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
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
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)
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
Mean changes from baseline in lipid levels and fasting glucose at week 144
||Baseline for ISENTRESS combination therapy
||Baseline for efavirenz combination therapy
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*
*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
• 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)
• 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
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.
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.
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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.
Source: Merck & Co., Inc.
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