Takeda Presents Additional Results from EXAMINE Cardiovascular Safety Outcomes
Trial at the 49th Annual Meeting of the European Association for the Study of
BARCELONA, Spain and ZURICH, Switzerland, Sept. 26, 2013
-- Fasiglifam Phase 3 Efficacy and Safety Data Also Presented
BARCELONA, Spain and ZURICH, Switzerland, Sept. 26, 2013 /PRNewswire/
--Takeda Pharmaceuticals International GmbH (Takeda), a leading contributor
to innovative Type 2 diabetes treatments, presented alogliptin and fasiglifam
data at the 49th Annual Meeting of the European Association for the Study of
Diabetes (EASD) in Barcelona, Spain. Data from the global EXAMINE ( EX
amination of C A rdiovascular Outco M es: Aloglipt IN vs. Standard of Car E in
Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) CV safety
outcomes trial indicated that alogliptin did not increase CV ischemic events
including all-cause mortality (death from any cause), nonfatal myocardial
infarction, nonfatal stroke, and urgent revascularization due to unstable
angina. Additionally, EXAMINE exploratory data presented showed rates of
hospitalization for heart failure were comparable across alogliptin and
The company also presented Phase 3 data on the investigational compound
fasiglifam, a potential first-in-class GPR40 agonist for the treatment of Type
2 diabetes, demonstrating the study's primary endpoint of change from baseline
in HbA1c at week 24 was met. Study findings showed that fasiglifam
significantly improved glycemic control with low incidence of hypoglycemia and
statistically significant reductions in HbA1c, compared with placebo, at 24
weeks in patients with Type 2 diabetes inadequately controlled by diet and
EXAMINE Data Results demonstrated that the EXAMINE exploratory adjudicated CV
composite endpoint of all-cause mortality, nonfatal myocardial infarction,
nonfatal stroke, urgent revascularization due to unstable angina, and
hospitalization for heart failure occurred at similar rates in the alogliptin
and placebo groups (16.0% vs. 16.5%; hazard ratio, 0.98; 95% confidence limits
[CL] of 0.86 to 1.12). For the post hoc composite endpoint of cardiovascular
death and hospitalization for heart failure, there was no difference in event
rates between the alogliptin and placebo groups (7.4% vs. 7.5%; hazard ratio,
0.98; 95% CL of 0.82 to 1.20).Rates of hospitalization for heart failure were
similar in the alogliptin versus placebo groups for both composite endpoints.
Among other published DPP-4i CV safety outcomes trials, EXAMINE was the only
trial to have evaluated Type 2 diabetes patients at high risk for major
adverse cardiac events (MACE) due to recent acute coronary syndrome (ACS).
Results of the global alogliptin EXAMINE trial were recently published in the
New England Journal of Medicine .
"As physicians, it is critical that we understand the impact of treating high
risk patient groups such as those evaluated by the EXAMINE trial," said Simon
Heller, D.M., EXAMINE Steering Committee member. "Many Type 2 diabetes
patients today are also living with cardiovascular disease and these
additional findings on heart failure hospitalizations will provide important
clinical insights for physicians helping patients manage their diabetes."
Fasiglifam Data The presentation entitled "Efficacy and safety of fasiglifam
(TAK-875), a GPR40 selective agonist, in Japanese Type 2 diabetes mellitus
patients: a Phase 3, double-blind, placebo controlled, comparative study"
includes findings from the CCT-003 study, which evaluated the efficacy and
safety of the investigational compound fasiglifam 25 mg and 50 mg,
administered once daily before breakfast for 24 weeks, in Japanese patients
with Type 2 diabetes inadequately controlled by diet and exercise. Findings
met the study's primary endpoint achieving a statistically significant change
from baseline in HbA1c compared to placebo (p-value less than 0.0001). The
difference in the least-square means in HbA1c versus placebo was -0.75% (95%
CL: -0.985 to -0.521) in the fasiglifam 25 mg group and -1.01% (95% CL: -1.244
to -0.777) in the fasiglifam 50 mg group. There were no significant
differences in incidence of adverse events between the fasiglifam groups and
the placebo group.
"We are pleased to present the Phase 3 findings from this study on fasiglifam,
which further help to demonstrate the clinical profile of this potential new
option for Type 2 diabetes," said Ajay Ahuja, M.D., vice president, Global
Medical Affairs, Takeda. "Takeda has built a strong foundation and maintained
a robust focus in diabetes for more than 20 years, and presenting a total of
seven abstracts at EASD with the scientific community underscores our
dedication to addressing the needs of this growing patient population."
Additional Data Additional abstracts presented include:
*"Durability of the efficacy and safety of alogliptin compared to glipizide
over 2 years when used in combination with metformin"
*"Efficacy and safety of alogliptin in subjects with type 2 diabetes: a
multicenter, randomized, double-blind, placebo-controlled, phase 3 study
in mainland China, Taiwan and Hong Kong"
*"Pharmacokinetics (PK) and pharmacodynamics (PD) of the GPR40 agonist
fasiglifam (TAK-875) and glimepiride following co-administration in type 2
*"Distribution of costs in patients with type 2 diabetes mellitus: a
retrospective claims database analysis"
*"Cost predictors in type 2 diabetes mellitus: a retrospective claims
About EXAMINE EXAMINE, a global, large, randomized, double-blind,
placebo-controlled clinical trial, was designed to evaluate CV safety
following treatment with alogliptin in addition to standard of care, versus
placebo in addition to standard of care, in patients with Type 2 diabetes and
a recent ACS (within 15 to 90 days prior to randomization). The trial had a
primary composite endpoint of CV death, nonfatal myocardial infarction and
nonfatal stroke. The EXAMINE primary endpoint of non-inferiority compared to
placebo in addition to standard of care was met showing no increase in CV risk
in a Type 2 diabetes patient population at high risk for CV events. The
primary endpoint occurred at similar rates in the alogliptin and placebo
groups (in 11.3% of patients vs. 11.8% of patients during a median follow-up
period of 18 months; hazard ratio, 0.96; one-sided repeated confidence
interval [CI] bound, 1.16).
In the alogliptin group, 71.4% of patients received 25 mg, 25.7% received 12.5
mg, and 2.9% received 6.25 mg daily. Alogliptin doses were adjusted according
to renal function: estimated glomerular filtration rate (eGFR) by the
Modification in Diet in Renal Disease formula greater than or equal to 60
ml/min, 25 mg daily;less than60 ml/min butgreater than or equal to30
ml/min, 12.5 mg daily; andless than30 ml/min, 6.25 mg daily. Premature
discontinuation of the study drug was similar in the alogliptin and placebo
groups (20.9% of patients vs. 22.6%). The median duration of exposure to study
drug was 533 days (interquartile range, 280 to 751 days). By the end of the
study, the mean change from baseline in HbA1c was -0.33% and 0.03% in the
alogliptin and placebo groups, respectively, and the least square means
difference in HbA1c between alogliptin and placebo was -0.36% (95% CL, -0.43,
-0.28, p-value less than 0.001). In the analysis of the components of the
primary endpoint, the hazard ratios were consistent with the overall result.
Hazard ratios for death from any cause and CV death were consistent with the
primary composite endpoint.
Takeda conducted the global EXAMINE trial in accordance with the United States
(U.S.) Food and Drug Administration's (FDA) 2008 Guidance, titled "Guidance
for Industry: Diabetes Mellitus – Evaluating Cardiovascular Risk in New
Antidiabetic Therapies to Treat Type 2 Diabetes," for all new Type 2 diabetes
About Type 2 Diabetes Type 2 diabetes is the most common form of diabetes
affecting millions of people globally. Type 2 diabetes is a progressive and
chronic condition and patients should work with a healthcare professional to
manage and monitor their disease. In addition to diet and exercise, patients
often need to take one or more medications in order to help them manage their
blood glucose levels. According to the International Diabetes Federation, the
global health care expenditures for diabetes (both Type 1 and 2) were
estimated at more than $471 billion USD in 2012. By 2030, this number is
projected to exceed $595 billion.
About Alogliptin Alogliptin is a dipeptidyl peptidase-4 inhibitor (DPP-4i) for
the treatment of Type 2 diabetes in adults as an adjunct to diet and exercise.
DPP-4 is are designed to slow the inactivation of incretin hormones GLP-1 and
GIP. As a result, an increased amount of active incretins enables the pancreas
to secrete insulin in a glucose-dependent manner, thereby assisting in the
management of blood glucose levels. A New Drug Application (NDA) for NESINA
(alogliptin) was approved in April 2010 by the Japanese Ministry of Health,
Labour and Welfare for the treatment of Type 2 diabetes, and the therapy is
available under the same brand name in Japan. A NDA for the alogliptin
fixed-dose combination (FDC) with pioglitazone was approved in July 2011 by
the Japanese Ministry of Health, Labour and Welfare for the treatment of Type
2 diabetes, and the therapy is available under the brand name LIOVEL in Japan.
NESINA (alogliptin) was approved by the U.S. FDA as a monotherapy and also in
FDC with pioglitazone (OSENI) and metformin HCl (KAZANO) in January 2013 for
the treatment of Type 2 diabetes in adults as adjuncts to diet and exercise.
Alogliptin as a monotherapy is currently approved for use in 6.25 mg, 12.5 mg,
and 25 mg dose tablets; the approved normal dose for alogliptin is 25 mg once
daily. For patients with moderate renal impairment (creatinine clearance
[CrCl]greater than or equal to30 mL/min toless than60 mL/min), the dose of
alogliptin is 12.5 mg once daily and for patients with severe renal impairment
(CrClgreater than or equal to15 toless than30 mL/min) and for patients
with end-stage renal disease (ESRD) (CrClless than15 mL/min or requiring
hemodialysis), the dose of alogliptin is 6.25 mg once daily.
In September 2013, the European Commission granted Marketing Authorization for
alogliptin (Vipidia™) and its FDC therapies, alogliptin with metformin
(Vipdomet™), and alogliptin with pioglitazone (Incresync™). The Committee for
Medicinal Products for Human Use (CHMP), of the European Medicines Agency
(EMA), issued a positive opinion for these products in July 2013. Alogliptin
is also approved for use in China, Mexico and South Korea, though the therapy
is not yet available in those markets.
The efficacy of alogliptin was studied as an adjunct to diet and exercise, and
as an add-on therapy to several other classes of anti-diabetic medications,
including biguanide, thiazolidinediones, insulin and sulfonylureas. In these
studies, alogliptin 25 mg tablets taken once daily, demonstrated clinically
and statistically significant reductions in HbA1c, with low incidence of
hypoglycemia compared with active control or placebo. Study results indicated
that alogliptin co-administered with either metformin or pioglitazone produced
significant improvements in glycemic control compared with the respective
Alogliptin Important Safety Information Alogliptin is contraindicated in
patients with knownhypersensitivity to alogliptin or any of its components.
Post-marketing events of acute pancreatitis have been reported for alogliptin
and have been associated with other DPP-4 inhibitors. After initiation of
alogliptin, patients should be observed carefully for signs and symptoms of
pancreatitis. If pancreatitis is suspected, alogliptin should be promptly
discontinued and appropriate management should be initiated.
Post-marketing events of serious hypersensitivity reactions in patients
treated with alogliptin such as angioedema and severe cutaneous adverse
reactions including Stevens-Johnson syndrome have been reported and have been
associated with other DPP-4 inhibitors. If a serious hypersensitivity reaction
is suspected, alogliptin should be discontinued.
Post-marketing reports of hepatic dysfunction including hepatic failure have
been received. Patients should be observed closely for possible liver
abnormalities. Measure liver tests promptly in patients who report symptoms
that may indicate liver injury. If an abnormality is found and an alternative
etiology is not established, consider discontinuation of alogliptin.
Insulin and insulin secretagogues, such as sulfonylureas, are known to cause
hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may
be required to minimize the risk of hypoglycemia when used in combination with
Other undesirable effects of alogliptin include headache, upper respiratory
tract infection, pruritus, and nasopharyngitis.
About Fasiglifam Fasiglifam is currently in development by Takeda and is the
first of a new class of drugs under investigation for the treatment of Type 2
diabetes. Fasiglifam works differently from other currently available
insulin-releasing pharmacotherapies and thus is believed to be complementary
to other mechanisms. Fasiglifam is an agonist of G-protein-coupled receptor 40
(GPR40) that is predominantly expressed on the surface of pancreatic beta
cells, which play a key role in the secretion of insulin. GPR40 agonists
enhance insulin secretion in a glucose-dependent manner, and are therefore
thought to have a low risk of hypoglycemia.
About Takeda's Diabetes Business Takeda's heritage in diabetes globally
includes significant contributions towards scientific discovery and exchange,
starting with the discovery of the thiazolidinedione (TZD) pioglitazone, the
more recent developments of alogliptin and the fixed-dose combinations (FDC)
alogliptin and pioglitazone, and alogliptin and metformin HCl, and ongoing
development of the investigational compound fasiglifam. The company's strong,
diverse diabetes pipeline and available medications mark important milestones
in Takeda's ongoing commitment to advancing patient care and helping to meet
the individual needs of this growing patient population.
About Takeda Pharmaceuticals International GmbH Takeda is a research-based
global company with its main focus on pharmaceuticals. As the largest
pharmaceutical company in Japan and one of the global leaders of the industry,
Takeda is committed to strive towards better health for people worldwide
through leading innovation in medicine.
The company has a commercial presence covering around 70 countries, with
particular strength in Asia, North America, Europe and fast-growing emerging
markets including Latin America, Russia-CIS and China. Takeda is ranked 12th
by global Rx sales, 14th in the BRIC countries and 18th in Europe. Areas of
focus include cardiovascular and metabolic, oncology, respiratory and
immunology, central nervous system, general medicine, and vaccines.
Through the integration of Millennium Pharmaceuticals and Nycomed, Takeda has
been transforming itself, broadening its therapeutic expertise and geographic
Takeda Pharmaceuticals International GmbH, headquartered in Zurich, is a
wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Additional information about Takeda is available through its corporate
website, www.takeda.com .
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