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Bristol-Myers Squibb and AstraZeneca

24-Week Phase 3 Study Found Investigational Drug Dapagliflozin Improved Glycosylated Hemoglobin (HbA1c) When Added to Glimepiride in Adults With Type 2 Diabetes Mellitus

Stockholm (ots/PRNewswire)

Bristol-Myers Squibb
Company (http://www.bms.com) and  AstraZeneca
(http://www.astrazeneca-us.com)  today announced results from a
randomized, double blind Phase 3 clinical  study, which demonstrated
that the addition of the investigational drug  dapagliflozin to
existing glimepiride (sulphonylurea) therapy produced  significant
reductions in glycosylated hemoglobin levels (HbA1c) in adult
patients with type 2 diabetes compared to glimepiride alone. The
study also  demonstrated that dapagliflozin plus glimepiride achieved
reductions in the  secondary efficacy endpoints of change in total
body weight, oral glucose  tolerance test (OGTT) and fasting plasma
glucose (FPG) levels from baseline  at week 24 compared to placebo
plus glimepiride. More people taking  dapagliflozin and glimepiride
were able to achieve a target HbA1c of less  than 7% compared to
patients taking glimepiride alone. Results from the study  were
presented at the 46th European Association for the Study of Diabetes
(EASD) Annual Meeting.
Overall, the frequency of drug-related adverse events was
reported at a similar rate between treatment groups, although signs,
symptoms and other reports suggestive of genital tract infections,
but not urinary tract infections, were more frequently reported in
dapagliflozin treated subjects.
Dapagliflozin, an investigational compound, is a first-in-class
sodium-glucose cotransporter-2 (SGLT2) inhibitor and is currently in
Phase 3 trials under joint development by Bristol-Myers Squibb and
AstraZeneca as a once-daily oral therapy for the treatment of adult
patients with type 2 diabetes. SGLT2 inhibitors, which act
independently of insulin mechanisms, facilitate the excretion of
glucose and associated calories in the urine, thereby lowering blood
glucose levels.
"With type 2 diabetes, we often see a progressive deterioration
of glycemic control in patients, which may require treatment
intensification with additional drug therapy," said Krzysztof
Strojek, Professor, Department of Internal Diseases Diabetology &
Nephrology Silesian Medical University, Zabrze (Poland), principal
investigator of the study. "This study, which adds to the Phase 3
data available for this investigational compound, demonstrated that
dapagliflozin improved glycemic control, as measured by HbA1c, FPG
and PPG, in adult patients with type 2 diabetes when added to the
commonly used oral diabetic agent - glimepiride."
About The Study
The study was a 24-week, multicenter, international, randomized,
parallel-group, double-blind, placebo-controlled Phase 3 study, which
was designed to assess the efficacy of dapagliflozin (2.5 mg, 5 mg or
10 mg per day) compared to placebo as add-on therapy to glimepiride
(4 mg/day) in improving glycemic control in adult patients with type
2 diabetes, as determined by the change in HbA1c levels from baseline
at week 24, and includes a 24-week double-blind extension. The study
included 597 type 2 diabetes patients (aged greater than or equal to
18 years) with inadequate glycemic control (HbA1c greater or equal to
7.0% and less than or equal to 10% at baseline) on at least half
maximal recommended dose of glimepiride alone. Individuals were
equally randomized to one of four treatment groups: dapagliflozin 2.5
mg plus glimepiride, dapagliflozin 5 mg plus glimepiride,
dapagliflozin 10 mg plus glimepiride or placebo plus glimepiride.
The primary endpoint of the study was to assess the change from
baseline in HbA1c at 24 weeks. Key secondary endpoints included the
change from baseline in body weight, change in oral glucose tolerance
test (OGTT), proportion of patients achieving an HbA1c of less than
7% and reduction in fasting plasma glucose (FPG) levels at week 24.
Study Results
Individuals taking dapagliflozin plus glimepiride achieved
significant dose-dependent reductions from baseline in HbA1c of
-0.58%, -0.63% and -0.82% for dapagliflozin 2.5 mg, 5 mg and 10 mg,
respectively compared to -0.13% for placebo plus glimepiride (p-value
of less than 0.0001 for all three treatment arms).
Patients treated with dapagliflozin plus glimepiride achieved
greater weight loss compared to those treated with placebo plus
glimepiride: -1.18 kg, -1.56 kg, -2.26 kg for dapagliflozin 2.5 mg, 5
mg and 10 mg, respectively compared to -0.72 kg for glimepiride plus
placebo at week 24 (p-value less than 0.01 and less than 0.0001 for
dapagliflozin 5 mg and 10 mg, respectively; p-value of dapagliflozin
2.5 mg was not statistically significant).
Individuals treated with dapagliflozin plus glimepiride achieved
significant reductions from baseline in the OGTT of -32.0 mg/dL and
-34.9 mg/dL for dapagliflozin 5 mg and 10 mg, respectively compared
to -6.0 mg/dL for placebo plus glimepiride (p-value less than 0.01
and less than 0.0001 for dapagliflozin 5 mg and 10 mg, respectively).
Dapagliflozin 2.5 mg reduced OGTT by 37.5 mg/dL.
The study demonstrated that more patients taking dapagliflozin
plus glimepiride achieved an HbA1c level of less than 7% compared to
placebo plus glimepiride at week 24: 30.3% and 31.7% for
dapagliflozin 5 mg and 10 mg, respectively compared to 13.0% for
glimepiride plus placebo (p-value less than 0.01 and less than 0.0001
for dapagliflozin 5 mg and 10 mg, respectively). For patients treated
with dapagliflozin 2.5 mg, 26.8% achieved HbA1c <7%.
Individuals treated with dapagliflozin 5 mg and 10 mg plus
glimepiride demonstrated significant improvements in FPG from
baseline at week 24:  -21.2 mg/dL for dapagliflozin 5 mg and -28.5
mg/dL for dapagliflozin 10 mg, compared to -2.0 mg/dL for placebo
plus glimepiride (p-value less than 0.0001 for both treatment arms).
Dapagliflozin 2.5 mg reduced FPG by -16.8 mg/dL.
The number of individuals experiencing adverse events after 24
weeks was 51.9%, 48.3% and 50.3% for dapagliflozin 2.5 mg, 5 mg, and
10 mg plus glimepiride, respectively compared to 47.3% for
glimepiride plus placebo. The percentage of patients experiencing the
most common adverse events for dapagliflozin 2.5 mg, 5 mg, 10 mg and
placebo when added to glimepiride, respectively was as follows: back
pain (1.9%, 2.1%, 4.6% vs. 2.7%), upper respiratory tract infection
(3.2%, 4.1%, 4.6% vs. 2.7%) and bronchitis (1.3%, 2.1%, 3.3% vs.
0.7%). Most cases of adverse events were mild to moderate.
Discontinuations due to adverse events were 3.2%, 3.4%, 2.6% for
dapagliflozin 2.5 mg, 5 mg, and 10 mg plus glimepiride vs. 2.1% for
glimepiride plus placebo.
Adverse events suggestive of urinary tract infection and genital
infection were analyzed based on predefined groupings of preferred
terms for each of these two categories. The percentage of patients
with signs, symptoms and other reports suggestive of urinary tract
infection was similar across treatment groups: 3.9%, 6.9% and 5.3%
for dapagliflozin 2.5 mg, 5 mg, and 10 mg, respectively compared to
6.2% for glimepiride plus placebo. One patient discontinued due to a
urinary tract infection. Signs, symptoms and other reports suggestive
of genital infection were higher for the dapagliflozin 2.5 mg, 5 mg,
and 10 mg plus glimepiride treatment groups compared to the
glimepiride plus placebo group: 3.9%, 6.2% and 6.6% vs. 0.7%,
respectively.
Serious adverse events were 7.1%, 6.9% and 6.0% for dapagliflozin
2.5 mg, 5 mg, and 10 mg plus glimepiride, respectively compared to
4.8% for glimepiride plus placebo.
The percentage of individuals with any hypoglycemic event at week
24 for patients treated with dapagliflozin 2.5 mg, 5 mg, and 10 mg
plus glimepiride was 7.1%, 6.9% and 7.9%, respectively compared to
4.8% for those treated with placebo plus glimepiride.
Effects upon blood pressure were examined as exploratory
endpoints. Changes in seated systolic blood pressure were -4.7 mmHg,
-4.0 mmHg and -5.0 mmHg and in seated diastolic blood pressure were
-1.1 mmHg, -1.7 mmHg and -2.8 mmHg in the dapagliflozin 2.5, 5 and 10
mg treatment groups respectively compared to changes in seated
systolic blood pressure of -1.2 mmHg and seated diastolic blood
pressure -1.4 mmHg for those treated with placebo plus glimepiride.
About Type 2 Diabetes
Type 2 diabetes (diabetes mellitus) is a chronic, progressive
disease that is characterized by dysfunction of beta cells in the
pancreas, which decreases insulin secretion and leads to elevated
glucose levels. Over time, this sustained hyperglycemia contributes
to worsening insulin resistance and further beta cell dysfunction.
Many patients with type 2 diabetes have co-morbidities such as
obesity and hypertension. Significant unmet needs exist as nearly
half of treated patients remain uncontrolled on their current
glucose-lowering regimen and even fewer are controlled across
multiple parameters. In the past, treatments for type 2 diabetes have
focused primarily on insulin-dependent mechanisms. An approach that
acts independently of insulin may provide an option for adults with
type 2 diabetes in helping manage their glucose levels.
About SGLT2 Inhibition
The renal SGLT system plays a major role in overall glucose
balance in the body. Normally, the kidney filters ~180g of glucose
each day, and virtually all is reabsorbed back into circulation.
Glucose reabsorbtion occurs in the proximal tubule of the kidney via
the SGLT system. Selective inhibition of SGLT2 by an insulin
independent mechanism of action facilitates the excretion of glucose
and associated calories in the urine, thereby lowering blood glucose
levels.
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 select investigational drugs for type 2 diabetes. 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 discover, develop and deliver innovative medicines that
help patients prevail over serious diseases. For more information
about Bristol-Myers Squibb, visit http://www.bms.com or follow us on
Twitter at http://twitter.com/bmsnews.
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding product development. 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
dapagliflozin will receive regulatory approval or, if approved, that
it will become a commercially successful product. Forward-looking
statements in this 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, 2009, in our Quarterly Reports on Form 10-Q and our
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 global, innovation-driven biopharmaceutical
business with a primary focus on the discovery, development and
commercialisation of prescription medicines. As a leader in
gastrointestinal, cardiovascular, neuroscience, respiratory and
inflammation, oncology and infectious disease medicines, AstraZeneca
generated global revenues of US $32.8 billion in 2009. For more
information please visit: http://www.astrazeneca.com

Contact:

CONTACT: Contacts: Media: Ken Dominski, Bristol-Myers
Squibb,+1-609-252-5251, ken.dominski@bms.com; Jim Minnick,
AstraZeneca,+1-302-885-5135, jim.minnick@astrazeneca.com; Investors:
John Elicker,Bristol-Myers Squibb, +1-609-252-4611,
john.elicker@bms.com; Karl Hard, AstraZeneca,
+44-20-7304-5322,karl.hard@astrazeneca.com; Clive Morris,
AstraZeneca, +44-20-7304-5084,clive.morris@astrazeneca.com

Plus de actualités: Bristol-Myers Squibb and AstraZeneca
Plus de actualités: Bristol-Myers Squibb and AstraZeneca