Data for Merck's Investigational Once-Daily Formulation of ISENTRESS® (raltegravir) Show That at Week 48, a Regimen Containing the Once-Daily Dosing Formulation...
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
Friday, July 22, 2016 7:00 am EDT
KENILWORTH, N.J.--(BUSINESS WIRE)--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.
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.
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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Please see Prescribing Information for ISENTRESS (raltegravir) at
Patient Information for ISENTRESS at
and Instructions for Use of ISENTRESS (raltegravir) for Oral Suspension at
Pam Eisele, 267-305-3558
Carmen de Gourville, 267-305-4195
Teri Loxam, 908-740-1986
Amy Klug, 908-740-1898