This study was submitted to the European Medicines Agency (EMEA) as part of the Marketing Authorization Application for ONGLYZA. Complete findings from this study will be submitted for publication in the first half of 2010.
ONGLYZA, a dipeptidyl peptidase 4 (DPP4) inhibitor, was recently approved by the European Commission as an adjunct to diet and exercise to improve blood sugar (glycemic) control in adults for the treatment of type 2 diabetes mellitus. ONGLYZA once daily can be used in combination with commonly prescribed oral anti-diabetic medications – metformin, sulfonylureas or thiazolidinediones (TZD) to significantly reduce HbA1c levels. ONGLYZA has also been approved by the U.S. Food and Drug Administration (July, 2009) as an adjunct to diet and exercise to improve blood sugar (glycemic) control in adults for the treatment of type 2 diabetes mellitus. ONGLYZA should not be used for the treatment of type 1 diabetes or for the treatment of diabetic ketoacidosis (high levels of certain acids, known as ketones, in the blood or urine). ONGLYZA has not been studied in combination with insulin.
“We are pleased with the findings from this study, which support that the addition of ONGLYZA to metformin lowers HbA1c in adults with inadequate glycemic control despite treatment with metformin,” said Andre Scheen, MD, Head of the Division of Diabetes, Nutrition and Metabolic Disorders and Clinical Pharmacology Unit, Academic Hospital, Liège, Belgium.
About the Study
This study was an 18-week international, multicenter, randomized, parallel-group, double-blind, active-controlled phase 3b study of 801 adults with type 2 diabetes (ages 22-87) whose HbA1c was greater than 6.5 percent and less than or equal to 10 percent at baseline. The study was designed to evaluate the efficacy and safety of ONGLYZA (saxagliptin) 5 mg and JANUVIA 100 mg in addition to metformin in adults with type 2 diabetes who did not attain adequate glycemic control on metformin therapy alone. Individuals were randomized to one of two separate treatment arms, ONGLYZA 5 mg once daily plus open-label metformin (n=403, baseline HbA1c = 7.68) or JANUVIA 100 mg once daily plus open-label metformin (n=398, baseline HbA1c = 7.69). The primary endpoint of the study was to assess if the change from baseline in HbA1c achieved with ONGLYZA 5 mg per day was non-inferior (defined in the study protocol as a treatment group numerical difference in the HbA1c reduction of less than 0.3 for the upper limit of the confidence interval [CI]) to JANUVIA 100 mg per day when both were added to a stable dose of metformin, 1500 mg or higher.
In the primary analysis of individuals who completed the study and complied with study procedures, ONGLYZA 5 mg per day achieved an adjusted mean change from baseline in HbA1c of –0.52 percent, compared to –0.62 percent for subjects taking JANUVIA 100 mg per day. Results of the study demonstrated that therapy with ONGLYZA 5 mg was non-inferior to JANUVIA 100 mg when added to metformin (difference in adjusted mean change from baseline vs. JANUVIA plus metformin 0.09 percent, 95 percent CI -0.01 to 0.20). Non-inferiority of ONGLYZA to JANUVIA was also demonstrated in a confirmatory analysis of all individuals receiving study treatment for whom a change from baseline in HbA1c could be calculated.
In the study, ONGLYZA 5 mg added to metformin demonstrated a safety profile similar to JANUVIA 100 mg added to metformin. The number of individuals experiencing adverse events or serious adverse events after 18 weeks was similar between the two treatment groups: (adverse events: 47.1 percent for ONGLYZA 5 mg plus metformin, 47.2 percent for JANUVIA 100 mg plus metformin; serious adverse events: 1.7 percent for ONGLYZA 5 mg plus metformin, 1.3 percent for JANUVIA 100 mg plus metformin). A total of 9 patients discontinued in each treatment arm due to an adverse event. Two patients (0.5 percent) in the ONGLYZA plus metformin arm discontinued treatment due to a serious adverse event. The number of individuals with any hypoglycemic event was similar between the two treatment groups (3.2 percent for ONGLYZA (saxagliptin) 5 mg plus metformin, 2.8 percent for JANUVIA plus metformin). The most common adverse events (greater than 5 percent in at least one study group) reported with ONGLYZA 5 mg plus metformin vs. JANUVIA plus metformin were influenza (5.7 percent vs. 5.8 percent, respectively) and urinary tract infection (5.7 percent vs. 5.3 percent, respectively).
To conclude, the study achieved its primary endpoint – demonstrating that treatment with ONGLYZA 5 mg plus metformin was non-inferior compared to treatment with JANUVIA 100 mg plus metformin as measured by a change from baseline in HbA1c. Treatment with ONGLYZA 5 mg plus metformin had a safety profile similar to JANUVIA 100 mg plus metformin.
Background On Previously Presented Studies of ONGLYZA When Used In Combination With Metformin
ONGLYZA was studied extensively with metformin, the most commonly-prescribed oral anti-diabetic medication. Two previously reported studies demonstrated that ONGLYZA, when used in combination with metformin, effectively lowered HbA1c, fasting plasma glucose and postprandial glucose, three key measures of glycemic control. In adult patients inadequately controlled on metformin, the addition of ONGLYZA 2.5 mg (n=192, baseline A1C 8.1 percent) and 5 mg (n=191, baseline A1C 8.1 percent) once daily reduced A1C levels from baseline to Week 24 by -0.6 percent and –0.7 percent respectively for ONGLYZA vs. +0.1 percent increase for placebo (p-values less than 0.0001 vs. placebo, n=179, baseline A1C 8.1 percent). The reported incidence of hypoglycemia in ONGLYZA 2.5 mg and 5 mg compared with placebo was 7.8 percent, 5.8 percent and 5 percent, respectively.
For those new to diabetes medications, the use of ONGLYZA 5 mg with metformin (n=320, baseline A1C 9.4 percent) as initial therapy lowered A1C from baseline to week 24 by -2.5 percent vs. -2 percent for metformin plus placebo (p-values less than 0.0001, n=313, baseline A1C 9.4 percent). Significantly more adult patients in the ONGLYZA plus metformin arm achieved the American Diabetes Association recommended A1C level of less than 7 percent than those treated with metformin plus placebo (60 percent vs. 41 percent, respectively, p-values less than 0.05). The reported incidence of hypoglycemia was 3.4 percent in adult patients given ONGLYZA (saxagliptin) 5 mg plus metformin and 4 percent in adult patients given metformin alone. The adverse reactions occurring in greater than or equal to 5 percent of adult patients and more commonly than in adult patients treated with metformin alone were headache (7.5 percent vs. 5.2 percent) and nasopharyngitis (6.9 percent vs. 4 percent).
IMPORTANT INFORMATION ABOUT ONGLYZA IN US PRESCRIBING INFORMATION
Indication and Important Limitations of Use
ONGLYZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
ONGLYZA should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
ONGLYZA has not been studied in combination with insulin.
Important Safety Information
Most common adverse reactions (regardless of investigator assessment of causality) reported in ≥5 percent of patients treated with ONGLYZA and more commonly than in patients treated with control were upper respiratory tract infection (7.7 percent, 7.6 percent), headache (7.5 percent, 5.2 percent), nasopharyngitis (6.9 percent, 4.0 percent) and urinary tract infection (6.8 percent, 6.1 percent). When used as add-on combination therapy with a thiazolidinedione, the incidence of peripheral edema for ONGLYZA (saxagliptin) 2.5 mg, 5 mg, and placebo was 3.1 percent, 8.1 percent and 4.3 percent, respectively.
Drug Interactions: Because ketoconazole, a strong CYP 3A4/5 inhibitor, increased saxagliptin exposure, the dose of ONGLYZA should be limited to 2.5 mg when coadministered with a strong CYP 3A4/5 inhibitor (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).
Patients with Renal Impairment: The dose of ONGLYZA is 2.5 mg once daily for patients with moderate or severe renal impairment, or with end-stage renal disease requiring hemodialysis (creatinine clearance ≤50 mL/min). ONGLYZA should be administered following hemodialysis. ONGLYZA has not been studied in patients undergoing peritoneal dialysis. Assessment of renal function is recommended prior to initiation of ONGLYZA and periodically thereafter.
Pregnant and Nursing Women: There are no adequate and well-controlled studies in pregnant women. ONGLYZA, like other antidiabetic medications, should be used during pregnancy only if clearly needed. It is not known whether saxagliptin is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when ONGLYZA is administered to a nursing woman.
Pediatric Patients: Safety and effectiveness of ONGLYZA in pediatric patients have not been established.
Bristol-Myers Squibb and AstraZeneca Collaboration
Bristol-Myers Squibb Company (NYSE: BMY) and AstraZeneca (NYSE/LSE: AZN) entered into a collaboration in January 2007 to develop and commercialize select investigational drugs for type 2 diabetes. These therapies address two key pathways in managing type 2 diabetes and seek to expand the range of current and future therapeutic options. Our collaboration is dedicated to global patient care, improving patient outcomes and creating a new vision for the treatment of patients living with type 2 diabetes.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company committed to discovering, developing and delivering innovative medicines that help patients prevail over serious diseases. For more information, please visit www.bms.com.
AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services. AstraZeneca is one of the world’s leading pharmaceutical companies with healthcare sales of US$ 31.6 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines.
ONGLYZA is a trademark of the Bristol-Myers Squibb Company.
JANUVIA is a trademark of Merck & Co. Inc.
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