WHITEHOUSE STATION, N.J., Aug. 4, 2010– Merck announced today that the U.S. Food and Drug Administration (FDA) has approved a labeling update for ISENTRESS® (raltegravir) tablets to include 96-week data, which demonstrates the durable efficacy of ISENTRESS in HIV-1 infected patients. ISENTRESS is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. The new labeling for ISENTRESS is based on analyses of plasma HIV-1 RNA levels through 96 weeks in three double-blind controlled clinical studies of ISENTRESS. Two of these studies were conducted in clinically advanced, three-class antiretroviral (ARV) [non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI), protease inhibitor (PI)] treatment-experienced adults and one was conducted in treatment-naïve adults. The safety and efficacy of ISENTRESS have not been established in pediatric patients. The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.
"These additional data highlight the durable efficacy of ISENTRESS in combination therapy to reduce HIV-1 viral load to below detectable levels through 96 weeks of treatment and provide additional information regarding the safety profile of ISENTRESS," said Bach-Yen Nguyen, M.D., senior director of Clinical Research, Merck Research Laboratories. "This revised labeling provides physicians additional guidance to help in making informed treatment decisions for people living with HIV-1."
The U.S. Department of Health and Human Services (HHS) HIV treatment guidelines issued in December 2009 recommends ISENTRESS plus tenofovir/emtricitabine as one of four preferred regimens in non-pregnant adult treatment-naïve (patients starting therapy for the first
time) HIV-1-infected patients. The HHS Guidelines recommend that healthcare providers consider a number of individualized factors before initiating therapy in HIV-infected adults.
For additional information regarding treatment considerations for these patients, please refer to the HHS guidelines at www.aidsinfo.nih.gov/Guidelines/Default.aspx.
"ISENTRESS in combination with other anti-HIV medicines is a valuable treatment option for both treatment-naïve and treatment-experienced patients with HIV-1 infection," said Edwin DeJesus, M.D., F.A.C.P., medical director of the Orlando Immunology Center in
Orlando, Fla. "The efficacy and tolerability profile through 96 weeks continue to make ISENTRESS a viable choice for patients."
The durable efficacy of ISENTRESS through 96 weeks has been demonstrated in both treatment-naïve and treatment-experienced HIV-1 adult patients. In treatment-naïve patients, 82 percent of patients taking ISENTRESS versus 78 percent of patients taking efavirenz, both in a combination regimen, achieved HIV-1 viral load suppression to undetectable levels.
In treatment-experienced patients, 55 percent of patients taking ISENTRESS versus 27 percent of patients taking placebo, both with optimized background therapy (OBT), achieved HIV-1 viral load suppression to undetectable levels. ISENTRESS does not require ritonavir boosting.
Study design of treatment-naïve trial for ISENTRESS (STARTMRK)
The evidence of durable efficacy of ISENTRESS is based on analyses of 563 treatment-naïve, HIV-1 infected adult patients through 96 weeks in an ongoing, multicenter, double-blind, randomized, active-controlled, Phase III study called STARTMRK. Patients in the study received either 400 mg ISENTRESS administered orally twice daily or 600 mg efavirenz, one of the leading ARVs prescribed for treatment-naïve patients, dosed orally once daily, both in combination with a fixed dose of emtricitabine plus tenofovir. During double-blind treatment, the total follow-up for patients receiving ISENTRESS plus emtricitabine/tenofovir was 480 patient-years and 463 patient-years for patients receiving efavirenz plus emtricitabine/tenofovir. Patients who entered the study were required to have HIV-1 viral loads greater than 5,000 copies/mL. At baseline, geometric mean HIV-1 RNA levels for patients on the regimen including ISENTRESS was 103,205 copies/mL (n=281) and for the efavirenz regimen was 106,215 copies/mL (n=282). Mean baseline CD4 cell counts were 219 and 217 cells/mm3 for the groups receiving ISENTRESS and efavirenz, respectively.
Durable efficacy and tolerability of ISENTRESS in treatment-naïve patients
In the STARTMRK trial, the regimen containing ISENTRESS was as effective as the
regimen containing efavirenz at reducing HIV-1 viral load to undetectable levels (less than 50 copies/mL).
Results for week 96 showed that 82 percent of patients taking the regimen with ISENTRESS versus 78 percent of patients taking the regimen with efavirenz achieved HIV-1 viral load suppression to undetectable levels. The rate of viral reduction was statistically non-inferior between the two treatment groups, with the difference in viral load reduction between the two treatment groups being 3.8 percent (95 percent CI; -2.8 percent, 10.4 percent). Mean changes in CD4 cell counts from baseline were 217 cells/mm3 in the group receiving the regimen with ISENTRESS versus 199 cells/mm3 in the group receiving the regimen with efavirenz.
Patients taking ISENTRESS had a low incidence of drug-related adverse events (AEs) of moderate to severe intensity that occurred in greater than or equal to two percent of patients and at a higher incidence than efavarienz (insomnia, four percent versus three percent; respectively).
Impact on lipids in treatment-naïve patients
Mean Changes from Baseline in Lipid Level at Week 96
Results from STARTMRK showed that in treatment-naïve patients ISENTRESS in combination therapy had less effect on total cholesterol, LDL and HDL cholesterols, and triglyceride levels than efavirenz in combination therapy through 96 weeks. The impact on the ratio of total cholesterol to HDL cholesterol was similar between the two treatment groups:
Study design of treatment-experienced trials for ISENTRESS (BENCHMRK-1 and BENCHMRK-2)
The use of a regimen including ISENTRESS in treatment-experienced patients is supported by two identical ongoing multicenter, double-blind, randomized, placebo-controlled Phase III studies (BENCHMRK-1 and BENCHMRK-2). In these studies, 699 treatment-experienced adult patients with triple-class-resistant HIV-1, who were failing ARV therapies, received ISENTRESS 400 mg orally twice daily in combination with OBT (n=462) or received placebo plus OBT (n=237). Patients who entered the study were 16 years of age or older with documented resistance to at least one drug in each of the three oral classes of ARVs (NNRTI, NRTI, PI).
In BENCHMRK-1, the mean baseline viral load was 4.6 log10 copies/mL for the ISENTRESS (raltegravir) regimen and 4.5 log10 copies/mL for the placebo regimen, respectively. The median baseline CD4 cell counts were 140 cells/mm3 for the ISENTRESS (raltegravir) regimen and 105 cells/mm3 for the placebo regimen, respectively.
In BENCHMRK-2, the mean baseline viral load was 4.7 log10 copies/mL for both the ISENTRESS (raltegravir) regimen and the placebo regimen, respectively. The median baseline CD4 cell counts were 102 cells/mm3 for the ISENTRESS (raltegravir) regimen and
132 cells/mm3 for the placebo regimen, respectively.
Efficacy and tolerability of ISENTRESS in treatment-experienced patients
In a pooled analysis of BENCHMRK-1 and BENCHMRK-2, ISENTRESS plus OBT suppressed viral load to undetectable levels in 55 percent of patients compared to 27 percent of patients who received placebo plus OBT. ISENTRESS plus OBT increased CD4 cell counts from baseline by 118 cells/mm3 compared to 47 cells/mm3 for patients receiving placebo plus OBT. The most commonly reported (greater than or equal to two percent in either treatment group) drug-related clinical AE of moderate or severe intensity in treatment-experienced patients receiving ISENTRESS and at a higher rate compared to placebo was headache
(2.0 percent vs. less than 1.0 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.
In treatment-experienced patients, rash occurred more often in patients taking ISENTRESS and darunavir together than with either drug separately. Rashes were mild to moderate in severity and did not limit therapy. There were no discontinuations due to rash.
ISENTRESS is the first medicine to be approved in a class of antiretroviral drugs called integrase inhibitors. 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. Other HIV-1 drugs in use inhibit two other enzymes critical to the HIV-1 replication process - protease and reverse transcriptase - but ISENTRESS is the only approved drug that inhibits the integrase enzyme.
ISENTRESS is now approved in more than 90 countries worldwide for treatment-experienced adult patients with evidence of viral replication, and is approved in 45 countries for
treatment-naïve and treatment-experienced adult patients. Merck is continuing to move forward with filings in additional countries around the world for use of ISENTRESS in both treatment-experienced and
Important safety information about ISENTRESS
ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. Healthcare providers should know that immune reconstitution syndrome has been reported in patients treated with ARV therapy, which may necessitate further evaluation and treatment.
Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported. ISENTRESS should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.
Dosing and administration
ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. The dose of ISENTRESS should be increased during coadmistration with rifampin to 800 mg twice daily.
Coadministration with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 may reduce plasma concentrations of ISENTRESS. Rifampin, a strong inducer of (UGT) 1A1 reduces plasma concentrations of ISENTRESS. Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of ISENTRESS is required when coadministered with other ARV agents. Also, preclinical studies show that ISENTRESS is not metabolized by cytochrome
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