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Merck's ISENTRESS (raltegravir) Tablets Studied in Comparison to Efavirenz in Combination Therapy Through 96 Weeks in HIV-1 Treatment-Naïve Patients - Merck press release
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September 13, 2009 2:15 PM ET
ISENTRESS , an integrase inhibitor fromMerck & Co., Inc., was studied in comparison to efavirenz in maintaining viral load suppression to undetectable levels (less than 50 copies/mL) and at improving CD4 cell counts in previously untreated (treatment-naïve) HIV-1-infected patients through 96 weeks in a Phase III study called STARTMRK. In STARTMRK, ISENTRESS patients received either ISENTRESS or efavirenz in combination therapy. The data was presented today at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICCAC) in San Francisco, CA.
The U.S. Food and Drug Administration (FDA) recently approved an expanded indication for ISENTRESS on July 8, 2009, to include the treatment of adult patients starting HIV-1 therapy for the first time, as well as treatment-experienced adult patients, in combination with other antiretroviral (ARV) medicines. The expanded indication for ISENTRESS was based on analyses of plasma HIV-1 RNA levels through 48 weeks in three double-blind controlled studies. Two of these studies were conducted in clinically advanced, three-class antiretroviral [nonnucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI)] treatment-experienced adults. The third study was a 48-week analysis of the STARTMRK trial in treatment-naïve patients.
ISENTRESS is used in combination with other ARV medicines for the treatment of HIV-1 infection in adult patients. 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.
"Results from the 96 week analysis of STARTMRK showed that ISENTRESS in combination therapy was as effective as efavirenz at suppressing HIV viral load and increasing immune system function," said Edwin de Jesus, M.D., F.A.C.P., medical director of the Orlando Immunology Center in Orlando, Florida. "These results further confirm the findings from the 48 week analysis of this ongoing study."
ISENTRESS studied through 96 weeks in 563 previously untreated adult patients
In this ongoing, multi-center, double-blind, randomized, active-controlled Phase III STARTMRK trial, 563 treatment-naïve adult patients received either 400 mg ISENTRESS administered orally twice daily in combination with tenofovir/emtricitabine or 600 mg efavirenz administered orally once daily in combination with the same agents. The primary endpoints were reductions in HIV-1 viral load to less than 50 copies/mL and an evaluation of safety and tolerability at Week 48. Secondary endpoints included ARV activity as measured by the proportion of patients achieving HIV viral load to less than 50 copies/mL, less than 400 copies/mL and change from baseline in CD4 count at Week 96, as well as tolerability and safety at Week 96.
Patients who entered the study were required to have HIV viral loads greater than 5,000 copies/mL. At baseline, geometric mean viral load 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 218.9 cells/mm3 and 217.4 cells/mm3 for the groups receiving ISENTRESS and efavirenz, respectively.
Viral load reductions and increase in CD4 cell counts maintained through 96 weeks
After 96 weeks of treatment, the ISENTRESS-based regimen suppressed HIV RNA levels below 50 copies/mL at a rate comparable to the regimen containing efavirenz (81 percent versus 79 percent, respectively); the treatment difference was two percent favoring ISENTRESS with an associated 95 percent confidence interval (CI) of (-4.3, 9.0). Results also showed that patients on the regimen containing ISENTRESS in combination therapy experienced a statistically similar yet numerically greater mean increase in CD4 cell count (240 cells/mm3) than those on the regimen containing efavirenz (225 cells/mm3). The treatment difference was 15 with an associated 95 percent CI of (-13, 42).
Impact on lipid levels and tolerability profile of ISENTRESS
At 96 weeks, ISENTRESS in combination therapy had less impact on lipid levels, including total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, as well as triglycerides than the regimen containing efavirenz in previously untreated adults:
Additionally, 47.0 percent of patients taking the regimen containing ISENTRESS experienced drug-related side effects versus 78.0 percent of patients receiving the efavirenz-based regimen; p-value <0.00.
In the study, the most commonly reported clinical adverse experiences (AEs) in the regimens containing ISENTRESS and efavirenz, respectively, were:
Additional posters on ISENTRESS presented at ICCAC
Three additional posters being presented at the ICCAC meeting described studies that evaluated the safety profile and efficacy of ISENTRESS in combination therapy. These posters include:
Metabolic analysis and body composition changes from the 48-week findings in STARTMRK (Poster 329 )
A review of the effect of ISENTRESS on the pharmacokinetics of methadone (Poster 1295)
The lack of a clinically important effect of rifabutin on raltegravir pharmacokinetics (Poster 29)
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 antiretroviral therapy, which may necessitate further evaluation and treatment.
Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported, however the relationship of ISENTRESS to these events is not known. 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.
In STARTMRK, the most commonly (greater than or equal to two percent in either treatment group) reported drug-related clinical AE of moderate or severe intensity in treatment-naïve patients receiving ISENTRESS and at a higher incidence compared to efavirenz was insomnia (four percent versus three percent).
In Phase III clinical trials of ISENTRESS, the most commonly (greater than or equal to two percent in either treatment group) reported drug-related clinical AEs of moderate or severe intensity in treatment-experienced patients receiving ISENTRESS and at a higher rate compared to placebo were headache (rate of three versus one, per 100- patient years), nausea (rate of two versus one, per 100- patient years), asthenia/weakness (rate of two versus one, per 100 patient years) and fatigue (rate of two versus one, per 100 patient years).
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.
Drug interactions
Coadmistration with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 may reduce 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 P450 enzymes.
About ISENTRESS
ISENTRESS is the first medicine to be approved in a class of ARV 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 80 countries worldwide for 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 treatment-naïve patients.
Patient assistance programs in the U.S.
Merck recently launched a co-pay assistance program in the U.S. for eligible patients on ISENTRESS who are commercially insured and have co-pays or coinsurance above $30 up to a maximum of $400 per month. With this program, eligible patients can receive savings off their out-of-pocket costs for up to one year. Information about the co-pay assistance program can be obtained by calling 866-350-9232 or at www.isentress.com.
In addition, for eligible patients with HIV, Merck provides patient assistance to ensure access to ISENTRESS through a program called SUPPORT™. The SUPPORT Program helps patients who have been prescribed ISENTRESS by providing personalized support and patient advocacy regarding individual reimbursement issues. The Program can also provide patient assistance which may provide ISENTRESS free of charge to eligible patients. Information about the SUPPORT Program can be obtained by calling 1-800-850-3430 or at www.isentress.com
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