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New Data on ISENTRESS® (raltegravir) Presented at the Conference on Retroviruses and Opportunistic Infections (CROI) - Merck announcement
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SAN FRANCISCO, February 17, 2010 - New data presented today at the Conference on Retroviruses and Opportunistic Infections (CROI) showed ISENTRESS® (raltegravir) tablets, an integrase inhibitor for HIV-1 from Merck & Co., Inc. was as effective as efavirenz at maintaining viral load suppression to undetectable levels and improving CD4 cell counts in previously untreated (treatment-naïve), HIV-1-infected, adult patients through 192 weeks in an ongoing Phase II study.
In an analysis of metabolic profiles and body composition changes from a separate ongoing Phase III study (STARTMRK), ISENTRESS in combination therapy showed less impact on lipids [total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol and triglycerides] and fasting blood sugar than patients receiving efavirenz at Week 96. Changes in body composition as assessed by DEXA scanning showed minimal gains in body fat for either treatment groups.
ISENTRESS is indicated in combination with other ARV agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients. This indication is based on analyses of plasma HIV-1 RNA levels up through 48 weeks in three double-blind controlled studies of ISENTRESS. Two of these studies were conducted in clinically advanced, three-class ARV [non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI)], treatment-experienced adults and one was conducted in treatment-naïve adults.
The use of other active agents with ISENTRESS is associated with a greater likelihood of treatments response.
The safety and efficacy of ISENTRESS have not been established in pediatric patients.
Phase II study results in treatment-naïve patients through 192 weeks
In the ongoing Phase II, multi-center, dose-ranging, double-blind, randomized trial (poster 514) of previously untreated HIV-infected adult patients,198 patients received either 400 mg ISENTRESS orally twice daily (n=160) or 600 mg efavirenz orally once daily (n=38), both administered in combination with tenofovir and lamivudine. During the first 48 weeks of the study, patients were randomized to one of four dose regimens of ISENTRESS (100, 200, 400 and 600 mg twice daily). After 48 weeks, all groups taking ISENTRESS received 400 mg of ISENTRESS dosed twice daily. The primary endpoints were reductions in HIV RNA below 400 copies/mL and the evaluation of the safety profile.
Viral load reductions and increase in CD4 cell counts maintained through 192 weeks
After 192 weeks of therapy, 75 percent of patients (95 percent CI: 68 percent, 82 percent) on the regimen containing ISENTRESS and 74 percent of patients (95 percent CI: 57 percent, 87 percent) on the regimen containing efavirenz maintained HIV-1 viral load suppression below 400 copies/mL. Seventy-four percent of patients in both the regimen containing ISENTRESS and the regimen containing efavirenz (95 percent CI: 66 percent, 80 percent and 57 percent, 87 percent, respectively) maintained viral load suppression below 50 copies/mLfor ISENTRESS and efavirenz respectively. Patients on both treatment regimens experienced increases from baseline in CD4 cell counts, specifically 295 cells/mm3 for patients receiving ISENTRESS (95 percent CI: 260, 329) and 274 cells/mm3 for patients receiving efavirenz (95 percent CI: 202, 346).
Tolerability profile through 192 weeks
Cumulative frequencies of drug-related clinical adverse experiences (AEs) were lower for patients on the regimen containing ISENTRESS vs the regimen containing efavirenz (55 percent vs. 76 percent, respectively).
In the Phase II study, the most commonly reported AEs occurring in patients on the regimens containing ISENTRESS and efavirenz, respectively, were nausea (13.1 vs. 10.5 percent), dizziness (8.8 vs. 26.3 percent), headache (8.8 vs. 23.7 percent), insomnia (8.1 vs. 13.2 percent), diarrhea (6.9 vs. 10.5 percent), abnormal dreams (6.3 vs. 18.4 percent) and nightmares (0.0 vs. 10.5 percent).
"As clinicians, we are encouraged by the longer term efficacy results and tolerability profile that we have seen with ISENTRESS in this study and what these results may mean to patients for the management of their disease," said Martin Markowitz, M.D., study investigator and clinical director of the Aaron Diamond AIDS Research Center in New York.
Metabolic profiles and body composition changes studied through 96 weeks in Phase III study (STARTMRK)
In the ongoing, multi-center, double-blind, randomized, active-controlled Phase III study (poster 720), 563 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 metabolic parameters, including fasting lipids and glucose abnormalities, were evaluated according to the National Institute of Health's Division of Acquired Immunodeficiency Syndrome (NIH-DAIDS) criteria and compared against the National Cholesterol Education Program
(NCEP) goals. To assess the body composition changes, dual energy X-ray absorptiometry or DEXA scans were evaluated in a subset of patients (n=112) who had scans at baseline.
Effects on lipid levels, blood sugar and body composition at 96 weeks
ISENTRESS in combination therapy had less impact on total, LDL and HDL cholesterol levels, triglycerides and blood sugar levels than efavirenz at Week 96. The impact on the ratio of total cholesterol to HDL cholesterol was similar between the two treatment groups.
Mean Changes from Baseline in Lipid and Glucose Levels at Week 96
Additionally, there were minimal gains in body fat in either treatment groups, with no patterns of fat loss:
Mean Percent (95 % CI) Body Composition Change from Baseline Through 96 Weeks
"Lipid and glucose levels and body composition are important factors in the management of HIV disease," said Edwin de Jesus, M.D., F.A.C.P., medical director of the Orlando Immunology Center in Orlando, Florida. "In this analysis of metabolic profiles and body composition changes from the STARTMRK study, ISENTRESS in combination therapy had less effect on lipids and resulted in minimal body composition changes."
Additional presentations on ISENTRESS at CROI
Oral Presentation
Presented by the National Institutes of Health: Interim Results from IMPAACT P1066: Raltegravir (RAL) Oral Chewable Tablet (OCT) Formulation in Children 6-11 Years (Abstract 161LB)
Additional Poster Presentations
Presented by the National Institutes of Health: Pharmacokinetic (PK), Safety and Efficacy Data on Cohort IIA; Youth Aged 6-11 years from IMPAACT P1066: A Phase I/II Study to Evaluate Raltegravir (RAL) in HIV-1 Infected Youth (Poster Abstract 873)
Hepatic Safety & Efficacy of Raltegravir in Patients Co-infected with HIV and Hepatitis B (HBV) and/or C (HCV) Virus (Poster Abstract 662)
Sustained Antiretroviral Effect of Raltegravir at Week 156 in the BENCHMRK Studies, and Exploratory Analysis of Late Outcomes based on Early Virologic Responses (Poster Abstract 515)
A Pharmacokinetic Comparison of Adult and Pediatric Formulations of Raltegravir (RAL) in Healthy Adults(Poster Abstract 872)
Short -Term Raltegravir Monotherapy Does Not Predispose Patients to Develop RAL Resistance During Subsequent Combination Therapy: Analysis of Samples from Protocol 004 (Poster Abstract 557)
About ISENTRESS
ISENTRESS is the first medicine to be approved in a class of antiretroviral (ARV) drugs called integraseinhibitors. 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 85 countries worldwide for treatment-experienced adult patients with evidence of viral replication, and is approved in 30 countries for treatment-naïve and 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.
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 rhabdomyolysishave 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.
Adverse event profile of ISENTRESS
In treatment-naïve patients receiving ISENTRESS, the most commonly (greater than or equal to two percent in either treatment group) reported drug-related clinical adverse event (AE) of moderate or severe intensity and at a higher incidence compared to efavirenz was insomnia (4 percent vs 3 percent).
In treatment-experienced patients receiving ISENTRESS, the most commonly (greater than or equal to 2 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 threevs one, per 100 patient years), nausea (rate of two vs one, per 100 patient years), asthenia/weakness (rate of twovs one, per 100 patient years) and fatigue (rate of two vs 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
Coadministration 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 Merck
Today's Merck is working to help the world be well. Through our medicines, vaccines, biologic therapies, and consumer and animal 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 health care through far-reaching programs that donate and deliver our products to the people who need them. Merck. Be Well. 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 and Schering-Plough'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, due to, among other things, the impact of pharmaceutical industry regulation and pending legislation that could affect the pharmaceutical industry; 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 2008 Annual Report on Form 10-K, Schering-Plough's Quarterly Report on Form 10-Q for the quarterly period ended Sept. 30, 2009, the proxy statement filed by Merck on June 25, 2009 and each company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).
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