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Merck's ISENTRESS« (raltegravir) Demonstrated Durable Reductions in HIV-1 Viral Load and Sustained Tolerability At Three Years of Treatment in Previously Untreated Adult Patients Infected with HIV-1

BOSTON, March 1, 2011 - Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced today that new Phase III data showed that adult patients with HIV-1 infection maintained undetectable viral loads and increases in CD4 cell counts at three years of treatment with ISENTRESS« (raltegravir) tablets in combination therapy, comparable to treatment with efavirenz in combination therapy. The new data demonstrated that the antiviral efficacy and safety profile of ISENTRESS seen at weeks 48 and 96 of treatment in this study were sustained through week 156. Data also showed that patients in both treatment arms of this study experienced similar changes in body fat composition. Additionally, ISENTRESS in combination therapy demonstrated less impact on lipids [total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol] and triglycerides at week 144. These findings from the ongoing STARTMRK clinical trial in previously untreated adult patients infected with HIV-1 (Poster Board 542) were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston.

"These three-year results for ISENTRESS reinforce what we saw previously at week 96 with sustained decreases in HIV-1 viral loads and increases in CD4 cell counts," said Dr. JŘrgen Rockstroh, University of Bonn, Bonn-Venusberg, Germany, who presented the data. "Also of note are the data on lipids, which were consistent with what we saw previously with the week 96 results."

ISENTRESS is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in treatment-na´ve and treatment-experienced adults. The label 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.

STARTMRK study design
In this ongoing multicenter, double-blind, randomized, active-controlled Phase III study, 563 previously untreated HIV-1 infected adult patients received either 400 mg ISENTRESS orally twice daily (n=281) or 600 mg efavirenz orally once daily (n=282), each in combination with tenofovir/emtricitabine. The primary endpoints of the study 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-1 viral load to less than 50 copies/mL, less than 400 copies/mL, and change from baseline in CD4 cell count at week 96, as well as tolerability and safety at week 96. The 156 week data reported at CROI represent three-year results from a planned five-year monitoring of outcomes.

Patients who entered the study were required to have HIV-1 viral loads greater than 5,000 copies/mL. At baseline, the geometric mean HIV-1 viral load level 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.

STARTMRK study showed sustained suppression of HIV-1 viral load and increases in CD4 cell counts maintained at 156 weeks
At week 156 of treatment, the regimen containing ISENTRESS suppressed HIV-1 viral load levels to below 50 copies/mL at a greater rate; 75.4 percent of patients (n=212/281) on the regimen containing ISENTRESS and 68.1 percent of patients (n=192/282) on the regimen containing efavirenz maintained HIV-1 viral load suppression below 50 copies/mL [treatment difference of 7.3 percent of patients with 95 percent confidence interval (CI): -0.2, 14.7].

Additionally, 79.7 percent of patients (n=224/281) on the regimen containing ISENTRESS and 72 percent of patients (n=203/282) on the regimen containing efavirenz maintained HIV-1 viral load suppression below 400 copies/mL [treatment difference of 7.6 percent of patients with 95 percent CI: 0.5, 14.6].

Results also showed that patients on the regimen containing ISENTRESS in combination therapy experienced an increase from baseline in mean CD4 cell count of 332 cells/mm3 and those on the regimen containing efavirenz of 295 cells/mm3 [treatment difference of 37 with 95 percent CI: 4, 69].

Metabolic profiles and body composition changes studied in STARTMRK
Metabolic parameters, including fasting lipids and glucose abnormalities, were evaluated according to the National Institutes of Health's Division of Acquired Immunodeficiency Syndrome (NIH-DAIDS) criteria and compared against the National Cholesterol Education Program (NCEP) goals.

A fasting lipid visit was conducted at week 144, and ISENTRESS in combination therapy had less impact on total, LDL and HDL cholesterol levels, and triglycerides levels. Total cholesterol/HDL-C ratio and fasting glucose levels did not differ between the two treatment groups.


Mean changes from baseline in lipid levels and fasting glucose at week 144
  Baseline for ISENTRESS combination therapy ISENTRESS Baseline for efavirenz combination therapy Efavirenz P Value
Total Cholesterol 159.5 mg/dL 12.60 mg/dL 155.5 mg/dL 39.77 mg/dL ≤0.001
HDL Cholesterol 38.37 mg/dL 4.48 mg/dL 37.94 mg/dL 10.54 mg/dL ≤0.001
LDL Cholesterol 96.87 mg/dL 7.16 mg/dL 91.61 mg/dL 22.52 mg/dL ≤0.001
Triglycerides 125.9 mg/dL 1.03 mg/dL 138.8 mg/dL 45.24 mg/dL 0.004
Total Cholesterol/
HDL-C Ratio
4.41 -0.20 4.38 0.04 0.061
Glucose 91.47 mg/dL 3.16 mg/dL 90.21 mg/dL 6.04 mg/dL 0.137

To assess the metabolic changes related to body fat distribution, dual energy X-ray absorptiometry (DEXA) scans were evaluated in a subset of patients. The scans measured body fat redistribution, known as lipodystrophy. Body fat composition changes as measured by DEXA scan were experienced in both treatment groups, with a majority of patients experiencing modest fat gain overall and modest increases in trunk and appendicular (limb) fat at week 156. One in 25 patients on the regimen containing ISENTRESS and two in 32 patients on the regimen containing efavirenz experienced at least a 20 percent loss of body fat, or lipoatrophy.

Mean percent (95% CI) body composition change from baseline at 156 weeks*
Region ISENTRESS (n=25) Efavirenz (n=32)
Arms 19.07 34.91
Legs 16.55 22.74
Appendicular 16.92 24.90
Trunk 21.31 37.85
Total 18.94 31.07
*Subset includes patients who had scans at baseline, week 48 and/or week 96; and week 156

Tolerability profile of ISENTRESS in treatment-na´ve patients at 156 weeks
At week 156, the overall incidence of drug-related clinical adverse events (AEs) in this study was lower for patients on the regimen containing ISENTRESS compared to the regimen containing efavirenz (49.5 percent vs. 79.8 percent, respectively). There were few treatment discontinuations due to clinical AEs for either regimen, 4.6 percent for patients on the regimen containing ISENTRESS vs. 7.4 percent for patients on the regimen containing efavirenz. The rate of serious clinical AEs seen in this study was similar (16.4 percent vs. 16.3 percent, respectively). Between week 96 and week 156, there were 32 new serious clinical AEs (n=15 and n=17, respectively). Although not considered drug-related, there were four deaths in the treatment group containing ISENTRESS and zero in the treatment group containing efavirenz.

At week 96, the most commonly reported drug-related adverse event of moderate to severe intensity that occurred in greater than or equal to two percent of patients and at a higher incidence than efavirenz in treatment-na´ve patients receiving ISENTRESS was insomnia (4 percent vs. 3 percent, respectively).

Additional ISENTRESS data presentations at CROI 2011
Oral presentation


• QDMRK, A Phase III Study of the Safety & Efficacy of Once Daily Versus Twice Daily Raltegravir (RAL) in Combination Therapy for Treatment-Naïve HIV-Infected Patients (Paper 150LB)

Poster presentation

• Interim Results from IMPAACT P1066: Raltegravir (RAL) Oral Chewable Tablet Formulation for 2-5 Year Olds (Poster Board 715)
In addition, a total of 19 data presentations evaluating ISENTRESS from the Merck Investigator Studies Program (MISP) were presented at the conference.

About ISENTRESS
ISENTRESS is Merck's integrase inhibitor for the treatment of HIV-1 infection in treatment-na´ve and treatment-experienced adult patients. ISENTRESS currently is the only approved integrase inhibitor for the treatment of HIV-1. 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. Merck is continuing to move forward with filings in additional countries around the world for use of ISENTRESS in both treatment-experienced and treatment-na´ve HIV-infected patients.

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.

The most commonly reported drug-related adverse event (AE) of moderate to severe intensity that occurred in greater than or equal to two percent of patients and at a higher incidence than efavirenz in treatment-naïve patients receiving ISENTRESS was insomnia (four percent versus three percent, respectively).

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 (two percent vs. less than two percent) for ISENTRESS plus optimized background therapy (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.

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
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 P450 enzymes.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com.

Forward-Looking Statement
This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2010 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

###

Before prescribing ISENTRESS® (raltegravir) Tablets, please read the attached prescribing information, which also is available at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf, and the attached patient information, which also is available at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_ppi.pdf.

Media Contacts:
Pamela Eisele
((908) 423-5042)

Robert Consalvo
(908) 423-6595

Investor Contacts:
Joe Romanelli
(908) 423-5088

Source: Merck & Co., Inc.


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