ISENTRESS™ (raltegravir), an Investigational Oral HIV Integrase Inhibitor, in Combination Therapy Demonstrated HIV RNA Reduction Comparable to Efavirenz in Treatment-Naïve HIV-Positive PatientsResults from an ongoing 48 week Phase II study of ISENTRESSTM (raltegravir), an investigational oral HIV integrase inhibitor, under development by Merck & Co., Inc., in combination with tenofovir (Viread®) and lamivudine (Epivir®) demonstrated that ISENTRESS provided reductions in HIV RNA to undetectable levels of less than 50 copies/mL (83 to 88 percent of patients) comparable to efavirenz (Sustiva®) combined with the same agents (87 percent of patients). These results were observed with all four doses of ISENTRESS studied (100 mg, 200 mg, 400 mg or 600 mg twice daily) in treatment-naïve (previously untreated) patients infected with HIV. In addition, ISENTRESS showed minimal impact on total and low-density lipoprotein (LDL) serum cholesterol, serum triglycerides and the ratio of total cholesterol to HDL cholesterol. These results indicate that ISENTRESS provided sustained viral load reduction and minimal lipid effects when compared with the initial 24-week results presented at the 2006 International AIDS Conference in Toronto.
These data were presented this week at the 4th International AIDS Society Conference (IAS) on HIV Pathogenesis, Treatment and Prevention in Sydney, Australia.
"In this study, the viral load reductions were sustained at Week 48 in treatment-naïve patients," said Martin Markowitz, MD, lead study investigator and clinical director of the Aaron Diamond AIDS Research Center in New York. "These findings are consistent with the efficacy and tolerability profiles that were seen with ISENTRESS at 24 weeks."
Study design
These findings are from an ongoing multi-center, dose-ranging double-blind, randomized trial of previously untreated HIV-positive patients. In this study, 198 treatment-naïve HIV-positive patients received either ISENTRESS (100mg, 200mg, 400mg, or 600 mg, each administered orally twice daily) in combination with tenofovir and lamivudine or received 600 mg efavirenz dosed orally once daily in combination with the same agents. The complete 48-week data being presented today compared ISENTRESS to efavirenz both in combination with tenofovir and lamivudine on three measures: sustained reductions in HIV viral RNA; improvements in CD4 cell counts from baseline; and evaluation of safety and tolerability.
Reduction in viral load
At 48 weeks of therapy, 83 to 88 percent of patients receiving the regimen containing ISENTRESS (at all doses studied) maintained reductions in HIV RNA viral load to less than 50 copies/mL. Results were comparable for patients taking the efavirenz combination, with 87 percent of patients maintaining reductions in HIV RNA viral load to less than 50 copies/mL at week 48.
At baseline, HIV RNA for patients on the ISENTRESS arm of the study was 58,206 copies/mL (100 mg; n=39), 64,715 copies/mL (200 mg; n=40), 43,083 copies/mL (400 mg; n=41) and 57,919 copies/mL (600 mg; n=40). Baseline HIV RNA for patients in the efavirenz arm of the study was 67,554 copies/mL (600 mg; n=38).
Increase in CD4 cell counts
Patients on both treatment regimens experienced increases in CD4 cell counts. Mean baseline CD4 cell counts ranged from 271 to 338 cells/uL across all treatment arms. At 48 weeks of treatment, the mean increase from baseline in CD4 cell counts of the groups receiving ISENTRESS ranged from 144 to 221 cells/uL, and mean increase from baseline in CD4 cell counts of the efavirenz group was 170 cells/uL.
Minimal effect on lipid levels
Both treatment regimens were generally well tolerated. ISENTRESS had minimal effect on total and LDL serum cholesterol, serum triglycerides and the ratio of total cholesterol to HDL cholesterol. The mean changes from baseline at Week 48 for ISENTRESS (all doses combined) and efavirenz, respectively, were -2.3 mg/dL and +20.7 mg/dL (p <.001) for total cholesterol; -7.5 mg/dL and +3.0 mg/dL (p=.0016) for LDL cholesterol; -1.0 mg/dL and +49.5 mg/dL (p=.068) for triglycerides and -0.59 mg/dL and -0.47 mg/dL (p=0.52) for the ratio of total cholesterol to HDL cholesterol.
Clinical safety profile
Clinical adverse experiences were generally mild to moderate, with nausea, dizziness and headache reported most frequently. Neuropsychiatric adverse events, such as abnormal dreams, depression, nightmare and suicidal thoughts were less frequent in patients on the ISENTRESS based regimens (all doses combined) compared to those on the efavirenz-based regimen, occurring respectively in 13 versus 29 percent, through week 48.
About ISENTRESS
ISENTRESS, previously referred to as MK-0518, is the first in a new class of investigational antiretroviral agents called integrase inhibitors that inhibit the insertion of HIV viral DNA into human DNA. Inhibiting integrase from performing this essential function blocks 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 replication process - protease and reverse transcriptase - but there are no approved drugs that inhibit integrase. ISENTRESS is being studied in a twice daily regimen as a single tablet administered without regard to food. ISENTRESS does not require boosting with ritonavir.
The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for ISENTRESS for use in treatment-experienced patients and has granted priority review status, a designation for investigational products that address unmet medical needs. Under the priority review designation, the FDA is expected to review and act on the NDA for ISENTRESS within six months of submission. Merck anticipates FDA action by mid-October and as planned is also moving forward with regulatory filings in countries outside of the United States.
ISENTRESS expanded access program
Expanded access programs with ISENTRESS are currently open to HIV/AIDS patients with limited or no treatment options. Expanded access is a mechanism supported by many regulatory agencies for getting investigational treatment to patients who have a life threatening disease and who cannot be satisfactorily treated with an alternative therapy or available drug. Currently, more than 4,000 patients worldwide are participating in the expanded access programs with ISENTRESS. For more information on the program visit www.benchmrk.com
Prevalence of HIV/AIDS
An estimated 40 million people are infected with HIV/AIDS worldwide, and more than 4 million new infections occurred worldwide in 2006i. In 2005, over 1 million Americans were living with HIV and approximately 40,000 new cases of HIV/AIDS were diagnosed.ii AIDS is one of the top causes of infectious disease-related mortality worldwide, responsible for nearly 3 million deaths last year alone.iii
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 and a vaccine against HIV/AIDS have been under way for almost 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.
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.
i UNAIDS, 2006 Report on the Global AIDS Epidemic
ii CDC. Basic Statistics. HIV/AIDS Surveillance Report: HIV Infection and AIDS in the United States and Dependent Areas, 2005.
iii UNAIDS and WHO. AIDS Epidemic Update. December 2006.
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