Merck’s Investigational Once-Daily Formulation of ISENTRESS® (raltegravir) Meets Primary and Secondary Endpoints in Pivotal Phase 3 Study
February 22, 2016 8:00 am ET
Results to be Presented at Future Medical Meeting, and Regulatory Submissions Planned for 2016
Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced top-line results from the company’s Phase 3 pivotal
trial, ONCEMRK. ONCEMRK is evaluating an investigational once-daily
formulation of ISENTRESS® (raltegravir), known as
raltegravir 600 mg (to be given as 2 x 600 mg once-daily), for
previously untreated HIV-1 infected adults. The study met its primary
efficacy endpoint: 1200 mg raltegravir (given as 2 x 600 mg once-daily)
was statistically non-inferior to the marketed formulation approved dose
of ISENTRESS 400 mg twice-daily, each in combination therapy with
TRUVADA™, as assessed by the proportion of patients achieving HIV-1 RNA
<40 copies/mL at Week 48. In addition, the secondary endpoints of
tolerability and immunologic efficacy (as measured by change from
baseline in CD4 cell counts at Week 48) were comparable. Later this
year, Merck plans to present detailed findings of the study at an
upcoming scientific conference, and to submit applications for licensure
to the U.S. Food and Drug Administration and the European Medicines
Agency for this investigational new formulation.
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.
“Merck has never wavered in our commitment to develop meaningful
therapeutic options for people with HIV-1 infection,” said Dr. Eliav
Barr, vice president clinical development, infectious diseases, Merck
Research Laboratories. “We are pleased that this study has met its
primary endpoint and look forward to presenting the data at a future
The ongoing Phase 3 multicenter, double-blind, randomized, active
comparator-controlled clinical trial is 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 <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
ISENTRESS 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.
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.
Coadministration of ISENTRESS with drugs that are strong inducers of
uridine diphosphate glucuronosyltransferase (UGT) 1A1 may result in
reduced plasma concentrations of raltegravir. Coadministration of
ISENTRESS (raltegravir) with drugs that inhibit UGT1A1 may increase
plasma levels of raltegravir.
Coadministration 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. Coadministration 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 coadministration with rifampin.
There are no data to guide coadministration 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 (raltegravir)
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-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 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.
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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
Pamela Eisele, 267-305-3558
Carmen de Gourville, 267-305-4195
Teri Loxam, 908-740-1986
Amy Klug, 908-740-1898