Squibb Company (NYSE: BMY) and AstraZeneca
(NYSE: AZN) today announced results from a Phase 3 clinical study that
showed the investigational compound dapagliflozin 10 mg demonstrated
significant reductions in blood sugar levels (glycosylated hemoglobin
levels, or HbA1c) compared with placebo at 24 weeks when either agent
was added to existing sitagliptin therapy (with or without metformin) in
adult patients with type 2 diabetes. The results were maintained over a
24-week extension and similar results were observed when the data were
stratified by background therapy. The findings were presented today at
the 72nd American Diabetes Association (ADA) Scientific
Sessions in Philadelphia, PA.
The study also demonstrated significant reductions in total body weight
and fasting plasma glucose (FPG) levels in patients taking dapagliflozin
added to sitagliptin (with or without metformin), with results
maintained throughout the duration of the study extension.
Patients were actively questioned at each study visit for signs,
symptoms or events suggestive of genital infections and urinary tract
infections. These events were more frequent with the dapagliflozin
treatment group compared to the placebo treatment group, and were
generally mild to moderate in intensity, with most patients responding
to standard treatment.
“Type 2 diabetes is a complex disease that often requires patients to
take multiple treatments to control their blood sugar levels, with DPP4
inhibitors being some of the most widely prescribed therapies,” said
Serge Jabbour, M.D., Division Director of Endocrinology, Thomas
Jefferson University. “In this study, dapagliflozin, in addition to diet
and exercise, resulted in reduced blood sugar levels when added to
sitagliptin, a DPP4 inhibitor. These findings add to our understanding
of the effect of dapagliflozin in combination with commonly prescribed
type 2 diabetes treatments.”
Dapagliflozin, an investigational oral compound, is a selective and
reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2), which
works independently of insulin. Dapagliflozin is under joint development
by Bristol-Myers Squibb and AstraZeneca, and is being investigated to
evaluate its safety and efficacy in improving glycemic control in adults
with type 2 diabetes as an adjunct to diet and exercise, for once-daily
use as a monotherapy and in combination with other glucose-lowering
drugs. If approved, dapagliflozin would potentially be the first in the
new SGLT2 inhibitor class for the treatment of type 2 diabetes, a
disease where high unmet medical need exists. In a comprehensive
clinical trial program of 19 studies, dapagliflozin has been studied
together with diet and exercise as a monotherapy, and as an add-on
therapy to commonly prescribed diabetes medications, including
metformin, sulfonylurea (glimepiride), thiazolidinedione (pioglitazone),
and insulin (with or without other diabetes therapies).
In January 2012, the U.S. Food and Drug Administration (FDA) issued a
complete response letter regarding the New Drug Application (NDA) for
dapagliflozin for the treatment of adults with type 2 diabetes,
requesting additional clinical data to allow a better assessment of the
benefit-risk profile for dapagliflozin. In April 2012, the Committee for
Medicinal Products for Human Use (CHMP) of the European Medicines Agency
(EMA) issued a positive opinion recommending the approval of
dapagliflozin for the treatment of type 2 diabetes as an adjunct to diet
and exercise, in combination with other glucose-lowering medicinal
products including insulin, and as a monotherapy in metformin intolerant
patients. The CHMP positive opinion for dapagliflozin will now be
reviewed by the European Commission, which has the authority to approve
medicines for the European Union.
About the Study
This was a 24-week, Phase 3, multicenter, randomized, double-blind,
placebo-controlled, parallel-group study with a 24-week blinded
extension. The study compared the efficacy of dapagliflozin to placebo
in patients with type 2 diabetes who are inadequately controlled on
sitagliptin monotherapy or on sitagliptin plus metformin therapy. The
primary efficacy endpoint at 24 weeks was mean change in HbA1c from
baseline for dapagliflozin 10 mg compared to placebo, both added to
sitagliptin (with or without metformin) in adults with type 2 diabetes
who had inadequate glycemic control. The 24-week extension was designed
to assess the maintenance of efficacy with the dapagliflozin treatment
group, as well as safety and tolerability over 48 weeks.
The study included 447 adults with type 2 diabetes (aged ≥ 18 years)
with inadequate glycemic control (HbA1c ≥ 7.0% and ≤ 10.0%) who were on
a stable dose of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor
(with or without metformin).
Patients were randomized equally to receive dapagliflozin or placebo
added to sitagliptin alone (stratum 1) or added to sitagliptin plus
metformin (stratum 2). Patients in stratum 1 received dapagliflozin 10
mg or placebo added to sitagliptin 100 mg/d. Patients in stratum 2
received dapagliflozin 10 mg or placebo added to sitagliptin 100 mg/d
plus metformin ≥ 1500 mg/d.
Patients (n = 223) receiving dapagliflozin 10 mg added to sitagliptin
with or without metformin demonstrated significantly greater
improvements in glycemic control at the end of 24 weeks compared to
patients (n = 224) taking placebo added to sitagliptin with or without
metformin, with a change in baseline in HbA1c of -0.48% (p-value <
0.0001, Last Observation Carried Forward [LOCF]).
Additional results of the key primary and secondary endpoints included
Dapagliflozin added to sitagliptin (stratum 1) resulted in a greater
reduction in HbA1c compared to placebo added to sitagliptin, with a
change in HbA1c of -0.56% (p-value < 0.0001, LOCF).
Dapagliflozin added to sitagliptin and metformin (stratum 2) resulted
in a greater reduction in HbA1c compared to placebo added to
sitagliptin plus metformin, with a change in HbA1c of -0.40% (p-value
< 0.0001, LOCF).
Reductions in HbA1c were notable at four weeks (the first recorded
time point) and maintained to 48 weeks.
Patients with a higher baseline HbA1c (≥ 8.0%) receiving treatment
with dapagliflozin achieved greater reductions in HbA1c.
Significant reductions in body weight were observed with dapagliflozin
compared to placebo in the entire treatment cohort (-1.89 kg, LOCF),
stratum 1 (-1.85 kg, LOCF) and stratum 2 (-1.87 kg, LOCF), and were
sustained out to 48 weeks.
Significant differences were also observed in adjusted mean FPG in
patients who received dapagliflozin.
Patients in the dapagliflozin group did not show a statistically
significant change from baseline in placebo subtracted seated systolic
blood pressure (SBP, baseline ≥ 130 mm Hg) compared to placebo: -5.98 mm
Hg (n = 101; dapagliflozin) vs. -5.12 mm Hg (n = 111; placebo) at week
24 (-0.86 [SE 1.47], p-value = 0.5583).
Over 24 weeks, 18.8% of patients receiving dapagliflozin discontinued
for lack of efficacy or were rescued for meeting pre-specified rescue
criteria vs. 41.5% receiving placebo.
Over the 48-week treatment period, the proportion of patients
experiencing at least one adverse event was 66.2% in the dapagliflozin
group compared to 61.1% in the placebo group. The most common adverse
events occurring in ≥ 4.0% of the study population were as follows:
nasopharyngitis, back pain, urinary tract infection, pharyngitis,
arthralgia and headache.
The proportion of patients who experienced at least one serious adverse
event was 6.7% in the dapagliflozin group compared to 8.0% in the
placebo group. In either treatment group, 3.1% discontinued treatment
due to an adverse event. Hypoglycemia was reported in 5.3% of the
dapagliflozin group compared to 6.2% in the placebo group.
The proportion of patients with diagnoses of genital infections was 9.3%
in the dapagliflozin group compared to 0.4% in the placebo group. The
proportion of patients with diagnoses of urinary tract infections was
5.8% in the dapagliflozin group and 3.5% in the placebo group.
Adverse events suggestive of renal impairment or failure were observed
in eight patients in the dapagliflozin group (3.6%) and four patients in
the placebo group (1.8%). In four patients in the dapagliflozin group
and in one patient in the placebo group, a decrease in renal creatinine
clearance was reported.
About Type 2 Diabetes
In 2011, diabetes was estimated to affect more than 365 million people
aged 20-79 worldwide. Because of the aging population and the growing
trend of obesity, the prevalence of diabetes is projected to reach more
than 550 million by 2030. Type 2 diabetes accounts for approximately 90
to 95% of all cases of diagnosed diabetes in adults. Type 2 diabetes is
a chronic disease characterized by insulin resistance and dysfunction of
beta cells in the pancreas, which decreases insulin sensitivity and
secretion, leading to elevated glucose levels. Over time, this sustained
hyperglycemia contributes to worsening insulin resistance and further
beta cell dysfunction. To date, treatments for type 2 diabetes have
focused primarily on insulin-dependent mechanisms. An approach that acts
independently of insulin could provide an additional option for adults
with type 2 diabetes.
Significant unmet needs still exist, as many patients remain
inadequately controlled on their current glucose-lowering regimen. Many
patients with type 2 diabetes have additional co-morbidities (such as
obesity) which may complicate glycemic control.
About SGLT2 inhibition
The kidney plays an important role in glucose balance, normally
filtering ~180g of glucose each day, with virtually all glucose being
reabsorbed back into circulation. SGLT2 is a major sodium-glucose
cotransporter in the kidney and is an insulin-independent pathway for
the reabsorption of glucose back into the blood.
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 www.bms.com
or follow us on Twitter at http://twitter.com/bmsnews.
AstraZeneca is a global, innovation-driven biopharmaceutical business
with a primary focus on the discovery, development and commercialization
of prescription medicines for gastrointestinal, cardiovascular,
neuroscience, respiratory and inflammation, oncology and infectious
disease. AstraZeneca operates in over 100 countries and its innovative
medicines are used by millions of patients worldwide. For more
information please visit: www.astrazeneca.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 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 European Commission 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, 2011, 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.
AstraZeneca Forward-Looking Statement
The statements contained 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 and Form 20-F Information 2011. Nothing contained herein should
be construed as a profit forecast.