Resulted in Non-Inferior Efficacy and Safety
to a Regimen Containing the Approved Twice-Daily
Formulation
EMA Accepts File Application, Plans Underway
to Submit for Licensure to FDA This Year
Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced efficacy and safety data in previously
untreated adults with HIV-1 infection for the company’s
investigational once-daily formulation of ISENTRESS® (raltegravir),
known as raltegravir 600 mg (to be given as 2 x 600 mg), from the
ongoing Phase 3 pivotal trial called ONCEMRK. The data evaluating
efficacy and safety at 48 weeks of therapy were presented as a
late-breaking abstract at the 21st International AIDS Conference
(AIDS 2016) being held in Durban, South Africa, from July 18-22,
2016.
The study found that after 48 weeks of treatment, 1200 mg
raltegravir (given as 2 x 600 mg once-daily) was statistically
non-inferior (88.9 percent, 472/531) to the marketed formulation
approved dose of ISENTRESS 400 mg twice-daily (88.3 percent,
235/266), each in combination therapy with TRUVADA®
(emtricitabine/tenofovir disoproxil fumarate); with a treatment
difference [95 percent confidence interval] of 0.5 (-4.2, 5.2), as
assessed by the proportion of patients achieving less than 40
copies/mL of HIV RNA. Furthermore, the study showed comparable
rates of reported drug-related clinical adverse events and rates of
discontinuation between the two treatment groups.
ISENTRESS is indicated twice-daily in combination with other
antiretroviral agents for the treatment of HIV-1 infection in
patients 4 weeks of age and older. The use of other active agents
with ISENTRESS is associated with a greater likelihood of treatment
response.
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 develops and
monitor clinical status, including liver aminotransferases
closely.
“It is important for patients living with HIV-1 to have
additional therapeutic options for the treatment of HIV-1 infection
to meet their diverse needs,” said Dr. Pedro Cahn, chief of the
infectious disease unit at Juan A. Fernandez Hospital, Buenos
Aires, Argentina, and lead study author. “This once-daily
investigational formulation of raltegravir has the potential to
simplify some HIV-1 infected patients’ regimens, which may be
beneficial to those patients as they continue to manage their
disease.”
The newly formulated 600 mg tablet for once-daily use (2 x 600
mg), used in the ONCEMRK study, is not currently approved for use
and this formulation is not interchangeable with the currently
marketed 400 mg tablet.
Based on these results from Week 48 of the ONCEMRK study, the
European Medicines Agency (EMA) has accepted the file for the
investigational once-daily formulation of ISENTRESS for review.
Merck plans to submit applications for licensure in several
countries, including the United States later this year.
Data for once-daily investigational formulation of ISENTRESS
shows comparable efficacy to approved twice-daily formulation at 48
weeks in Phase 3 pivotal trial, ONCEMRK
The primary efficacy objective of ONCEMRK is the proportion of
patients achieving HIV RNA less than 40 copies/mL at Week 48. At 48
weeks, the regimen containing a once-daily dose of 1200 mg
ISENTRESS (given as 2 x 600 mg once-daily) achieved similar rates
of viral suppression as those patients receiving the regimen
containing 400 mg ISENTRESS twice-daily (both regimens in
combination with TRUVADA®) of 88.9 percent (472/531) and
88.3 percent (235/266), respectively; with a treatment difference
[95 percent confidence interval] of 0.5 (-4.2, 5.2). Additionally,
more than 50 percent of patients in either treatment arm achieved
viral suppression of less than 40 copies/mL of HIV RNA after 4
weeks of treatment; 53.5 percent (284/531) for the once-daily arm
vs. 51.9 percent (138/266) for the twice-daily arm, respectively;
with a treatment difference [95 percent confidence interval] of 1.3
[-5.1, 7.7].
Also, comparable efficacy was achieved for patients with
baseline viral RNA greater than 100,000 copies/mL (86.7 percent
[124/143] with HIV RNA less than 40 copies/mL for the once-daily
formulation vs. 83.8 percent [62/74] for the twice-daily
formulation, respectively); with a treatment difference [95 percent
confidence interval] of 2.9 [-6.5, 14.1] Both regimens showed
similar rates of reported drug-related clinical adverse events
(24.5 percent [n=130] vs. 25.6 percent [n=68], respectively; with a
treatment difference [95 percent confidence interval] of -1.1
(-7.6, 5.1). Overall, there was a low rate of discontinuation
between the two treatment groups (7.7 percent for the once-daily
formulation [n=41] vs. 8.9 percent for the twice-daily formulation
[n=24]) and treatment-emergent viral mutations leading to treatment
resistance were found in less than 1 percent (5/531) of patients
receiving the once-daily formulation.
Results from this study showed increases in CD4 counts for the
once-daily arm (232 cells/mm3) comparable to the twice-daily arm
(234 cells/mm3) at Week 48.
About ONCEMRK
The ONCEMRK study is an ongoing Phase 3 multicenter,
double-blind, randomized, active comparator-controlled clinical
trial evaluating the efficacy and safety of raltegravir 1200 mg
(given as 2 x 600 mg) once-daily compared to ISENTRESS 400 mg
twice-daily each in combination therapy with TRUVADA® in
previously untreated HIV-1 infected adult patients. The primary
efficacy objective is the proportion of patients achieving HIV RNA
less than 40 copies/mL at Week 48. Secondary objectives included
change from baseline in CD4 cell counts and tolerability at Week
48. The newly formulated 600 mg tablet for once-daily use (2 x 600
mg), in this study, is not currently approved for use and this
formulation is not interchangeable with the currently marketed 400
mg tablet.
The planned total treatment duration for this study is 96
weeks.
For further information regarding ONCEMRK please visit
clinicaltrials.gov, clinical trial registry number NCT02131233.
Important Selected Safety Information for Approved
Formulations of ISENTRESS
Immune reconstitution syndrome can occur, including the
occurrence of autoimmune disorders with variable time to onset,
which may necessitate further evaluation and treatment.
ISENTRESS chewable tablets contain phenylalanine, a component of
aspartame, which may be harmful to patients with
phenylketonuria.
Co-administration of ISENTRESS with drugs that are strong
inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1
may result in reduced plasma concentrations of raltegravir.
Co-administration of ISENTRESS (raltegravir) with drugs that
inhibit UGT1A1 may increase plasma levels of raltegravir.
Co-administration of ISENTRESS and other drugs may alter the
plasma concentration of raltegravir. The potential for drug-drug
interactions must be considered prior to and during therapy.
Co-administration or staggered administration of aluminum and/or
magnesium hydroxide-containing antacids and ISENTRESS is not
recommended.
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
co-administration 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. In
treatment-experienced adult patients receiving ISENTRESS, the most
commonly reported (≥2%) drug-related clinical adverse reactions of
moderate to severe intensity and at a higher incidence compared
with placebo was headache (2% vs <1%). In both studies,
intensities were defined as: Moderate (discomfort enough to cause
interference with usual activity); or Severe (incapacitating with
inability to work or do usual activity). In treatment-experienced
pediatric patients 4 weeks through 18 years of age receiving
ISENTRESS, the frequency, type and severity of drug-related adverse
reactions were comparable to those observed in adults.
Grade 2-4 creatine kinase laboratory abnormalities were observed
in subjects treated with ISENTRESS. 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 and
patients with a history of rhabdomyolysis, myopathy or increased
serum creatine kinase.
Rash occurred more commonly in treatment-experienced subjects
receiving regimens containing ISENTRESS + 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 3 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. There are no
adequate and well-controlled studies in pregnant women. In
addition, there have been no pharmacokinetic studies conducted in
pregnant patients.
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
ISENTRESS is Merck's integrase inhibitor for the treatment of
HIV-1 infection in adult and pediatric patients ages four weeks and
older and weighing at least 3 kg as part of combination HIV
therapy. ISENTRESS works by inhibiting the insertion of HIV-1DNA
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 approved as part of combination therapy in 115
countries for treatment of HIV-1 infection in adult patients.
ISENTRESS, in combination therapy, for use in children and
adolescents with HIV-1 ages two years and older has also been
approved for use in 64 countries, and ISENTRESS oral suspension for
infants at least four weeks of age is approved for use in 34
countries. Please refer to the Prescribing Information for
ISENTRESS for information about dosage and administration for each
formulation.
About Merck
Today's Merck is a global health care 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 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. For more information, visit www.merck.com and connect
with us on Twitter, Facebook, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, NJ, 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.
There can be no guarantees with respect to pipeline products that
the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. 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 2015
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
(raltegravir) at
http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf,
Patient Information for ISENTRESS at
http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_ppi.pdf
and Instructions for Use of ISENTRESS (raltegravir) for Oral
Suspension at
http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_ifu.pdf.
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MerckMedia:Pam Eisele, 267-305-3558Carmen de Gourville,
267-305-4195orInvestors:Teri Loxam, 908-740-1986Amy Klug,
908-740-1898
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