Results from Two Phase III Studies on ISENTRESS(TM) (raltegravir, MK-0518), Merck's Oral Investigational Integrase Inhibitor Presented at the Annual Conference on Retroviruses and Opportunistic Infections (CROI)
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- Published on Friday, 02 March 2007 02:00
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LOS ANGELES, CA, USA | Mar 01, 2007 | Results from two ongoing Phase III studies of ISENTRESS™ (raltegravir), an investigational oral integrase inhibitor, demonstrated significantly greater antiretroviral activity of ISENTRESS when used in combination with optimized background therapy (OBT) versus placebo plus OBT in treatment-experienced HIV-infected patients who had failed antiretroviral therapies (ARTs), and who had HIV virus resistant to at least one drug in each of the three available classes of oral ARTs. These data were collected from the 16-week primary analysis time point called for in the 156 week-long study protocol. ISENTRESS has been previously referred to as MK-0518. The brand name ISENTRESS is currently under review by the U.S. Food and Drug Administration (FDA).
In both of these studies, more than 75 percent of patients receiving ISENTRESS [pronounced i-sen-tris] plus OBT achieved viral load (HIV RNA) reductions to less than 400 copies/mL compared to more than 40 percent of patients receiving placebo plus OBT (BENCHMRK-1, 77 percent of patients (N=232) receiving ISENTRESS plus OBT vs. 41 percent of patients (N=118) receiving placebo plus OBT; and BENCHMRK-2, 77 percent of patients (N=230) receiving ISENTRESS plus OBT vs. 43 percent of patients (N=119) receiving placebo plus OBT, p<0.001 for both studies respectively). Both studies also showed that after 16 weeks of treatment, ISENTRESS plus OBT was generally well tolerated. In addition, there were few discontinuations due to adverse experiences (BENCHMRK-1, four patients receiving ISENTRESS plus OBT and four patients receiving placebo plus OBT; for BENCHMRK-2, five patients receiving ISENTRESS plus OBT and one patient receiving placebo plus OBT).
ISENTRESS is under development by Merck & Co., Inc., Whitehouse Station, N.J. These results were presented as late breakers this week at the 14th Annual Conference on Retroviruses and Opportunistic Infections (CROI).
"The efficacy results and tolerability profile that have been seen thus far with ISENTRESS in combination with OBT in this patient population with multi-drug resistant virus are exciting," said David Cooper, M.D., D.Sc., professor of medicine and director, National Centre in HIV Epidemiology and Clinical Research, University of New Wales, Sydney, Australia. "HIV integrase inhibitors may be a new promising class of antiretroviral agents."
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 the 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 the other two enzymes - protease and reverse transcriptase - but there are no approved drugs that inhibit integrase.
BENCHMRK-1 and BENCHMRK-2 are ongoing, 156-week, multi-center, triple-blind randomized placebo controlled studies that compare ISENTRESS in combination with OBT to placebo plus OBT in terms of reduction in HIV viral load, change from baseline in CD4 cell counts and evaluation of safety and tolerability. Patients who entered the study had failed antiretroviral therapies as documented by HIV RNA of greater than 1000 copies/mL on stable ARTs for at least two months and were infected with HIV resistant to one or more drugs in each of the three oral classes of ARTs [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs)].
Patients received ISENTRESS 400mg or placebo, each dosed orally twice daily in combination with OBT. OBT was selected based on patients' prior treatment history and results from HIV resistance testing. In order to allow for the best possible treatment regimen to be constructed for each patient, darunavir and tipranavir, which were investigational ARTs in many countries at the time of this study were allowed to be included in OBT. In addition, patients who were co-infected with Hepatitis B or C were allowed to enroll in these studies.
"We are very encouraged by the results that we've seen from these clinical trials after sixteen weeks of combination therapy with ISENTRESS, as the findings are very similar to what has been observed in Phase II studies," said Roy Steigbigel M.D., professor of medicine, pathology, microbiology and pharmacology, State University of New York at Stony Brook.
16 week results of BENCHMRK-1
Results show that after 16 weeks of therapy, 77 percent of patients (N=232) receiving ISENTRESS in combination with OBT achieved HIV RNA viral load reduction below 400 copies/mL compared to 41 percent of patients (N=118) receiving placebo plus OBT, p<0.001.
In addition, 61 percent of patients receiving ISENTRESS plus OBT achieved viral load reduction to below 50 copies/mL compared to 33 percent of patients receiving placebo plus OBT, p<0.001. Increases in CD4 cell counts from baseline were 83 and 31 cells/mm³ for patients receiving ISENTRESS and for those receiving placebo respectively, p<0.001.
Patients in this study were enrolled in Europe, Asia/Pacific and Peru. The mean baseline viral load was 4.6 log10 copies/mL for the regimen that included ISENTRESS and 4.5 log10 copies/mL for the placebo regimen, respectively. The mean baseline CD4 cell counts were 156 cells/mm³ for the regimen with ISENTRESS and 153 cells/mm³ for the placebo regimen, respectively. These patients had approximately 11 years of prior ARTs; and approximately 90 percent had a diagnosis of AIDS at study entry.
The regimen of ISENTRESS plus OBT was generally well tolerated. There were few discontinuations due to adverse experiences; specifically, for BENCHMRK-1, four patients receiving ISENTRESS plus OBT and four patients receiving placebo plus OBT discontinued therapy. The most commonly reported (reported in at least three percent of patients) study therapy-related side effects were diarrhea, nausea and injection-site reaction (due to enfuvirtide).
16-week results of BENCHMRK-2
Results showed that after 16 weeks of therapy, 77 percent of patients (N=230) receiving ISENTRESS in combination with OBT achieved HIV RNA viral load reduction to below 400 copies/mL compared to 43 percent of patients (N=119) receiving placebo plus OBT alone, p<0.001.
In addition, 62 percent of patients receiving ISENTRESS plus OBT achieved RNA viral load reduction to below 50 copies/mL compared to 36 percent of patients receiving placebo plus OBT, p<0.001. Increases in CD4 cell counts from baseline were 86 and 40 cells/mm³ for the groups receiving ISENTRESS and placebo, respectively, p<0.001. Patients in this study were enrolled in North, Central and South America. The mean baseline viral load was 4.7 log10 copies/mL for both the regimen that included ISENTRESS and the regimen that included placebo, respectively. The mean baseline CD4 cell counts were 146 cells/mm³ for the ISENTRESS regimen and 163 cells/mm³ for the placebo regimen, respectively. These patients had approximately 10 years of prior ARTs; and approximately 90 percent had a diagnosis of AIDS at study entry.
The regimen of ISENTRESS plus OBT was generally well tolerated. There were few discontinuations due to adverse experiences; specifically, for BENCHMRK-2, five patients receiving ISENTRESS plus OBT and one patient receiving placebo plus OBT discontinued therapy. The most commonly reported (reported in at least three percent of patients) study therapy-related side effects were abdominal distension, abdominal pain, diarrhea, flatulence, nausea, injection site reaction (due to enfuvirtide), headache and fatigue.
Prevalence of HIV/AIDS
Despite the availability of drugs to treat HIV/AIDS, the epidemic continues. An estimated 40 million people are currently infected worldwide, and it is estimated that more than four million new infections occur worldwide annually. AIDS is one of the top causes of infectious disease-related mortality worldwide, responsible for approximately three million deaths each year.
Merck HIV research
Merck's efforts to develop investigational treatments and a vaccine against HIV/AIDS have been underway for almost 20 years and continue today. Merck began its HIV integrase inhibitor research in the early 1990's, and Merck was the first to demonstrate integrase strand transfer inhibition and to define the mechanism of action. Merck was also the first to demonstrate inhibition of HIV integrase in vitro and in vivo.
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