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FDA Approves New U.S. Labeling for ISENTRESS® (raltegravir) to Include 240-Week Results from STARTMRK Study of ISENTRESS

  FDA Approves New U.S. Labeling for ISENTRESS® (raltegravir) to Include
  240-Week Results from STARTMRK Study of ISENTRESS Containing Regimen in
  Previously Untreated HIV-1 Infected Adult Patients

Business Wire

WHITEHOUSE STATION, N.J. -- July 1, 2013

Merck (NYSE: MRK), known as MSD outside the United States and Canada,
announced today that the U.S. Food and Drug Administration (FDA) has approved
new labeling for ISENTRESS^® (raltegravir) Film-coated Tablets, Merck’s
integrase inhibitor for the treatment of HIV-1 infection in adult patients as
part of combination HIV therapy. The updated prescribing information now
includes 240-week results from the STARTMRK study, the longest double-blind
Phase III non-inferiority study evaluating an integrase inhibitor in
treatment-naïve adult patients with HIV-1 infection. The results show that the
regimen containing ISENTRESS in combination therapy demonstrated long-term
viral suppression and a greater immunologic response than the
efavirenz-containing regimen, as well as a proven, long-term safety and
tolerability profile through 240 weeks in previously untreated
(treatment-naïve) adult HIV-1 infected patients.

ISENTRESS is an integrase inhibitor indicated in combination with other
antiretroviral (ARV) agents for the treatment of HIV-1 infection in adults.
This indication is based on analyses of plasma HIV-1 RNA levels in three
double-blind controlled studies of ISENTRESS. Two of these studies were
conducted in clinically advanced, three-class ARV [non-nucleoside reverse
transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor
(NRTI), protease inhibitor (PI)] treatment-experienced adult patients through
96 weeks and one was conducted in treatment-naïve adults through 240 weeks.

The use of other active agents with ISENTRESS (raltegravir) is associated with
a greater likelihood of treatment response.

Severe, potentially life-threatening and fatal skin reactions have been
reported with ISENTRESS. Additionally, during the initial phase of combination
ARV treatment, immune reconstitution syndrome may occur. (See Important
Selected Safety Information below.)

“As the care of HIV evolves, ISENTRESS continues to be an important treatment
option for adult patients with HIV-1,” said Jürgen Rockstroh, M.D., University
of Bonn, Bonn-Venusberg, Germany. “These 240-week results are important for
physicians to consider when initiating treatment with ISENTRESS in combination
therapy in treatment-naïve adult patients with HIV-1.”

“Merck has been at the forefront of HIV research for close to 30 years. The
discovery of ISENTRESS and its clinical development program are a testament to
Merck’s long-term commitment to the research and development of medicines for
HIV,” said Daria Hazuda, Ph.D., vice president of Early Development and
Discovery Sciences Research for infectious diseases, Merck.

STARTMRK study design

STARTMRK was a multi-center, double-blind, randomized, active-controlled,
Phase III non-inferiority study. In the study, ^ 563 previously untreated
HIV-1 infected adult patients with HIV-1 RNA greater than 5,000 copies/mL
received either 400 mg ISENTRESS orally twice daily (n=281) or 600 mg
efavirenz orally once daily (n=282), each in combination with
tenofovir/emtricitabine. The primary endpoint of the study was a reduction in
HIV-1 viral load to less than 50 copies/mL at week 48. Secondary endpoints
included ARV activity, as measured by the proportion of patients achieving
HIV-1 viral load to less than 50 copies/mL at 96 weeks, as well as achieving
viral load less than 400 copies/mL and change from baseline in CD4 cell count,
both measured at 48 and 96 weeks. Pre-specified exploratory endpoints also
included the proportion of patients achieving HIV-1 viral load to less than 50
copies/mL at 240 weeks, as well as change from baseline in CD4 cell count at
240 weeks. Safety was evaluated throughout the study period. ^ Merck presented
the 240-week STARTMRK study results for the first time at AIDS 2012 in
Washington, D.C. and the results were subsequently published in Journal of
Acquired Immune Deficiency Syndromes (JAIDS) in May 2013.

ISENTRESS (raltegravir) in combination therapy shows long-term efficacy in
previously untreated adult HIV-1 patients through 240 weeks

In the STARTMRK trial, the regimen containing ISENTRESS was non-inferior to
the regimen containing efavirenz at reducing HIV-1 viral load to undetectable
levels (less than 50 copies/mL) at 240 weeks. At the study entry, the
geometric mean baseline plasma HIV-1 RNA for patients was over 100,000
copies/mL (103,205 copies/mL for those on a regimen containing ISENTRESS
(raltegravir) and 106,215 copies/mL for patients on a regimen containing
efavirenz). Results for the 240-week analysis showed long-term viral
suppression (HIV-1 RNA less than 50 copies/mL) for patients on the regimen
containing ISENTRESS of 66 percent and 60 percent for the regimen containing
efavirenz [treatment difference of 6.6 percent of patients with 95 percent
confidence interval (CI): -1.4 percent, 14.5 percent].

The regimen containing ISENTRESS demonstrated a greater immunologic response
than the regimen containing efavirenz at 240 weeks. Patients on the regimen
containing ISENTRESS had a mean baseline CD4 cell count of 219 cells/mm^3
compared to 217 cells/mm^3 for patients on the regimen containing efavirenz.
From study entry to week 240, patients on the regimen containing ISENTRESS had
a mean baseline increase in CD4 cell count of 295 cells/mm^3 versus 236
cells/mm^3 for patients on the regimen containing efavirenz.

Safety and tolerability profile for ISENTRESS (raltegravir) through 240 weeks
in STARTMRK

In the STARTMRK trial, through 240 weeks, there was a low incidence of
drug-related adverse reactions of moderate to severe intensity that occurred
in greater than or equal to 2 percent of patients treated with ISENTRESS.
These adverse drug reactions as compared to efavirenz were insomnia (4
percent, in both arms), headache (4 percent versus 5 percent), nausea (3
percent versus 4 percent), fatigue (2 percent versus 3 percent) and dizziness
(2 percent versus 6 percent). "Moderate" reactions were defined as discomfort
enough to cause interference with usual activity. "Severe" reactions were
defined as incapacitating with inability to work or do usual activity.

Patients on the regimen containing ISENTRESS also demonstrated a lower
treatment discontinuation rate due to clinical adverse reactions versus
patients on the regimen containing efavirenz through 240 weeks (5 percent
versus 10 percent, respectively). Additionally, ISENTRESS in combination
therapy had less effect on lipids [total, low-density lipoprotein (LDL),
high-density lipoprotein (HDL) cholesterol] and triglycerides fasting serum
lipids at week 240, as shown in the table below.

Lipid Values, Mean Change from Baseline at Week 240
                  ISENTRESS 400 mg
Laboratory
                  Twice Daily + Emtricitabine       Efavirenz 600 mg
Parameter         (+)
                                                At Bedtime + Emtricitabine    
Preferred         Tenofovir                         (+) Tenofovir

Term              N = 207                           N = 187

                  
                                       Change                            Change
                                       from                              from

                                 Baseline                    Baseline 
                                       at                                at

                                      Week 240                          Week 240
                  Baseline   Week                   Baseline   Week
                             240       Mean                    240       Mean
                Mean               Change     Mean               Change   
                             Mean                              Mean
                  (mg/dL)              (mg/dL)      (mg/dL)              (mg/dL)
                             (mg/dL)                           (mg/dL)
LDL-             96        106      10         93        118      25
Cholesterol*
                                                                                  
HDL-              38         44        6            38         51        13
Cholesterol*
                                                                                  
Total             159        175       16           157        201       44
Cholesterol*
                                                                                  
Triglyceride*
                128       130      2          141       178      37       

                                                                                  

*Fasting (non-random) laboratory tests at Week 240.

Notes:

N = Total number of subjects per treatment group with at least one lipid test
result available. The analysis is based on all available data.

If subjects initiated or increased serum lipid-reducing agents, the last
available lipid values prior to the change in therapy were used in the
analysis. If the missing data was due to other reasons, subjects were censored
thereafter for the analysis.

At baseline, serum lipid-reducing agents were used in 5% of subjects in the
group receiving ISENTRESS (raltegravir) and 3% in the efavirenz group. Through
Week 240, serum lipid-reducing agents were used in 9% of subjects in the group
receiving ISENTRESS and 15% in the efavirenz group.


Important Selected Safety Information

ISENTRESS (raltegravir) does not cure HIV-1 infection or AIDS.

Severe, potentially life-threatening and fatal skin reactions have been
reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity
reaction and toxic epidermal necrolysis. Immediately discontinue treatment
with ISENTRESS and other suspect agents if severe hypersensitivity, severe
rash, or rash with systemic symptoms or liver aminotransferase elevations
develop and monitor clinical status, including liver aminotransferases
closely.

Immune reconstitution syndrome can occur, including the occurrence of
autoimmune disorders with variable time to onset, which may necessitate
further evaluation and treatment.

Co-administration of ISENTRESS with drugs that are strong inducers of uridine
diphosphate glucuronosyltransferase (UGT1A1) may result in reduced plasma
concentrations of raltegravir.  Rifampin, a strong inducer of UGT1A1, reduces
plasma concentrations of ISENTRESS. Therefore, the dose of ISENTRESS for
adults should be increased to 800 mg twice daily during coadministration with
rifampin. There are no data to guide co-administration of ISENTRESS with
rifampin in patients below 18 years of age.

The most commonly reported (≥2%) drug-related clinical adverse reactions of
moderate to severe intensity in treatment-naïve adult patients receiving
ISENTRESS compared with efavirenz were insomnia (4% vs 4%), headache (4% vs
5%), nausea (3% vs 4%), fatigue (2% vs 3%), and dizziness (2% vs 6%),
respectively. Intensities were defined as follows: Moderate (discomfort enough
to cause interference with usual activity); or Severe (incapacitating with
inability to work or do usual activity).

Grade 2 to 4 creatine kinase laboratory abnormalities were observed in
patients treated with ISENTRESS (raltegravir). Myopathy and rhabdomyolysis
have been reported. Use with caution in patients at increased risk of myopathy
or rhabdomyolysis, such as patients receiving concomitant medications known to
cause these conditions.

Rash occurred more commonly in treatment-experienced subjects receiving
regimens containing ISENTRESS plus darunavir/ritonavir, compared to subjects
receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without
ISENTRESS. However, rash that was considered drug-related occurred at similar
rates for all three groups. These rashes were mild to moderate in severity and
did not limit therapy; there were no discontinuations due to rash.

ISENTRESS should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. To monitor maternal-fetal outcomes
of pregnant patients exposed to ISENTRESS, an Antiretroviral Pregnancy
Registry has been established. Physicians are encouraged to register patients
by calling 1-800-258-4263.

About ISENTRESS (raltegravir)

ISENTRESS is Merck's integrase inhibitor for the treatment of HIV-1 infection
in adult patients and pediatric patients ages 2 years and older and weighing
at least 10 kg as part of combination HIV therapy. ISENTRESS works by
inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme
and has demonstrated rapid antiviral activity. Inhibiting integrase from
performing this essential function limits the ability of the virus to
replicate and infect new cells. ISENTRESS is now approved in combination
therapy in more than 76 countries for use in treatment-naïve adult patients
with HIV-1 and in more than 110 countries for use in treatment-experienced
adult patients with HIV-1. ISENTRESS, in combination therapy, for use in
pediatric patients with HIV-1 has also been approved for use in 33 countries.
Merck is continuing to move forward with filings in additional countries
around the world.

To assist patients taking ISENTRESS, Merck offers the SUPPORT™ program, which
provides personal support and patient advocacy regarding individual
reimbursement issues. For more information about the SUPPORT™ program, please
visit www.merckhelps.com or call 1-800-850-3430.

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.

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).

Please see Prescribing Information for ISENTRESS at
http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf and
Patient Information for ISENTRESS at
http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_ppi.pdf.

ISENTRESS^® is a registered trademark of Merck & Co., Inc., Whitehouse
Station, N.J., USA

INFC-1083968-0000 7/1

Contact:

Merck
Media Contacts:
Caroline Lappetito, 267-305-7639
Claire Mulhearn, 908-423-7425
or
Investor Contacts:
Carol Ferguson, 908-423-4465
Justin Holko,908-423-5088
 
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