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Onglyza® (saxagliptin) Achieves Primary Safety Endpoint, Demonstrating No Increased Risk for Cardiovascular Death, Heart Attack



  Onglyza® (saxagliptin) Achieves Primary Safety Endpoint, Demonstrating No
  Increased Risk for Cardiovascular Death, Heart Attack or Stroke in SAVOR
  Cardiovascular Outcomes Trial

  * SAVOR provides information on cardiovascular safety for Onglyza in the
    wake of past questions about cardiovascular safety of type 2 diabetes
    treatments
  * SAVOR is the largest cardiovascular outcomes trial to study a diverse
    population of type 2 diabetes patients at high risk for cardiovascular
    events
  * Onglyza did not meet the primary efficacy endpoint of superiority to
    placebo
  * In additional analyses, patients treated with Onglyza had improved
    glycemic control over two years

Business Wire

WILMINGTON, Del. & PRINCETON, N.J. -- September 2, 2013

AstraZeneca (NYSE: AZN) and Bristol-Myers Squibb Company (NYSE: BMY) today
announced the full results of the SAVOR clinical trial in 16,492 adult
patients with type 2 diabetes at high risk for cardiovascular events. In this
study, Onglyza^® (saxagliptin) met the primary safety objective, demonstrating
no increased risk for the primary composite endpoint of cardiovascular death,
non-fatal myocardial infarction (MI) or non-fatal ischemic stroke, when added
to a patient’s current standard of care (with or without other anti-diabetic
therapies), as compared to placebo. Onglyza did not meet the primary efficacy
endpoint of superiority to placebo for the same composite endpoint. Patients
treated with Onglyza experienced improved glycemic control and reduced
development and progression of microalbuminuria over two years as assessed in
exploratory analyses.

The major secondary composite endpoint of cardiovascular death, non-fatal MI,
non-fatal ischemic stroke or hospitalization for heart failure, unstable
angina or coronary revascularization was balanced across the two arms. One
component of the composite secondary endpoint, hospitalization for heart
failure, occurred more in the Onglyza group compared to placebo. Rates of
pancreatitis were low and balanced between Onglyza and placebo. Overall rates
of malignancy were balanced, and the observed rates of pancreatic cancer were
lower in the Onglyza group than in the placebo group. More patients in the
Onglyza group reported at least one hypoglycemic event compared to placebo.
Results were presented today during a Hot Line session at the ESC Congress
2013 in Amsterdam, Netherlands, and published in The New England Journal of
Medicine.

In the past, questions have been raised about the safety of many diabetes
treatments, in particular regarding their impact on the risk of cardiovascular
death, heart attack or stroke. Led by the academic research organizations TIMI
Study Group and Hadassah University Medical Center and conducted at more than
700 sites worldwide, SAVOR (Saxagliptin Assessment of Vascular Outcomes
Recorded in Patients with Diabetes Mellitus) was a randomized, double-blind,
placebo-controlled trial of 16,492 patients designed to evaluate the
cardiovascular safety and efficacy of Onglyza (saxagliptin) in adults with
type 2 diabetes at risk for cardiovascular death, heart attack and stroke,
compared to placebo.

“Given the correlation between diabetes and cardiovascular complications,
there is a need for thorough assessments of the cardiovascular risks among
therapies that improve glycemic control,” said Deepak L. Bhatt, MD, MPH,
Senior Investigator of the TIMI Study Group, Brigham and Women’s Hospital, and
a Principal Investigator for the trial. “The results from SAVOR add important
evidence to the overall body of data to further define the clinical profile of
saxagliptin for the treatment of type 2 diabetes.”

“No other DPP-4 inhibitor and few other anti-hyperglycemic agents have been
studied as extensively as Onglyza to address the question of cardiovascular
safety,” said Brian Daniels, MD, senior vice president, Global Development and
Medical Affairs, Research and Development, Bristol-Myers Squibb.
“Bristol-Myers Squibb and AstraZeneca are dedicated to meeting needs of
physicians and patients in diabetes care and helping to ensure a better
understanding of the value of our medications.”

“SAVOR is an important contribution to our knowledge of the safety of Onglyza
in type 2 diabetes patients at an increased risk for cardiovascular events
similar to those found in a real-world population,” said Briggs Morrison, MD,
executive vice president, Global Medicines Development, AstraZeneca. “In
addition, the data on pancreatitis and pancreatic cancer in a study of more
than 16,000 patients provide important and timely scientific information from
a robust, randomized trial for the diabetes community.”

Study Results

In the study, the primary composite endpoint of cardiovascular death,
non-fatal MI or non-fatal ischemic stroke occurred in 613 patients (7.3%) in
the Onglyza group vs. 609 patients (7.2%) in the placebo group (Hazard Ratio
[HR]: 1.00; 95% Confidence Interval [CI]: 0.89, 1.12; non-inferiority p-value
< 0.001; superiority p-value = 0.99). The major secondary endpoint, consisting
of the primary composite endpoint and hospitalization for heart failure,
unstable angina or coronary revascularization, occurred in 1,059 patients
(12.8%) in the Onglyza (saxagliptin) group vs. 1,034 patients (12.4%) in the
placebo group (HR: 1.02; 95% CI: 0.94, 1.11; p-value = 0.66). Hospitalization
for heart failure, a component of this secondary composite endpoint, occurred
at a greater rate in the Onglyza group (3.5%) than in the placebo group (2.8%)
(HR: 1.27; 95% CI: 1.07, 1.51; p-value = 0.007). The pre-specified secondary
endpoint of all-cause mortality occurred in 420 patients (4.9%) in the Onglyza
group compared to 378 patients (4.2%) in the placebo group (HR: 1.11; 95% CI:
0.96, 1.27; p-value = 0.15).

Study physicians were allowed to actively manage patients’ glucose through
concomitant use of other anti-diabetic drugs and dose titration. Fewer
patients in the Onglyza group required the addition or increase of any new
anti-diabetic medication compared to placebo (1,938 patients [23.7%] vs. 2,385
patients [29.3%], respectively; HR: 0.77; 95% CI: 0.73, 0.82; p-value < 0.001)
or the initiation of insulin therapy for more than three months (454 patients
[5.5%] vs. 634 patients [7.8%], respectively; HR: 0.70; 95% CI: 0.62, 0.79;
p-value < 0.001). ^ Patients in the Onglyza group had greater reductions in
blood sugar levels both from baseline and compared to those in the placebo
group, with mean reductions in glycosylated hemoglobin (HbA1c) levels of 0.5%
at two years of treatment in the Onglyza group vs. 0.2% in the placebo group
(p-value < 0.001). More patients in the Onglyza group achieved or maintained
goal HbA1c of less than seven percent compared to those in the placebo group
at two years (40.0% vs. 30.3%; p-value < 0.001).

A total of 1,264 patients (15.3%) in the Onglyza group reported at least one
hypoglycemic event compared to 1,104 (13.4%) in the placebo group (p-value <
0.001), which included patients with both major (177 patients [2.1%] vs. 140
patients [1.7%]; p-value = 0.047) and minor (1,172 patients [14.2%] vs. 1,028
patients [12.5%]; p-value = 0.002) events for the Onglyza and placebo groups,
respectively. Hospitalization for hypoglycemia was infrequent and similar
between groups (0.6% vs. 0.5%; p-value = 0.33).

Patients in the Onglyza group experienced reduced development and progression
of microalbuminuria, and were more likely to have an improved
albumin:creatinine ratio at two years (372 patients [11.1%] in the Onglyza
group vs. 295 patients [9.2%] in the placebo group), and less likely to have a
worsening ratio (414 patients [12.4%] in the Onglyza group vs. 457 patients
[14.2%] in the placebo group), compared to placebo.

A number of pre-specified safety endpoints for diabetes treatments were
evaluated (pancreatitis, cancer, liver abnormalities, renal abnormalities,
thrombocytopenia, lymphocytopenia, infections, hypersensitivity or skin
reactions, bone fractures and hypoglycemia).

All suspected cases of pancreatitis were independently reviewed and
adjudicated by a committee of medical experts external to the sponsors and
investigators. Pancreatitis occurred infrequently and the number of patients
with acute or chronic pancreatitis was similar between the treatment groups
(24 [0.3%] in the Onglyza (saxagliptin) group vs. 21 [0.3%], in the placebo
group; p-value = 0.77). Definite/possible acute pancreatitis occurred in 22
patients (0.3%) in the Onglyza group vs. 16 patients (0.2%) in the placebo
group (p-value = 0.42); definite acute pancreatitis in 17 patients (0.2%) vs.
nine patients (0.1%) (p-value = 0.17); and chronic pancreatitis in two
patients (< 0.1%) vs. six patients (0.1%) (p-value = 0.18), respectively.
There were five cases of pancreatic cancer in the Onglyza group and 12 cases
in the placebo group (p-value = 0.095). Renal abnormalities were observed more
frequently in the Onglyza group compared to the placebo group (5.8% vs. 5.1%,
respectively; p-value = 0.04). The incidence of the other pre-specified safety
endpoints was balanced between the two groups.

Study Design

The study included 16,492 adult patients with type 2 diabetes, 8,280 of whom
were randomized to receive Onglyza and 8,212 of whom were randomized to
receive placebo. Recruitment included patients with type 2 diabetes and
baseline HbA1c levels of 6.5% to 12% on any diabetes treatment including diet,
insulin and/or oral therapy (excluding GLP-1 agonists and DPP-4 inhibitors)
who were at elevated risk for cardiovascular events according to two
categories:

  * Patients ≥ 40 years of age with established cardiovascular disease,
    defined as ischemic heart disease, peripheral vascular disease or ischemic
    stroke.
  * Males ≥ 55 years of age and females ≥ 60 years of age with at least one of
    the following risk factors: dyslipidemia, hypertension or current smoking,
    but without established cardiovascular disease.

Further grouping was based on renal function, including patients with
normal/mild (eGFR > 50 mL/min), moderate (30 - 50 mL/min) or severe (eGFR < 30
mL/min) renal impairment.

The primary safety objective was to establish that the upper bound of the 95%
confidence interval for the estimated risk ratio comparing the incidence of
the composite endpoint (cardiovascular death, non-fatal MI or non-fatal
ischemic stroke) observed with Onglyza to that observed in the placebo group
was less than 1.3. The primary efficacy objective was to determine, as a
superiority assessment, whether treatment with Onglyza compared to placebo
when added to current background therapy would result in a reduction in the
composite endpoint of cardiovascular death, non-fatal MI or non-fatal ischemic
stroke in patients with type 2 diabetes. Secondary efficacy objectives
included a reduction in the primary composite endpoint together with
hospitalization for heart failure, coronary revascularization or unstable
angina pectoris, and reduction of all-cause mortality. Secondary safety
objectives included the evaluation of safety and tolerability by assessment of
overall adverse events and adverse events of special interest.

Patients were randomized between May 2010 and December 2011. The median
follow-up was 2.1 years and maximum follow-up was 2.9 years.

About Onglyza^® (saxagliptin)

As of September 2013, Onglyza is approved in 86 countries including those in
the European Union, the United States, Canada, Mexico, India, Brazil and
China.

Indication and Limitations of Use for Onglyza

Onglyza is indicated as an adjunct to diet and exercise to improve glycemic
control in adults with type 2 diabetes mellitus in multiple clinical settings.

Onglyza should not be used for the treatment of type 1 diabetes mellitus or
diabetic ketoacidosis.

Onglyza has not been studied in patients with a history of pancreatitis.

Important Safety Information for Onglyza

Contraindications

  * History of a serious hypersensitivity reaction to Onglyza (e.g.,
    anaphylaxis, angioedema, or exfoliative skin conditions)

Warnings and Precautions

  * Pancreatitis: There have been post-marketing reports of acute pancreatitis
    in patients taking Onglyza. After initiating Onglyza, observe patients
    carefully for signs and symptoms of pancreatitis. If pancreatitis is
    suspected, promptly discontinue Onglyza and initiate appropriate
    management. It is unknown whether patients with a history of pancreatitis
    are at increased risk of developing pancreatitis while using Onglyza.
  * Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin: When Onglyza
    was used in combination with a sulfonylurea or with insulin, medications
    known to cause hypoglycemia, the incidence of confirmed hypoglycemia was
    increased over that of placebo used in combination with a sulfonylurea or
    with insulin. Therefore, a lower dose of the insulin secretagogue or
    insulin may be required to minimize the risk of hypoglycemia when used in
    combination with Onglyza.
  * Hypersensitivity Reactions: There have been post-marketing reports of
    serious  hypersensitivity reactions in patients treated with Onglyza,
    including anaphylaxis, angioedema, and exfoliative skin conditions. Onset
    of these reactions occurred within the first 3 months after initiation of
    treatment with Onglyza, with some reports occurring after the first dose.
    If a serious hypersensitivity reaction is suspected, discontinue Onglyza,
    assess for other potential causes for the event, and institute alternative
    treatment for diabetes. Use caution in patients with a history of
    angioedema to another DPP-4 inhibitor as it is unknown whether they will
    be predisposed to angioedema with Onglyza.
  * Macrovascular Outcomes: There have been no clinical studies establishing
    conclusive evidence of macrovascular risk reduction with Onglyza or any
    other antidiabetic drug.

Most Common Adverse Reactions

  * Most common adverse reactions reported in ≥5% of patients treated with
    Onglyza and more commonly than in patients treated with control were upper
    respiratory tract infection (7.7%, 7.6%), headache (7.5%, 5.2%),
    nasopharyngitis (6.9%, 4.0%) and urinary tract infection (6.8%, 6.1%).
  * When used as add-on combination therapy with a thiazolidinedione, the
    incidence of peripheral edema for Onglyza 2.5 mg, 5 mg, and placebo was
    3.1%, 8.1% and 4.3%, respectively.
  * Confirmed hypoglycemia was reported more commonly in patients treated with
    Onglyza 2.5 mg and Onglyza 5 mg compared to placebo in the add-on to
    glyburide trial (2.4%, 0.8% and 0.7%, respectively), with Onglyza 5 mg
    compared to placebo in the add-on to insulin (with or without metformin)
    trial (5.3% and 3.3%, respectively),with Onglyza 2.5 mg compared to
    placebo in the renal impairment trial (4.7% and 3.5%, respectively), and
    with Onglyza 5 mg compared to placebo in the add-on to metformin plus
    sulfonylurea trial (1.6% and 0.0%, respectively).

Drug Interactions

Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin
exposure, the dose of Onglyza should be limited to 2.5 mg when coadministered
with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir,
itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and
telithromycin).

Use in Specific Populations

  * 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 [CrCl] ≤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.

Please click here for full U.S. Prescribing Information and Medication Guide
for Onglyza^® (saxagliptin).

About Diabetes

In 2012, diabetes was estimated to affect more than 370 million people
worldwide. 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, leading to elevated glucose levels. Over time, this sustained
hyperglycemia contributes to further progression of the disease. Significant
unmet needs still exist, as many patients remain inadequately controlled on
their current glucose-lowering regimen.

The major cause of death and complications in patients with type 2 diabetes is
cardiovascular disease. As many as 80% of patients with type 2 diabetes will
develop and possibly die from a cardiovascular event.

About the AstraZeneca / Bristol-Myers Squibb Diabetes Alliance

Dedicated to addressing the global burden of diabetes by advancing
individualized patient care, AstraZeneca and Bristol-Myers Squibb are working
in collaboration to research, develop and commercialize a versatile portfolio
of innovative treatment options for diabetes and related metabolic disorders
that aim to provide treatment effects beyond glucose control. Find out more
about the Alliance and our commitment to meeting the needs of health care
professionals and people with diabetes at www.astrazeneca.com or www.bms.com.

About AstraZeneca

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.

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, please visit http://www.bms.com
or follow us on Twitter at http://twitter.com/bmsnews.

AstraZeneca Cautionary Statement Regarding Forward-Looking Statement

In order, among other things, to utilise the 'safe harbour' provisions of the
US Private Securities Litigation Reform Act 1995, we are providing the
following cautionary statement: This press release contains certain
forward-looking statements with respect to the operations, performance and
financial condition of the Group. 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 preparation of this press release and AstraZeneca
undertakes no obligation to update these forward-looking statements. We
identify the forward-looking statements by using the words 'anticipates',
'believes', 'expects', 'intends' and similar expressions in such 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: the loss or expiration of patents,
marketing exclusivity or trade marks, or the risk of failure to obtain patent
protection; the risk of substantial adverse litigation/government
investigation claims and insufficient insurance coverage; exchange rate
fluctuations; the risk that R&D will not yield new products that achieve
commercial success; the risk that strategic alliances and acquisitions will be
unsuccessful; the impact of competition, price controls and price reductions;
taxation risks; the risk of substantial product liability claims; the impact
of any failure by third parties to supply materials or services; the risk of
failure to manage a crisis; the risk of delay to new product launches; the
difficulties of obtaining and maintaining regulatory approvals for products;
the risk of failure to observe ongoing regulatory oversight; the risk that new
products do not perform as we expect; the risk of environmental liabilities;
the risks associated with conducting business in emerging markets; the risk of
reputational damage; the risk of product counterfeiting; the risk of failure
to successfully implement planned cost reduction measures through productivity
initiatives and restructuring programmes; the risk that regulatory approval
processes for biosimilars could have an adverse effect on future commercial
prospects; and the impact of increasing implementation and enforcement of more
stringent anti-bribery and anti-corruption legislation. Nothing in this press
release should be construed as a profit forecast.

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. 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, 2012, 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.

Contact:

Media:
Bristol-Myers Squibb
Ken Dominski, 609-252-5251
ken.dominski@bms.com
or
AstraZeneca
Kirsten Evraire, 302-885-0435
kirsten.evraire@astrazeneca.com
or
Investors:
Bristol-Myers Squibb
Ranya Dajani, 609-252-5330
ranya.dajani@bms.com
or
Bristol-Myers Squibb
Ryan Asay, 609-252-5020
ryan.asay@bms.com
or
AstraZeneca
Kårl Hard, 44-20-7604-8123
karl.j.hard@astrazeneca.com
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