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ISENTRESS® (raltegravir), Merck’s First in Class Integrase Inhibitor, Reduced HIV Viral Load and Increased CD4 Cell Counts Through 96 Weeks in Treatment-Naïve HIV-Infected Patients When Taken With Other Anti-HIV Medicines


Efficacy and Tolerability Profile Consistent With Data Seen in Approved Treatment-Experienced Indication

WHITEHOUSE STATION, N.J. - ISENTRESS® (raltegravir), Merck & Co., Inc.’s first-in-class integrase inhibitor, in combination with two other anti-HIV medicines, reduced HIV viral load to undetectable levels (less than 50 copies/mL) in 83 percent of previously untreated (treatment-naïve) HIV-infected patients which was comparable to that seen with efavirenz (Sustiva®/STOCRIN®)*, which reduced HIV viral load to undetectable levels in 84 percent of treatment-naïve HIV-infected patients when also combined with the same anti-HIV medicines in patients through 96 weeks of treatment. Patients taking ISENTRESS experienced a mean increase in CD4 cell counts of 221 cells/mm³ without adverse impact on total or low-density lipoprotein (LDL) cholesterol, or triglycerides (exploratory endpoints). Results from this ongoing Phase II study were presented today at the 17th International AIDS Conference (AIDS 2008) in Mexico City, Mexico.

The use of ISENTRESS in treatment-naïve patients is investigational. ISENTRESS is approved for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy. This indication is based on analyses of plasma HIV-1 RNA levels up through 24 weeks in two controlled studies of ISENTRESS. These studies were conducted in clinically advanced, three-class antiretroviral [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)] treatment-experienced adults. The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response. The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients. There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection.

“These findings are consistent with the efficacy and safety data seen with ISENTRESS in treatment-experienced patients,” said Martin Markowitz, M.D., study investigator and clinical director of the Aaron Diamond AIDS Research Center in New York. “Viral load reductions were sustained through 96 weeks in this study, the longest conducted to date with ISENTRESS.”

ISENTRESS studied in nearly 200 previously untreated patients
These findings are from an ongoing multi-center, dose-ranging, double-blind, randomized trial of previously untreated HIV-infected patients. In this study, 198 treatment-naïve, HIV-infected patients received either ISENTRESS administered orally twice daily in combination with tenofovir (Viread® ) and lamivudine (Epivir®) or 600 mg efavirenz dosed orally once daily in combination with the same agents. During the first 48 weeks of the study, four dose regimens of ISENTRESS (100, 200, 400 and 600 mg twice daily) were studied. After 48 weeks, all ISENTRESS groups received 400 mg dosed twice daily. The primary endpoints were reductions in HIV RNA less than 400 copies/mL and the evaluation of safety at 96 weeks. The evaluation of total cholesterol, LDL cholesterol and triglycerides were exploratory endpoints.

Reduction in viral load and increase in CD4 cell counts maintained through 96 weeks of treatment with ISENTRESS
At baseline, geometric mean HIV RNA for patients on the combined regimen including ISENTRESS was approximately 55,000 copies/mL (n=160) and for the efavirenz regimen was approximately 68,000 copies/mL (n=38). Mean baseline CD4 cell counts were 305 and 280 cells/mm³ for the groups receiving ISENTRESS and efavirenz, respectively.

After 96 weeks of therapy, 83 percent of patients receiving the regimen with ISENTRESS achieved reductions in HIV RNA levels below 50 copies/mL. Results were comparable for patients taking the regimen containing efavirenz, with 84 percent of patients achieving reductions in HIV RNA levels below 50 copies/mL in the same time period. Similarly, 84 percent of patients receiving the regimen containing ISENTRESS maintained reductions in HIV RNA levels to below 400 copies/mL compared to 84 percent of patients taking the regimen containing efavirenz.

Patients on both treatment regimens experienced increases in CD4 cell counts. At 96 weeks of treatment, the mean increase from baseline in CD4 cell count was 221 cells/mm3 for patients taking ISENTRESS and 232 cells/mm³ for patients taking efavirenz.

Tolerability profile and effect on lipid levels
The most commonly reported adverse experiences in patients receiving ISENTRESS and efavirenz, respectively, were diarrhea (6.9 percent versus 10.5 percent), nausea (12.5 versus 13.2 percent), dizziness (8.8 versus 28.9 percent), headache (8.8 percent versus 23.7 percent), abnormal dreams (6.3 percent versus 18.4 percent), insomnia (8.1 percent versus 10.5 percent) and nightmares (0 percent versus 10.5 percent). Neuropsychiatric adverse events, which included abnormal dreams, depression, nightmare and suicidal thoughts, were reported less frequently with the ISENTRESS group compared to the efavirenz group, occurring respectively in 16 versus 32 percent of patients through Week 96; most of these had occurred earlier in the study by Week 48.

ISENTRESS had neutral effect on total and LDL cholesterol, or triglycerides. The mean changes from baseline at Week 96 for ISENTRESS and efavirenz, respectively, were +1.1 mg/dL and +24.0 mg/dL (p=0.002) for total cholesterol; -5.8 mg/dL and +4.4 mg/dL (p=0.045) for LDL cholesterol; +7.4 mg/dL and +13.0 mg/dL (p=0.017) for HDL cholesterol; -10.8 mg/dL and +13.4 mg/dL (p=0.145) for triglycerides; and -0.7 mg/dL and -0.7 mg/dL (P=0.689) for total: HDL ratio.

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.

In the clinical trials involving treatment-experienced patients, the most commonly reported adverse experiences of any severity (mild, moderate or severe) for ISENTRESS plus optimized background therapy (OBT) versus placebo plus OBT, respectively, regardless of drug relationship were diarrhea (16.6 percent vs. 19.5 percent), nausea (9.9 percent vs. 14.2 percent), headache (9.7 percent vs. 11.7 percent) and fever (4.9 percent vs. 10.3 percent).

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.

Results from pooled safety analyses from three separate studies (BENCHMRK-1, BENCHMRK-2 and a Phase II dose ranging study) in treatment-experienced patients taking 400 mg of ISENTRESS dosed twice daily plus OBT or placebo plus OBT showed that after 24 weeks of therapy the rates of discontinuation of therapy due to adverse experiences were 2.0 percent in patients receiving ISENTRESS plus OBT and 1.4 percent in patients receiving placebo plus OBT. In addition, drug-related clinical adverse events of moderate to severe intensity occurring in greater than or equal to 2.0 percent of patients were diarrhea (3.7 percent vs. 4.6 percent), nausea (2.2 percent vs. 3.2 percent) and headache (2.4 percent vs. 1.4 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.

Drug interactions
Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of ISENTRESS is required when coadministered with other antiretroviral agents. Also, preclinical studies show that ISENTRESS is not metabolized by cytochrome P450 enzymes. Caution should be used when coadministering ISENTRESS with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g., rifampin) due to reduced plasma concentrations of ISENTRESS.

ISENTRESS is the first medicine to be approved in a new class of antiretroviral drugs called integrase inhibitors. ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. There are drugs in use that inhibit two other enzymes critical to the HIV-1 replication process – protease and reverse transcriptase - but ISENTRESS is the only drug approved that inhibits the integrase enzyme.

In October 2007, the U.S. Food and Drug Administration granted ISENTRESS accelerated approval for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication with HIV-1 strains resistant to multiple antiretroviral agents. ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. ISENTRESS does not require boosting with ritonavir.

Merck HIV Research
Merck is committed to developing innovative therapies that offer advances in the treatment of infectious diseases - including HIV. Merck’s efforts to develop investigational treatments for HIV and AIDS have been under way for more than 20 years and continue today. Merck began its HIV integrase inhibitor research in 1993 and was the first to demonstrate inhibition of HIV integrase in vitro and in vivo.

Prevalence of HIV and AIDS
In 2006, more than one million Americans were living with HIV and AIDS, and it is estimated that approximately more than 56,000 new cases of HIV and AIDS are diagnosed each year in the United States.

Worldwide, an estimated 33 million people are infected with HIV and AIDS, and more than two million new infections occurred in 2007.

Merck’s commitment to providing access to treatment
Merck is committed to ensuring access to our antiretroviral medicines (ARVs) through a differential pricing policy that provides our ARVs at dramatically lower prices-at which Merck does not profit-to people living in the world’s least developed countries and those hardest hit by the pandemic, as defined by various United Nations indices.

Also, Merck is committed to seeking additional ways to reduce the cost of its ARVs for people living in the world’s poorest countries and those hardest hit by the pandemic, including through partnering with external manufacturers and suppliers to achieve incremental efficiencies and cost savings.

In the United States, Merck is freezing the price for AIDS Drug Assistance Programs (ADAP) of ISENTRESS at its launch price until December 31, 2010. ADAP is a unique fixed-funding program with a flat federal budget whose cost burden and patient load continues to grow. In freezing the price of ISENTRESS, Merck will help mitigate the funding challenges of these programs.

Since 2006, when Merck established a worldwide expanded access program with ISENTRESS for HIV patients with limited or no treatment options, more than 9,000 patients have enrolled in early access programs for ISENTRESS globally.


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