AstraZeneca
(NYSE:AZN) and Bristol-Myers
Squibb Company (NYSE:BMY) today announced additional results from
the SAVOR cardiovascular outcomes trial, which found no increased rate
of hypoglycemia among patients treated with Onglyza®
(saxagliptin) compared to placebo when added to metformin
monotherapy and higher rates of hypoglycemia only in the Onglyza
group compared to the placebo group among patients taking sulfonylureas,
agents known to cause hypoglycemia, at baseline. Additionally, a greater
percentage of patients taking Onglyza reached their target HbA1c
without hypoglycemia, except patients who were treated with
sulfonylureas alone at baseline. These findings are consistent with
previous studies of Onglyza. Results were presented today at the
49th Annual Meeting of the European Association for the Study
of Diabetes (EASD) in Barcelona, Spain.
“Treating diabetes often requires the use of multiple therapies to help
lower blood glucose levels without increasing the risk of hypoglycemia,”
said Itamar Raz, MD, Co-Primary Study Investigator and Head of the
Diabetes Unit, Department of Medicine, Hadassah University Hospital,
Jerusalem, Israel. “In a post-hoc analysis from SAVOR, the data
reflected that when saxagliptin was used in combination with metformin,
there was a lowering of blood sugar and no increase in the risk of
hypoglycemia.”
Additionally, results from SAVOR found rates of any events of
adjudication-confirmed pancreatitis were balanced between the Onglyza
and placebo treatment groups (24 patients in the Onglyza arm
versus 21 patients in the placebo arm). Moreover, in patients who
experienced pancreatitis, the duration of the event, study drug actions
and outcome of the adverse event were balanced across the two treatment
arms. Observed rates of pancreatic cancer were also low (five patients
in the Onglyza arm versus 12 patients in the placebo arm).
“Recent discussions regarding the pancreatic safety of some type 2
diabetes medicines, including incretin-based therapies such as DPP-4
inhibitors, have been largely based on non-randomized studies with
significant limitations,” said Prof. Raz. “SAVOR is the first
large-scale, randomized, blinded study of a type 2 diabetes treatment to
report an adjudicated review of pancreatitis events, and results from
this trial showed no overall increased risk of pancreatitis or
pancreatic cancer in patients taking saxagliptin.”
Study Results
SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in
Patients with Diabetes Mellitus), a randomized, double-blind,
placebo-controlled trial of 16,492 adult patients with type 2 diabetes,
was designed to minimize glycemic control differences between Onglyza
and placebo by allowing study physicians to actively manage blood
glucose through use of additional antidiabetic drugs or dose titration.
In this assessment of hypoglycemia, patients were analyzed by
antidiabetic medication at baseline (not treated with antidiabetic
drugs, treated with metformin alone, treated with sulfonylurea, treated
with insulin alone or treated with insulin in combination with other
antidiabetic drugs) and HbA1c at baseline (entire study population,
HbA1c < 7% or HbA1c ≥ 7%). Results showed there was no significant
increase in the incidence of hypoglycemia with Onglyza compared
to placebo when added to patients who were treated with metformin alone
(2.4 events per 100 patient years for Onglyza versus 2.6 for
placebo; Hazard Ratio [HR]: 0.92), insulin alone (17.4 events per 100
patient years for both the Onglyza and placebo groups; HR: 1.00),
or patients not treated with other antidiabetic medications at baseline
(3.0 events per 100 patient years for Onglyza versus 2.1 for
placebo; HR: 1.44), regardless of baseline HbA1c. There was an increased
incidence of hypoglycemia with Onglyza compared to placebo in
patients who were taking a sulfonylurea (a class of agents known to
cause hypoglycemia) at baseline, regardless of HbA1c (9.7 events per 100
patient years for Onglyza versus 6.8 for placebo; HR: 1.42) and
in patients who were treated with insulin in combination with other
antidiabetic drugs, but only those with a baseline HbA1c < 7% (HR:
1.42). There was no increase in rates of major hypoglycemia between Onglyza
and placebo, in any subgroup, other than patients taking sulfonylurea
with baseline HbA1c < 7% (HR: 2.24). At two years, the percentage of
patients achieving HbA1c < 7% without hypoglycemic events was greater
among patients who were treated with Onglyza and metformin alone
(36.1% vs. 23.6%), insulin alone (12.1% vs. 7.6%) or other antidiabetic
medications (16.1% vs. 11.4%), compared to placebo. Among patients
treated with Onglyza and sulfonylurea alone, fewer patients
(20.6% vs. 22.4%) achieved their target HbA1c without hypoglycemia
compared to placebo.
The SAVOR trial also included evaluation of possible events of
pancreatitis and pancreatic cancer, which were reported by
investigators. All reports of pancreatitis were, in addition,
adjudicated without knowledge of treatment assignment by an independent
external expert committee, which included two pancreatic disease
experts. Reported cases of pancreatitis were classified into four
categories: definite acute pancreatitis, possible acute pancreatitis,
chronic pancreatitis or unlikely to be pancreatitis.
Overall, a total of 33 patients treated with Onglyza and 30
patients who received placebo were reported by investigators to have
pancreatitis, with 35 cases in each group. By adjudication, pancreatitis
was confirmed in 24 patients (26 cases) in the Onglyza arm versus
21 patients (25 cases) in the placebo arm. Additional results from the
adjudicated analysis on pancreatitis found that:
-
Definite or possible acute pancreatitis was observed in 38 patients,
22 patients in the Onglyza arm versus 16 patients in the
placebo arm. Out of these patients, 17 (0.2%) in the Onglyza
arm and nine (0.1%) in the placebo arm were classified as having
definite acute pancreatitis.
-
Recovery rates from pancreatitis were similar between the two
treatment groups (21 patients [80.8%] in the Onglyza arm versus
21 patients [84.0%] in the placebo arm were resolved, three patients
[11.5%] versus one patient [4.0%] was recovering, two patients [7.7%]
versus one patient [4.0%] was not resolved, zero patients versus one
patient [4.0%] was resolved with sequelae and zero patients vs. one
patient [4.0%] died in the Onglyza and placebo groups,
respectively).
-
Chronic pancreatitis was reported in two patients (0.02%) in the Onglyza
arm versus six patients (0.07%) in the placebo arm.
-
Among patients with pancreatitis, the majority remained on treatment,
with four patients (15.4%) discontinuing study medication and two
patients (7.7%) interrupting study medication in the Onglyza
arm versus six patients (24.0%) discontinuing study medication and one
patient (4.0%) interrupting study medication in the placebo arm.
-
Pancreatic cancer was reported in five patients in the Onglyza
arm versus 12 patients in the placebo arm (p-value = 0.095).
Primary Study Results and Study Design
The primary study results from the SAVOR trial were presented at the
2013 European Society of Cardiology (ESC) Congress in Amsterdam,
Netherlands and published in The New England Journal of Medicine.
Led by the academic research organizations TIMI Study Group and Hadassah
University Medical Center and conducted at more than 700 sites
worldwide, SAVOR was a randomized, double-blind, placebo-controlled
trial designed to evaluate the cardiovascular safety and efficacy of Onglyza
in adults with type 2 diabetes at risk for cardiovascular death, heart
attack and stroke, compared to placebo.
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% and < 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
myocardial infarction [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.
Results from the primary analysis of SAVOR found that 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 (HR: 1.00; 95% Confidence
Interval [CI]: 0.89, 1.12; non-inferiority p-value < 0.001). Onglyza
did not meet the primary efficacy endpoint of superiority to placebo for
the same composite endpoint (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 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).
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 6
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.
Copyright Business Wire 2013