest within the company's global research network. Boehringer Ingelheim is committed to researching and developing new diabetes compounds with novel modes of action to improve patients' health.

Boehringer Ingelheim is filing linagliptin for market authorization in key countries across the globe in 2010.

In addition to linagliptin, Boehringer Ingelheim is also investigating the sodium-dependent glucose co-transporter-2 (SGLT-2) inhibitor, BI-10773, which belongs to a new, emerging class of antidiabetic compounds that block tubular reabsorption of glucose in the kidney. The Phase II clinical trials for BI-10773 have concluded. There are no SGLT-2 inhibitors approved for use in the U.S.

Boehringer Ingelheim is also developing an 11beta-HSD1 inhibitor. Inhibition of 11beta-HSD1 offers a novel potential therapy for the management of diabetes by lowering intracellular cortisol concentrations, which are believed to result in improved insulin sensitivity, blood lipid levels and vascular function. The 11beta-HSD1 inhibitor compound is in the early stages of clinical development.

About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates in 50 countries and more than 41,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2009, Boehringer Ingelheim posted net sales of US $17.7 billion (12.7 billion euro) while spending 21 percent of net sales in its largest business segment, Prescription Medicines, on research and development.

For more information, please visit http://us.boehringer-ingelheim.com and follow us on Twitter at http://twitter.com/boehringerus.

1. Lewin AJ, Arvay L, Liu D, et al. Safety and efficacy of linagliptin as add-on therapy to a sulphonylurea in inadequately controlled type 2 diabetes. Poster no. 821-P, European Association for the Study of Diabetes Annual Meeting, 20–24 September 2010, Stockholm, Sweden.
2. Barnett AH, Harper R, Toorawa R, et al. Linagliptin monotherapy improves glycaemic control in type 2 diabetes patients for whom metformin therapy is inappropriate. Poster no. 823-P, European Association for the Study of Diabetes Annual Meeting, 20–24 September 2010, Stockholm, Sweden.
3. Graefe-Mody U, Friedrich C, Port A, et al. Linagliptin, a novel DPP-4 inhibitor: no need for dose adjustment in patients with renal impairment. Poster no. 822-P, European Association for the Study of Diabetes Annual Meeting, 20-24 September 2010, Stockholm, Sweden.
4. National Kidney Foundation. Diabetes and Chronic Kidney Disease; Stages 1-4. Available at: http://www.kidney.org/atoz/pdf/diabetes.pdf. Accessed on August 25, 2010.
5. International Diabetes Federation. Diabetes Atlas. 4rth edn. Brussels: International Diabetes Federation, 2009.
6. World Health Organization. Fact Sheet No. 312: What is Diabetes? Available at: http://www.who.int/mediacentre/factsheets/fs312/en/. Accessed on: February 4, 2009.
7. International Diabetes Federation. Diabetes Atlas. 3rd edn. Brussels: International Diabetes Federation, 2006.

SOURCE Boehringer Ingelheim Pharmaceuticals, Inc.