Merck Statement Regarding CHMP Review of Incretin-Based Therapies for Type 2 Diabetes, Including Sitagliptin

  Merck Statement Regarding CHMP Review of Incretin-Based Therapies for Type 2
  Diabetes, Including Sitagliptin

Business Wire

WHITEHOUSE STATION, N.J. -- July 26, 2013

Merck, known as MSD outside the United States and Canada, issued the following
statement regarding the conclusion of the European Medicines Agency’s (EMA)
Committee for Medicinal Products for Human Use(CHMP) review of GLP-1, or
incretin-based, therapies, including sitagliptin. The EMA issued a news
release today, “Investigation into GLP-1 based diabetes therapies concluded:
No new concerns for GLP-1 therapies identified on the basis of available
evidence.” The EMA’s full news release is available here.

“Nothing is more important to us than the safety of our medicines and the
people who take them. We appreciate the important role that the EMA and its
CHMP play in monitoring the safety of medicines in Europe,” said Michael
Rosenblatt, M.D., executive vice president and chief medical officer, Merck.
“We are confident in the safety profile of sitagliptin, an important medicine
to help adults with type 2 diabetes lower their blood sugar levels.”

Earlier this year, the U.S. Food and Drug Administration (FDA) issued a Drug
Safety Communication on incretin-based drugs, including sitagliptin. The
statement indicated that the FDA has not reached any new conclusions about
safety risks with incretin mimetic drugs, and recommended that patients
continue to take their medicine as directed until they talk to their health
care professional, and that health care professionals continue to follow the
prescribing recommendations in the drug labels. The FDA said “it will
communicate its final conclusions and recommendations when its review is
complete or when the Agency has additional information to report.”

The American Diabetes Association (ADA), the European Association for the
Study of Diabetes (EASD) and the International Diabetes Federation(IDF) said
that they have reviewed the data available to date and found that there is
insufficient information to modify current treatment recommendations. On June
28, the three organizations issued a joint statement, which is available here.

“The efficacy and safety profile of sitagliptin supports its use in a wide
range of adult patients with type 2 diabetes,” Rosenblatt said. “We will
continue to monitor the safety of sitagliptin in close collaboration with
regulatory agencies and scientific experts.”

About JANUVIA^® (sitagliptin) 25 mg, 50 mg, and 100 mg tablets

JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic
control in adults with type 2 diabetes mellitus. JANUVIA should not be used in
patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
JANUVIA has not been studied in patients with a history of pancreatitis. It is
unknown whether patients with a history of pancreatitis are at increased risk
of developing pancreatitis while taking JANUVIA.

Selected important risk information about JANUVIA

JANUVIA is contraindicated in patients with a history of a serious
hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

There have been postmarketing reports of acute pancreatitis, including fatal
and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking
JANUVIA. After initiating JANUVIA, observe patients carefully for signs and
symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue
JANUVIA and initiate appropriate management. It is unknown whether patients
with a history of pancreatitis are at increased risk of developing
pancreatitis while taking JANUVIA.

About Merck’s review of the data on the safety profile of sitagliptin

In June, Merck presented data regarding the safety profile of sitagliptin at
the National Institutes of Health(NIH) Workshop on
Pancreatitis-Diabetes-Pancreatic Cancer in the United States. In that
presentation, Merck reviewed the available safety data from the company’s
non-clinical studies, data from randomized clinical trials with sitagliptin in
more than 14,000 patients, post-marketing data including reports of pancreatic
cancer, independent observational studies, and a meta-analysis conducted by an
independent academic research group of published clinical trials with DPP-4
inhibitors involving more than 33,000 patients^1.

Safety information from randomized controlled clinical trial data

Randomized, controlled clinical trials continue to be the gold standard for
evaluation of the safety of any medicine. Merck conducted a large pooled
analysis that included data from 25 randomized controlled clinical studies
that enrolled more than 14,000 patients who were followed for up to two years.
In this analysis, which was recently published in Diabetes Therapy^2, there
were no differences in the incidence of pancreatitis or pancreatic cancer
between patients taking sitagliptin and those who did not take sitagliptin.
There were five reports of pancreatitis/acute pancreatitis in the group
treated with sitagliptin and five reports in the group that was not treated
with sitagliptin, and there were three reports of pancreatic cancer in the
group treated with sitagliptin and three reports in the group that was not
treated with sitagliptin. Studies in the pooled analysis were not designed or
powered to identify or adjudicate events of pancreatitis or pancreatic cancer,
and do not allow for inference on the potential for long-term effects.

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) is the
largest randomized controlled clinical study with sitagliptin, with more than
14,000 patients enrolled. This study, which began in 2008, is being led by an
independent academic research collaboration between the University of Oxford
Diabetes Trials Unit and the Duke University Clinical Research
Institute.TECOS continues to be monitored through an independent Data and
Safety Monitoring Board (DSMB), which has access to unblinded safety reports.
The DSMB most recently reviewed data from TECOS in February 2013 and did not
identify any safety concerns to Merck or recommend any changes to the study.

Information from Merck non-clinical safety studies

The safety of sitagliptin is also supported by an extensive non-clinical
safety program and none of these studies has shown an association or
established a causal relationship between sitagliptin and pancreatitis or
pancreatic cancer.The non-clinical program includes FDA-requested studies to
assess for carcinogenicity in rodents. These are conducted over the lifetime
of the animals, and the absence of tumors in rodent carcinogenicity studies is
highly predictive of an absence of human cancer risk. The carcinogenicity
studies were conducted using doses that achieved levels of sitagliptin
approximately 60 to 70 times higher than the levels of sitagliptin achieved in
patients taking the maximum recommended daily adult human dose of sitagliptin
(100 mg/day). In these studies, no adverse effects on the pancreas were
observed and sitagliptin was not associated with an increase in the incidence
of pancreatic malignancies.

About DPP-4 inhibitors

Both DPP-4 inhibitors and GLP-1 analogues are incretin-based treatments;
however, DPP-4 inhibitors and GLP-1 analogues have different mechanism of
actions. DPP-4 inhibitors enhance the body’s own ability to lower blood sugar
levels by increasing the levels of the body’s own active incretins, called
GLP-1 and glucose-dependent insulinotropic polypeptide, or GIP. GLP-1
analogues are biological products that act as incretin mimetics by directly
stimulating the GLP-1 receptors and have no known effect on GIP.

Selected important risk information about JANUVIA^® (sitagliptin), continued

Assessment of renal function is recommended prior to initiating JANUVIA and
periodically thereafter. A dosage adjustment is recommended in patients with
moderate or severe renal insufficiency and in patients with end-stage renal
disease requiring hemodialysis or peritoneal dialysis. Caution should be used
to ensure that the correct dose of JANUVIA is prescribed.

There have been postmarketing reports of worsening renal function, including
acute renal failure, sometimes requiring dialysis. A subset of these reports
involved patients with renal insufficiency, some of whom were prescribed
inappropriate doses of sitagliptin.

When JANUVIA was used in combination with a sulfonylurea or insulin,
medications known to cause hypoglycemia, the incidence of hypoglycemia was
increased over that of placebo. Therefore, a lower dose of sulfonylurea or
insulin may be required to reduce the risk of hypoglycemia.

The incidence (and rate) of hypoglycemia based on all reports of symptomatic
hypoglycemia were: 12.2 percent (0.59 episodes per patient-year) for JANUVIA
100 mg in combination with glimepiride (with or without metformin), 1.8
percent (0.24 episodes per patient-year) for placebo in combination with
glimepiride (with or without metformin), 15.5 percent (1.06 episodes per
patient-year) for JANUVIA 100 mg in combination with insulin (with or without
metformin), and 7.8 percent (0.51 episodes per patient-year) for placebo in
combination with insulin (with or without metformin).

There have been postmarketing reports of serious hypersensitivity reactions in
patients treated with JANUVIA, such as anaphylaxis, angioedema, and
exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these
reactions occurred within the first 3 months after initiation of treatment
with JANUVIA, with some reports occurring after the first dose. If a
hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other
potential causes for the event, and institute alternative treatment for
diabetes.

Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4)
inhibitors. Use caution in a patient with a history of angioedema with another
DPP-4 inhibitor because it is unknown whether such patients will be
predisposed to angioedema with JANUVIA.

There have been no clinical studies establishing conclusive evidence of
macrovascular risk reduction with JANUVIA^® (sitagliptin) or with any other
antidiabetic drug.

In clinical studies, the adverse reactions reported, regardless of
investigator assessment of causality, in greater than or equal to 5 percent of
patients treated with JANUVIA as monotherapy and in combination therapy and
more commonly than in patients treated with placebo, were upper respiratory
tract infection, nasopharyngitis, and headache.

About Merck

Today’s Merck is a global healthcare leader working to help the world be well.
Merck is known as MSD outside the United States and Canada. Through our
prescription medicines, vaccines, biologic therapies, and consumer care and
animal health products, we work with customers and operate in more than 140
countries to deliver innovative health solutions. We also demonstrate our
commitment to increasing access to healthcare through far-reaching policies,
programs and partnerships. For more information, visit www.merck.com and
connect with us on Twitter, Facebook and YouTube.

Merck Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of
the safe harbor provisions of the United States Private Securities Litigation
Reform Act of 1995. These statements are based upon the current beliefs and
expectations of Merck’s management and are subject to significant risks and
uncertainties. If underlying assumptions prove inaccurate or risks or
uncertainties materialize, actual results may differ materially from those set
forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry
conditions and competition; general economic factors, including interest rate
and currency exchange rate fluctuations; the impact of pharmaceutical industry
regulation and health care legislation in the United States and
internationally; global trends toward health care cost containment;
technological advances, new products and patents attained by competitors;
challenges inherent in new product development, including obtaining regulatory
approval; Merck’s ability to accurately predict future market conditions;
manufacturing difficulties or delays; financial instability of international
economies and sovereign risk; dependence on the effectiveness of Merck’s
patents and other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking
statement, whether as a result of new information, future events or otherwise.
Additional factors that could cause results to differ materially from those
described in the forward-looking statements can be found in Merck’s 2012
Annual Report on Form 10-K and the company’s other filings with the Securities
and Exchange Commission (SEC) available at the SEC’s Internet site
(www.sec.gov).

Prescribing Information and Medication Guide for JANUVIA^® (sitagliptin) are
available at
http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf and
http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_mg.pdf.

JANUVIA^® is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary
of Merck & Co., Inc.

^1 Current Medical Research & Opinion Vol. 27, No. S3, 2011, 57–64
^2 Engel, S. et al. Diabetes Ther. 2013, 4:1

Contact:

Merck
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Pam Eisele, 908-423-5042
Mary Elizabeth Blake, 908-423-5550
or
Investors:
Carol Ferguson, 908-423-4465