Results from an interim analysis of a long-term Phase 3 study at 102
weeks with ONGLYZA? (saxagliptin), an investigational,
selective, reversible inhibitor of the dipeptidyl peptidase-4 (DPP-4)
enzyme under joint development by Bristol-Myers
Squibb Company (NYSE: BMY) and AstraZeneca
(NYSE: AZN), when added to metformin in people with inadequately
controlled type 2 diabetes, demonstrated an overall profile of adverse
events consistent with that seen at 24 weeks, and produced long-term
glycemic improvement [as measured by glycosylated hemoglobin level
(A1C)]. Results were presented at the 69th American Diabetes
Association Annual Scientific Sessions.
“Type 2 diabetes is a progressive and chronic disease, with patients
struggling every day to control their blood glucose levels,” said Roland
Chen, MD, group director, Cardiovascular/ Metabolics, Bristol-Myers
Squibb.
“It is, therefore, important for us to understand how investigational
diabetes medicines work over an extended period of time,” said Peter
Ohman, medical science director, Cardiovascular/Gastrointestinal Therapy
Area, AstraZeneca.
About the Study: Saxagliptin Added To Metformin Over 102 Weeks
The study is an interim analysis of a 42-month long-term extension study
designed to assess the safety, tolerability and efficacy of saxagliptin
when added to metformin in people with inadequately controlled type 2
diabetes, compared to metformin plus placebo. The current data represent
interim findings after 102 weeks for this randomized, double blind,
placebo controlled, multi-center international study of 743 individuals
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 percent on a stable
metformin dose alone (1500 to 2500 mg/day). Individuals were randomized
to one of four separate treatment arms: saxagliptin 2.5 mg + metformin
1500 to 2500 mg/day (n=192), saxagliptin 5 mg + metformin 1500 to 2500
mg/day (n=191), saxagliptin 10 mg + metformin 1500 to 2500 mg/day
(n=181), or placebo + metformin 1500 to 2500 mg/day (n=179), given once
daily.
All individuals who completed the 24-week short-term study were eligible
to enroll in the long-term extension study, including individuals who
met prespecified glycemic rescue criteria during the short-term study
period and received open-label pioglitazone 15 to 45 mg + blinded study
medication. Pioglitazone rescue therapy was also available during the
long-term extension study based on a prespecified glycemic criteria.
The primary endpoint of the study was the long-term safety and
tolerability of saxagliptin when added to metformin. The efficacy
endpoints of the study included changes from baseline in A1C, fasting
plasma glucose (FPG), and post-prandial glucose (PPG), measured 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 were based on the Last Observation
Carried Forward (LOCF) method.
Study ResultsSafety and Tolerability
After 102 weeks, results from the interim analysis demonstrated that the
incidence of adverse events was similar for saxagliptin 5 mg + metformin
compared to placebo + metformin; the rates of adverse events were
slightly greater for saxagliptin 2.5 mg + metformin and saxagliptin 10
mg + metformin versus placebo + metformin.
Adverse event rates were as follows: 89.6 percent for saxagliptin 2.5 mg
+ metformin, 78 percent for saxagliptin 5 mg + metformin, and 86.7
percent for saxagliptin 10 mg + metformin; the incidence of adverse
events was 78.8 percent for placebo + metformin. The percentages of the
most commonly reported adverse events for the saxagliptin 2.5 mg +
metformin, saxagliptin 5 mg + metformin, saxagliptin 10 mg + metformin
and placebo + metformin treatment arms, were: nasopharyngitis [13.0,
11.0, 13.8, 10.6], influenza [10.4, 11.5, 12.7, 12.8], upper respiratory
tract infection [12.0, 8.9, 10.5, 7.8], urinary tract infection [9.9,
7.9, 9.4, 6.7], bronchitis [6.3, 9.4, 5.0, 6.1], diarrhea [14.1, 7.3,
9.4, 12.8] back pain [7.8, 7.9, 5.0, 8.9] and headache [13.5, 8.9, 12.2,
11.2].
The rate of reported hypoglycemic events was similar among all treatment
arms: 10.4 percent for saxagliptin 2.5 + metformin, 8.9 percent for
saxagliptin 5 mg + metformin, and 11 percent for saxagliptin 10 mg +
metformin; the incidence of reported hypoglycemic events was 10.1
percent for placebo + metformin. The occurrence of confirmed
hypoglycemia (symptoms of hypoglycemia with a fingerstick glucose less
than or equal to 50 mg/dL) was less than or equal to 1.1 percent for all
treatment arms.
The proportion of individuals who discontinued the long-term study for
lack of glycemic control or were rescued for meeting prespecified
glycemic criteria was lower in the saxagliptin treatment arms compared
to the placebo arm: 58.3 percent for saxagliptin 2.5 mg + metformin,
51.8 percent for saxagliptin 5 mg + metformin, 56.9 percent for
saxagliptin 10 mg + metformin, and 71.5 percent for placebo + metformin.
At 102 weeks, there was a numerically higher incidence of skin-related
adverse events in the saxagliptin + metformin treatment arms compared to
the placebo + metformin treatment arm: 15.6 percent for saxagliptin 2.5
mg + metformin, 13.6 percent for saxagliptin 5 mg + metformin, 22.7
percent for saxagliptin 10 mg plus metformin, and 11.2 percent for
placebo plus metformin.
Small decreases in mean body weight at week 102 (before rescue, last
observation carried forward) versus baseline were observed in all
treatment arms: -1.0 kg, -0.4 kg and -0.5 kg for saxagliptin 2.5 +
metformin, saxagliptin 5 mg + metformin and saxagliptin 10 mg +
metformin, respectively, compared to -0.8 kg for placebo + metformin.
Glycemic Efficacy
After 102 weeks, individuals in the saxagliptin + metformin treatment
arms demonstrated a placebo-adjusted mean change in A1C from baseline of
-0.62 percent for saxagliptin 2.5 mg + metformin, -0.72 percent for
saxagliptin 5 mg + metformin, and -0.52 percent for saxagliptin 10 mg +
metformin. Changes in other measures of glycemic control were consistent
with the observed changes in A1C.
About ONGLYZA
ONGLYZA, the trade name 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.
Saxagliptin Phase 3 data have previously been presented as a
monotherapy, as well as in combination with metformin, sulfonylureas and
thiazolidinediones, commonly prescribed oral anti-diabetic medications.
The overall clinical development program included over 5,000 individuals
— more than 4,000 of whom were given saxagliptin.
The companies submitted a New Drug Application to the U.S. Food & Drug
Administration (FDA) on June 30, 2008, which has been officially filed
by the FDA, and a Marketing Authorization Application to the European
Medicines Agency (EMEA) on July 1, 2008, which has been accepted for
review by the Agency.
About DPP-4 Inhibitors
DPP-4 inhibitors are a class of compounds that are believed to 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 post-prandial 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 collaboration in
January 2007 to enable the companies to research, develop and
commercialize two investigational drugs for type 2 diabetes — ONGLYZA
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 http://www.bms.com.
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 US $31.6 billion and is a leader in gastrointestinal,
cardiovascular, neuroscience, respiratory, oncology and infectious
disease medicines. For more information about AstraZeneca, please visit: http://www.astrazeneca.com/.
ONGLYZA? is a trademark of the Bristol-Myers Squibb Company.