Merck Presents New Data from the Comparative Trials with Sitagliptin (CompoSIT) Clinical Trial Program with JANUVIA® (sitagliptin) | Financial Buzz

Merck Presents New Data from the Comparative Trials with Sitagliptin (CompoSIT) Clinical Trial Program with JANUVIA (sitagliptin)

Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced new data from the Comparative Trials with Sitagliptin
(CompoSIT) clinical trials with JANUVIA® (sitagliptin). In
the CompoSIT-I study, initiation of insulin therapy while continuing
treatment with JANUVIA resulted in greater blood glucose reductions and
more patients reaching A1C goal compared to those who discontinued
JANUVIA. In the CompoSIT-R study, among patients with mild renal
impairment inadequately controlled on metformin, with or without a
sulfonylurea, treatment with JANUVIA showed non-inferiority and
superiority in reducing A1C levels compared with patients treated with
dapagliflozin. These results were presented at the 78th
Scientific Sessions of the American Diabetes Association (ADA) in
Orlando, Florida.

“Taken together, the results offer further insight into JANUVIA as a
treatment option in these settings that impact substantial numbers of
the type 2 diabetes patient population: those initiating insulin therapy
and those with mild renal impairment,” said Dr. Sam Engel, associate
vice president, diabetes, endocrinology and women’s health, Merck
Research Laboratories. “These studies further support the clinical
profile of JANUVIA and may help to inform the individualization of
treatment, which is the cornerstone of diabetes care.”

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. JANUVIA is contraindicated in patients with a history of
a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis
or angioedema. Selected important risk information is continued below.

Efficacy and Safety of Continuing Sitagliptin When Initiating Insulin
Therapy in Subjects with Type 2 Diabetes Mellitus (Abstract #112-LB;
CompoSIT-I)

In this randomized, controlled double-blind study of patients with
inadequately controlled type 2 diabetes taking metformin in dual
combination therapy with JANUVIA (sitagliptin) and initiating insulin
treatment, continuing treatment with JANUVIA (n=373) resulted in greater
blood glucose reduction at week 30 compared to discontinuing JANUVIA
(n=370), with LS mean changes from baseline A1C of -1.88 percent with
JANUVIA and -1.42 percent with placebo, a between-group difference of
-0.46 percent (95 percent CI [-0.58, -0.34], p<0.001).

More than half of the patients (54 percent) who continued treatment with
JANUVIA (n=202) achieved the ADA target A1C goal of less than 7.0
percent, compared to 35 percent of patients who were taking insulin
alone (n=131), a between-group difference of 18.8 percent (95 percent CI
[11.6, 25.7], p<0.001). Mean change from baseline reductions in fasting
plasma glucose were -84.8 mg/dL with JANUVIA and -78.3 mg/dL with
placebo, a between-group difference of -6.5 mg/dL (95 percent CI [-11.9,
-1.0]).

Furthermore, in this study, there was no increased risk of hypoglycemia
with JANUVIA; patients who continued JANUVIA had a rate of documented
symptomatic hypoglycemia of 1.55 events per patient-year compared with
2.12 events per patient-year in the group that discontinued JANUVIA,
resulting in an event rate ratio of 0.73, (95 percent CI [0.54, 0.98],
p=0.039). Additionally, patients continuing JANUVIA required a lower
daily insulin dose (53.2 daily units with JANUVIA compared to 61.3 daily
units in those who discontinued JANUVIA), a between-group difference of
-8.0 units, (95 percent CI [-14.6, -1.5], p=0.016). The Prescribing
Information states that when JANUVIA was used in combination with a
sulfonylurea or with insulin, medications known to cause hypoglycemia,
the incidence of hypoglycemia was increased over that of placebo used in
combination with a sulfonylurea or with insulin. Therefore, a lower dose
of sulfonylurea or insulin may be required to reduce the risk of
hypoglycemia.

In this study, change in body weight was similar in the two treatment
groups after 30 weeks. The mean change in body weight was 3.3 ± 7.5 lbs
with JANUVIA and 3.7 ± 8.6 lbs with placebo. Adverse events (AEs) were
also similar in the two groups (five patients taking JANUVIA and six
patients taking placebo discontinued due to an AE; 216 patients taking
JANUVIA and 222 patients taking placebo experienced one or more AEs).

“Though continuation with oral agents upon initiation of insulin is
consistent with treatment guidelines, when insulin therapy is initiated,
physicians may still choose to discontinue the use of oral agents,” said
Dr. Ronan Roussel, Clinical Professor of Diabetology, Université Paris
Diderot, Hôpital Bichat, Centre de Recherche des Cordeliers, Paris,
France. “This study could help physicians as they consider treatment
options for patients whose disease has progressed and require treatment
with insulin.”

In this study, 746 patients with a mean A1C of 8.8 percent and disease
duration of 10.6 years were randomized to continuing or discontinuing
JANUVIA (sitagliptin), with both groups initiating insulin glargine.
Eligible patients had inadequately controlled type 2 diabetes taking
metformin greater or equal to 1500 mg/day in dual or triple combination
therapy with a DPP-4 inhibitor with or without a sulfonylurea. Those
taking metformin and JANUVIA 100 mg/day directly entered the trial; all
others were switched to metformin and JANUVIA and stabilized during a
run-in period.

Safety and Efficacy of Sitagliptin Compared with Dapagliflozin in
Subjects with Type 2 Diabetes, Mild Renal Impairment and Inadequate
Glycemic Control on Metformin ± a Sulfonylurea (Abstract #1142-P;
CompoSIT-R)

In this randomized, double-blind, active comparator-controlled clinical
study of patients with mild renal impairment taking metformin with or
without a sulfonylurea, LS mean changes from baseline A1C were -0.51
percent with the addition of JANUVIA (n=307) and -0.36 percent with the
addition of dapagliflozin (n=306), a between-group difference of -0.15
percent (95 percent CI [-0.26, -0.04], p=0.006), meeting both
non-inferiority and superiority criteria for JANUVIA at week 24. The
ADA-recommended A1C goal of less than 7.0 percent was met by 43 percent
of patients with JANUVIA (n=116) and 27 percent with dapagliflozin
(n=71), a between-group difference of 16 percent (95 percent CI [7.7,
23.2]), a secondary outcome.

The pre-specified analysis of two-hour post-prandial glucose showed no
significant difference between groups (mean change from baseline -42.9
mg/dL with JANUVIA and -39.3 mg/dL with dapagliflozin, a between-group
difference of -3.6 mg/dL (95 percent CI [-12.3, 5.0]). Mean reductions
from baseline in fasting plasma glucose were -16.5 mg/dL with JANUVIA
and -20.1 mg/dL with dapagliflozin, a between-group difference of 3.5
mg/dL (95 percent CI [-1.2, 8.3]). Mean change from baseline in systolic
blood pressure was -0.6 ± 0.8 mm Hg with JANUVIA and -3.3 ± 0.7 mm Hg
with dapagliflozin. Mean reduction from baseline in body weight was 0.9
± 0.4 lbs with JANUVIA and 5.3± 0.4 lbs with dapagliflozin.

There were significantly fewer patients with drug-related AEs with
JANUVIA than with dapagliflozin (24 vs. 42 patients). Summary AE
profiles were generally similar: discontinuation due to an AE, 10
patients taking JANUVIA (sitagliptin) and 10 patients taking
dapagliflozin; one or more events of hypoglycemia, seven patients taking
JANUVIA and metformin and eight patients taking dapagliflozin and
metformin, and 15 patients taking JANUVIA, metformin and a sulfonylurea
and 13 patients taking dapagliflozin, metformin and a sulfonylurea.

The study assessed the safety and efficacy of adding JANUVIA
(sitagliptin) 100 mg once-daily or dapagliflozin 10 mg once-daily to
treatment of patients with mild renal impairment (eGFR ?60 and <90
mL/min/1.73 m2) and A1C between 7.0 and 9.5 percent while on
metformin with or without a sulfonylurea. Patients initiated
dapagliflozin 5 mg once-daily at randomization and were up-titrated to
dapagliflozin 10 mg once-daily at week 4. The primary efficacy endpoint
was change from baseline A1C at week 24, with a primary hypothesis of
non-inferiority of JANUVIA to dapagliflozin based on the pre-specified
criterion of the upper bound of the between-treatment difference 95
percent CI (JANUVIA minus dapagliflozin) of less than 0.3 percent; if
the upper bound was less than 0.0 percent, JANUVIA would be declared
superior. Treatment groups were well-balanced at baseline (n=307 and
306, mean A1C of 7.7 and 7.8 percent, mean eGFR [mL/min/1.73 m2]
of 79.4 and 76.9 for JANUVIA and dapagliflozin, respectively).

“Approximately 38 percent of patients with type 2 diabetes in the U.S.
have mild renal impairment,i,ii” said Dr. Russell Scott,
clinical professor, University of Otago, and director, Lipid and
Diabetes Research, Christchurch Hospital, Christchurch, New Zealand.
“These data from the study of sitagliptin and dapagliflozin in those
with mild renal impairment may help physicians to evaluate how to
individualize diabetes treatment for their patients.”

Selected Important Risk Information about JANUVIA (sitagliptin)
(continued)

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.

An association between dipeptidyl peptidase-4 (DPP-4) inhibitor
treatment and heart failure has been observed in cardiovascular outcomes
trials for two other members of the DPP-4 inhibitor class. These trials
evaluated patients with type 2 diabetes mellitus and atherosclerotic
cardiovascular disease. Consider the risks and benefits of JANUVIA prior
to initiating treatment in patients at risk for heart failure, such as
those with a prior history of heart failure and a history of renal
impairment, and observe these patients for signs and symptoms of heart
failure during therapy. Advise patients of the characteristic symptoms
of heart failure and to immediately report such symptoms. If heart
failure develops, evaluate and manage according to current standards of
care and consider discontinuation of JANUVIA (sitagliptin).

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 impairment 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 impairment, 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/patient-year)
for JANUVIA 100 mg in combination with glimepiride (with or without
metformin), 1.8 percent (0.24 episodes/patient-year) for placebo in
combination with glimepiride (with or without metformin), 15.5 percent
(1.06 episodes/patient-year) for JANUVIA 100 mg in combination with
insulin (with or without metformin), and 7.8 percent (0.51
episodes/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 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 postmarketing reports of severe and disabling arthralgia
in patients taking DPP-4 inhibitors. The time to onset of symptoms
following initiation of drug therapy varied from one day to years.
Patients experienced relief of symptoms upon discontinuation of the
medication. A subset of patients experienced a recurrence of symptoms
when restarting the same drug or a different DPP-4 inhibitor. Consider
DPP-4 inhibitors as a possible cause for severe joint pain and
discontinue drug if appropriate.

Postmarketing cases of bullous pemphigoid requiring hospitalization have
been reported with DPP-4 inhibitor use. In reported cases, patients
typically recovered with topical or systemic immunosuppressive treatment
and discontinuation of the DPP-4 inhibitor. Tell patients to report
development of blisters or erosions while receiving JANUVIA
(sitagliptin). If bullous pemphigoid is suspected, JANUVIA should be
discontinued and referral to a dermatologist should be considered for
diagnosis and appropriate treatment.

There have been no clinical studies establishing conclusive evidence of
macrovascular risk reduction with JANUVIA.

In clinical studies, the adverse reactions reported, regardless of
investigator assessment of causality, in ?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 the Comparative Trials with Sitagliptin (CompoSIT) Clinical
Trial Program

Merck has continued to invest in the sitagliptin clinical development
program. The objective of the Comparative Trials with Sitagliptin
(CompoSIT) Clinical Trial Program is to better understand the use of
JANUVIA in certain patient populations, specifically in patients already
on JANUVIA who are initiating insulin (CompoSIT-I), patients with mild
renal impairment (CompoSIT-R), and patients not at A1C goal on a
submaximal dose of metformin (CompoSIT-M). For more information about
these studies, visit https://clinicaltrials.gov/.

Our Commitment to Diabetes

At Merck, we’re committed to scientific innovation, and we believe it’s
our responsibility to help address the global diabetes epidemic, one
community and one patient at a time.iii

Our legacy in diabetes is rooted in research, which led to the first FDA
approval in 2006 of a DPP-4 inhibitor in the U.S., JANUVIA
(sitagliptin), but our work didn’t stop there.iv We continue
to invest our resources and capabilities and collaborate with others to
develop and deliver a range of treatments and educational tools for
patients and healthcare providers to help address this public health
challenge.iii

For more information about our commitment to diabetes, visit www.merck.com/about/our-work/diabetes.html.

About Merck

For more than a century, Merck, a leading global biopharmaceutical
company known as MSD outside of the United States and Canada, has been
inventing for life, bringing forward medicines and vaccines for many of
the world’s most challenging diseases. Through our prescription
medicines, vaccines, biologic therapies 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 health care through far-reaching policies, programs
and partnerships. Today, Merck continues to be at the forefront of
research to advance the prevention and treatment of diseases that
threaten people and communities around the world – including cancer,
cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease
and infectious diseases including HIV and Ebola. For more information,
visit www.merck.com
and connect with us on Twitter, Facebook, Instagram,
YouTube
and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the
“company”) includes “forward-looking statements” within the meaning of
the safe harbor provisions of the U.S. Private Securities Litigation
Reform Act of 1995. These statements are based upon the current beliefs
and expectations of the company’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; the company’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 the company’s patents
and other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory actions.

The company 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 the company’s 2017 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).

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

i Bailey RA, et al. Chronic kidney disease in US adults with
type 2 diabetes: an updated national estimate of prevalence based on
Kidney Disease: Improving Global Outcomes (KDIGO) staging. BMC Research
Notes. 2014; 7:415.ii Wang T, et al. Chronic kidney
disease in US adults with type 2 diabetes and cardiovascular diseases: a
national estimate of prevalence by KDIGO 2012 classification. Presented
at the American Diabetes Association (ADA) 78th Annual
Scientific Sessions; June 22-26, 2018; Orlando, FL.iii
International Diabetes Federation. Diabetes Atlas. 8th ed. Brussels,
Belgium. International Diabetes Federation. 2018.1-150.iv
Sitagliptin U.S. PI. Pages 1-23. Accessed: June 2018.

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