ONGLYZA™ Significant Improvements Across Key Measures Of Glucose Control When Added To A Sulfonylurea Or Thiazolidinedione
The companies submitted a New Drug Application to the U.S. Food & Drug Administration (FDA) on June 30, which has been officially filed by the FDA, and a Marketing Authorization Application to the European Medicines Agency (EMEA) on July 1, which has been accepted for review by the Agency. The submissions are based on data from a comprehensive clinical trial program conducted in addition to standard therapies, as well as in treatment naïve patients as a monotherapy. The clinical trial program included studies that evaluated the drug at up to 80 times the proposed usual clinical dose of 5 mg, once daily. The six core Phase III trials assessing the safety and efficacy of saxagliptin involved more than 4,000 patients, including 3,000 who were treated with saxagliptin. The companies have proposed the name ONGLYZA which, if approved by the FDA and the EMEA, will serve as the trade name for saxagliptin.
"A large number of people with type 2 diabetes have difficulty managing their disease, and remain uncontrolled," said Dr. Priscilla Hollander, Baylor University Medical Center, Director of Diabetes Programs, Dallas, Texas. "Given the growing number of people with diabetes around the world, it is important to investigate new therapeutic options as we fight this chronic disease."
About the Study: Saxagliptin Added to Sulfonylurea
This study was designed to assess the addition of saxagliptin to a submaximal dose of sulfonylurea vs. increasing the dose of the sulfonylurea. The data represent findings from a 24-week, randomized, double-blind, placebo-controlled, three-arm, parallel-group, multi-center international study of 768 people with type 2 diabetes (ages 18-77) whose A1C level was greater than or equal to 7.5 percent and less than or equal to 10 percent after at least two months on a submaximal dose of a sulfonylurea at enrollment. After a four-week, open-label, lead-in phase, where all individuals received glyburide (GLY) 7.5 mg, individuals were randomized to one of three separate treatment arms: saxagliptin 2.5 mg + GLY 7.5 mg (n=248), saxagliptin 5 mg + GLY 7.5 mg (n=253), or placebo (PBO) + GLY 10 mg (n=267), given daily. In the PBO + GLY 10 mg group, blinded up-titration of GLY was allowed to a maximum total daily dose of 15 mg (UP-GLY). Approximately 92 percent of individuals in the UP-GLY group reached the maximum total daily dose during the study.
The primary endpoint of the study was the change from baseline to Week 24 in A1C. The secondary endpoints of the study included changes from baseline to Week 24 in FPG, PPG response, as indicated by PPG area under the curve (AUC) from 0-180 minutes during an oral glucose tolerance test (OGTT), and the proportion of individuals achieving the American Diabetes Association recommended A1C target of less than 7 percent.
Study Results
After 24 weeks, individuals in the saxagliptin + GLY treatment arms demonstrated a significant adjusted mean change in A1C from baseline of -0.5 percent for saxagliptin 2.5 mg + GLY and -0.6 percent for saxagliptin 5 mg + GLY, compared to +0.1 percent for UP-GLY (p-value less than 0.0001 for both treatment arms). Reductions were observed at four weeks, the earliest assessment point in the study. More than twice as many individuals receiving saxagliptin + GLY achieved A1C of less than 7 percent compared to UP-GLY: 22.4 percent for saxagliptin 2.5 mg + GLY and 22.8 percent for saxagliptin 5 mg + GLY, compared to 9.1 percent for UP-GLY (p-value less than 0.0001 for both treatment arms).
Individuals treated with saxagliptin + GLY demonstrated a significant adjusted mean change in FPG from baseline to Week 24: -7.1 mg/dL for saxagliptin 2.5 mg + GLY and -9.7 mg/dL for saxagliptin 5 mg + GLY, compared to +0.7 mg/dL for UP-GLY (p-value less than or equal to 0.0218 for both treatment arms). Reductions were observed at two weeks, the earliest assessment point in the study. The two saxagliptin + GLY treatment arms also demonstrated significant adjusted mean decreases in PPG from baseline to Week 24, compared to UP-GLY (p-value less than 0.0001 for both treatment arms).
Over 24 weeks, the reported hypoglycemic events were: 13.3 percent for saxagliptin 2.5 mg + GLY, 14.6 percent for saxagliptin 5 mg + GLY and 10.1 percent for UP-GLY (p-value equals NS). The occurrence of confirmed hypoglycemia (symptoms of hypoglycemia with a fingerstick glucose less than or equal to 50 mg/dL) was: 2.4 percent for saxagliptin 2.5 mg + GLY, 0.8 percent for saxagliptin 5 mg + GLY and 0.7 percent for UP-GLY.
Incidence of adverse events was: 75.0 percent for saxagliptin 2.5 mg + GLY, 72.3 percent for saxagliptin 5 mg + GLY and 76.8 percent for UP-GLY. The percentages of the most commonly reported (greater than or equal to 5 percent) adverse events for the saxagliptin 2.5 mg + GLY, saxagliptin 5 mg + GLY and UP-GLY treatment arms, respectively, were: urinary tract infection [5.2, 10.7, 8.2]; nasopharyngitis [5.6, 5.9, 6.7]; upper respiratory tract infection [4.4, 6.3, 6.7]; influenza [5.2, 4.0, 6.0]; diarrhea [5.6, 4.0, 5.2]; back pain [4.8, 5.9, 4.5]; pain in extremity [4.4, 3.6, 5.6]; headache [7.7, 7.5, 5.6]; cough [5.2, 4.0, 4.9]; and hypertension [3.6, 6.3, 2.2].
About the Study: Saxagliptin Added to Thiazolidinedione
This study was designed to assess the addition of saxagliptin to thiazolidinedione (TZD) vs. the addition of placebo to TZD. The data represent findings from a 24-week, multinational, randomized, placebo-controlled, three-arm, parallel group, double-blind study of 565 people with type 2 diabetes (ages 18-77) whose A1C level was greater than or equal to 7 percent and less than or equal to 10.5 percent and who were receiving stable TZD monotherapy (pioglitazone 30 mg or 45 mg, or rosiglitazone 4 mg or 8 mg, total daily dose) for at least twelve weeks prior to screening. After a two-week lead in period during which all individuals continued on their previous pioglitazone or rosiglitazone dose, individuals were randomized to one of three treatment arms: saxagliptin 2.5 mg (n=195), saxagliptin 5 mg (n=186) or PBO (n=184), given once daily, in addition to continuing on their previously prescribed TZD dose.
The primary endpoint of the study was the change from baseline to Week 24 in A1C. The secondary endpoints of the study included changes from baseline to Week 24 in FPG, PPG response, as indicated by PPG area under the curve (AUC) from 0-180 minutes during an oral glucose tolerance test (OGTT), and the proportion of individuals achieving the ADA recommended A1C target of less than 7 percent.
Study Results
After 24 weeks, individuals in the saxagliptin + TZD treatment arms demonstrated a significant adjusted mean change in A1C from baseline: -0.7 percent for saxagliptin 2.5 mg + TZD and -0.9 percent for saxagliptin 5 mg + TZD, compared to -0.3 percent for PBO + TZD (p-value less than or equal to 0.0007 for both treatment arms). A greater percentage of individuals treated with saxagliptin + TZD achieved an A1C of less than 7 percent at Week 24: 42.2 percent for saxagliptin 2.5 mg + TZD and 41.8 percent for saxagliptin 5 mg + TZD, compared to 25.6 percent for PBO + TZD (p-value less than or equal to 0.0013 for both treatment arms).
Individuals treated with saxagliptin + TZD demonstrated a significant adjusted mean change from baseline in FPG: -14.3 mg/dL for saxagliptin 2.5 mg + TZD and -17.3 mg/dL for saxagliptin 5 mg + TZD, compared to -2.8 mg/dL for PBO + TZD (p-value less than or equal to 0.0053 for both treatment arms). Both saxagliptin + TZD treatment arms also demonstrated significant adjusted mean decreases from baseline in PPG, compared to PBO + TZD (p-value less than 0.0001 for both treatment arms).
One case of confirmed hypoglycemia (symptoms of hypoglycemia with a fingerstick glucose less than or equal to 50 mg/dL) was reported in the saxagliptin 2.5 mg + TZD treatment arm. There were no cases of confirmed hypoglycemia in the saxagliptin 5 mg + TZD or PBO + TZD treatment arms. Reported hypoglycemic events were: 4.1 percent for the saxagliptin 2.5 mg + TZD, 2.7 percent for saxagliptin 5 mg + TZD and 3.8 percent for PBO + TZD.
Over 24 weeks, the incidence of adverse events was: 62.1 percent for saxagliptin 2.5 mg + TZD, 74.2 percent for saxagliptin 5 mg + TZD and 66.8 percent for PBO + TZD. The percentages of the most commonly reported (greater than or equal to 5 percent) adverse events from the saxagliptin 2.5 mg + TZD, saxagliptin 5 mg + TZD and PBO + TZD treatment arms, respectively, were: upper respiratory tract infection [7.7, 9.1, 7.1]; urinary tract infection [3.6, 6.5, 6.5]; nasopharyngitis [3.1, 4.8, 6.0]; arthralgia or joint pain [5.6, 2.7, 2.7]; headache [4.6, 5.4, 3.8]; dizziness [2.6, 3.2, 5.4]; peripheral edema [3.1, 8.1, 4.3]; and hypertension [5.6, 4.3, 4.9].
About ONGLYZA
ONGLYZA, the proposed tradename for saxagliptin, is an investigational DPP-4 inhibitor, under joint development by Bristol-Myers Squibb and AstraZeneca for the treatment of type 2 diabetes. Saxagliptin is being studied in clinical trials as a once-daily therapy to determine its efficacy and safety. Saxagliptin was specifically designed to be a selective inhibitor with extended binding to the DPP-4 enzyme, with dual routes of clearance. The name ONGLYZA, if approved by the FDA and the EMEA, will serve as the trade name for saxagliptin.
Saxagliptin Phase III data have previously been presented as a monotherapy, as well as in combination with metformin, the most commonly prescribed oral anti-diabetic medication. Further Phase III data on saxagliptin as initial combination therapy with metformin will be disclosed this week. The overall clinical development program included over 5,000 individuals -- more than 4,000 of whom were given saxagliptin.
About DPP-4 Inhibitors
DPP-4 inhibitors are a class of compounds that work by affecting the action of natural hormones in the body called incretins. Incretins decrease elevated blood sugar levels (glucose) by increasing the body's utilization of sugar, mainly through increasing insulin production in the pancreas, and by reducing the liver's production of glucose.
About Type 2 Diabetes
Diabetes (diabetes mellitus) is a chronic disease in which the body does not produce or properly use insulin. Insulin is a hormone that is needed to convert sugar, starches (carbohydrates) and other nutrients into energy needed for daily life. The cause of diabetes continues to be investigated, and both genetic and environmental factors such as obesity and lack of exercise appear to play a role. Diabetes is associated with long-term complications that affect almost every part of the body. The disease may lead to blindness, heart and blood vessel disease, stroke, kidney failure, amputations and nerve damage.
There are two primary underlying causes associated with type 2 diabetes: the body does not produce enough insulin (insulin deficiency), or the cells ignore the insulin (insulin resistance). Symptoms of type 2 diabetes develop gradually, and their onset is not as sudden as in type 1 diabetes. Symptoms may include fatigue, frequent urination, increased thirst and hunger, weight loss, blurred vision, and slow healing of wounds or sores. Some people, however, have no symptoms.
Type 2 diabetes is most often associated with older age, obesity, family history of diabetes, previous history of gestational diabetes, physical inactivity and certain ethnicities. People with type 2 diabetes often are characterized with: insulin resistance, abdominal obesity, a sedentary lifestyle, having low HDL-C ("good") cholesterol levels and high triglyceride levels and hypertension.
Type 2 diabetes accounts for approximately 90 to 95 percent of all diabetes. This equates to roughly 221 million people with type 2 diabetes globally, and 21.2 million people in the U.S. alone.
The American Diabetes Association recommends a hemoglobin A1C measurement of less than 7 percent for most people with type 2 diabetes. Hemoglobin A1C is a measurement of a person's average blood glucose level over a two-to-three month period and is considered an important marker of long-term glucose control. Other important markers for type 2 diabetes include fasting plasma glucose, a measure of a person's blood glucose after at least eight hours of fasting, and postprandial glucose, a measure of a person's blood glucose after a meal.
Bristol-Myers Squibb and AstraZeneca Collaboration
Bristol-Myers Squibb and AstraZeneca entered into a collaboration in January 2007 to enable the companies to research, develop and commercialize two investigational drugs for type 2 diabetes - saxagliptin and dapagliflozin. The Bristol-Myers Squibb/AstraZeneca diabetes collaboration is dedicated to global patient care, improving patient outcomes and creating a new vision for the treatment of type 2 diabetes.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to extend and enhance human life. For more information, visit www.bms.com.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995, regarding the research, development and commercialization of products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee that the product described in this release will receive regulatory approval. There can be no assurance that if approved, the product will be commercially successful. Forward-looking statements in the press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2007, its Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.
About AstraZeneca
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 $29.55 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. In the United States, AstraZeneca is a $13.35 billion dollar healthcare business with 12,200 employees committed to improving people's lives. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index.
For more information about AstraZeneca, please visit http://www.astrazeneca-us.com.
AstraZeneca Forward-Looking Statement
The statements contain herein include forward-looking statements. Although we believe our expectations are based on reasonable assumptions, any forward-looking statements, by their very nature, involve risks and uncertainties and may be influenced by factors that could cause actual outcomes and results to be materially different from those predicted. The forward-looking statements reflect knowledge and information available at the date of the preparation of this press release and the Company undertakes no obligation to update these forward-looking statements. Important factors that could cause actual results to differ materially from those contained in forward-looking statements, certain of which are beyond our control, include, among other things, those risk factors identified in the Company's Annual Report/Form 20-F for 2007. Nothing contained herein should be construed as a profit forecast.
ONGLYZA is a trademark of the Bristol-Myers Squibb Company
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