New Merck & Co., Inc. Phase 3 HIV Drug Works in Untreated Patients

WASHINGTON--(BUSINESS WIRE)--In a new Phase III study that compared Merck & Co., Inc.'s HIV integrase inhibitor ISENTRESS® (raltegravir) to efavirenz [one of the leading antiretrovirals prescribed for previously untreated (treatment-naïve) HIV-infected patients], ISENTRESS reduced HIV viral load to undetectable levels (less than 50 copies/mL) in 86 percent of patients compared to 82 percent of patients treated with efavirenz in previously untreated HIV patients at Week 48. Both medicines were taken in combination with tenofovir/emtricitabine. Patients taking ISENTRESS had a greater increase in CD4 cell counts, an average increase of 189 cells/mm3, compared to patients taking efavirenz who had an average increase of 163 cells/mm3 at Week 48. In addition, drug-related adverse events of any severity occurred in fewer patients (44 percent vs. 77 percent; p<0.001) treated with ISENTRESS. The use of ISENTRESS in treatment-naïve patients is investigational. These 48 week findings were presented today at the late-breaker session of the joint 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)/Infectious Diseases Society of America (IDSA) 46th Annual Meeting in Washington, D.C.

“This study showed that when paired with other anti-HIV medicines, ISENTRESS lowered the amount of virus in the blood to below detectable (less than 50 copies/mL) levels in over 8 out of 10 treatment-naïve patients and had fewer side effects than the standard of care," said Daniel S. Berger, M.D., clinical associate professor, College of Medicine University of Illinois at Chicago and medical director of NorthStar Medical Center. “These results further demonstrate that, if approved for such use, ISENTRESS may be another important option for patients when first initiating HIV therapy."

ISENTRESS is the first integrase inhibitor approved 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. 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. In these studies 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 or pediatric patients. There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection.

ISENTRESS studied in more than 500 previously untreated HIV patients in Phase III trial

These findings presented today are from an ongoing multi-center, double-blind, randomized, active-controlled Phase III trial of previously untreated HIV-infected patients called STARTMRK. In this study, 563 treatment-naïve, HIV-infected patients received either 400 mg ISENTRESS administered orally twice daily in combination with tenofovir/emtricitabine or 600 mg efavirenz dosed orally once daily in combination with the same agents. The primary endpoints were reductions in HIV RNA to less than 50 copies/mL and an evaluation of safety and tolerability at Week 48. Secondary endpoints included antiretroviral activity as measured by the proportion of patients achieving HIV RNA <400 copies/mL and change from baseline in CD4 cell counts at Week 48. An additional secondary safety endpoint was the proportion of patients experiencing nervous system symptoms through week eight.

Suppression of viral load and increase in CD4 cell counts maintained through 48 weeks

At baseline, geometric mean HIV 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.

After 48 weeks of treatment, 86 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 efavirenz regimen, with 82 percent of patients achieving reductions in HIV RNA levels below 50 copies/mL in the same time period. Similarly, 90 percent of patients receiving the regimen containing ISENTRESS maintained reductions in HIV RNA levels to below 400 copies/mL compared to 86 percent of patients taking the regimen containing efavirenz. Time to virologic response was significantly shorter for patients taking ISENTRESS compared to those taking the efavirenz regimen, confirming the rapid viral load reductions demonstrated by ISENTRESS in previous trials. At week eight, 74 percent of patients receiving the regimen with ISENTRESS achieved HIV RNA levels below 50 copies/mL compared to 38 percent of patients receiving the regimen with efavirenz.

Patients receiving the regimen with ISENTRESS had greater immunologic response as measured by change from baseline in CD4 cell count. At Week 48 the mean increase from baseline in CD4 cell count was 189 cells/mm3 for patients receiving ISENTRESS and 163 cells/mm3 for patients receiving efavirenz.

Tolerability profile of ISENTRESS in STARTMRK study

The most commonly (=2.0 percent in either treatment group) reported drug-related clinical adverse experiences of moderate or severe intensity in patients receiving ISENTRESS and efavirenz, respectively, were headache (3.9 percent vs. 4.6 percent), nausea (2.8 percent vs. 3.5 percent), dizziness (1.4 percent vs. 6.4 percent), insomnia (3.6 percent vs. 3.2 percent), diarrhea (1.1 percent vs. 2.8 percent), fatigue (1.4 percent vs. 2.8 percent), rash (0.0 percent vs. 2.8 percent), and maculo-papular rash (0.0 percent vs. 2.5 percent). Central nervous system symptoms were reported significantly less frequently with the group receiving ISENTRESS compared to the group receiving efavirenz through week eight (20.3 percent vs. 52.1 percent). Cancer occurred in one patient taking the regimen with ISENTRESS and nine patients taking the regimen with efavirenz.

Researchers also assessed lipid levels based upon the profile observed with ISENTRESS and efavirenz in an earlier Phase II trial in a similar population. Results from the STARTMRK study showed that ISENTRESS had minimal effect on lipid levels. The mean changes from baseline at Week 48 for ISENTRESS and efavirenz, respectively, were 10 mg/dL and 32.7 mg/dL (p<0.001) for total cholesterol; 5.9 mg/dL and 16.1 mg/dL (p<0.001) for LDL cholesterol; 4.2 mg/dL and 10.0 mg/dL (p<0.001) for HDL cholesterol; and -2.8 mg/dL and 37.4 mg/dL (p<0.001) for triglycerides.

“These findings reinforce the efficacy and safety data seen with ISENTRESS in Phase II trials in treatment-naïve patients, and are consistent with efficacy already established in treatment-experienced patients for whom it is currently approved,” said Robin Isaacs, M.D., executive director, Infectious Disease/Vaccines Clinical Research, Merck Research Laboratories. “Viral load reductions and CD4 cell count increases were sustained through 48 weeks in this study.”

Important safety information about ISENTRESS

ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. 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 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).

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. 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.

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. 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 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.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2007, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

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