Data for Merck’s Investigational Once-Daily Formulation of ISENTRESS® (raltegravir) Show That at Week 48, a Regimen Containing the Once-Daily Dosing Formulation…
July 22, 2016 6:00 am ET
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
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
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
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
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.
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
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.
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.
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“company”) includes “forward-looking statements” within the meaning of
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Please see Prescribing Information for ISENTRESS (raltegravir) at
Patient Information for ISENTRESS at
and Instructions for Use of ISENTRESS (raltegravir) for Oral Suspension
Pam Eisele, 267-305-3558
Carmen de Gourville, 267-305-4195
Teri Loxam, 908-740-1986
Amy Klug, 908-740-1898