New England Journal of Medicine Reports ISENTRESS® (raltegravir), Merck’s First in Class Integrase Inhibitor, Suppressed HIV-1 Viral Load and Increased CD4 Cell Counts through 48-Weeks in Treatment-Experienced Adult Patients When Taken with Other Anti-HIV Medicines
In Additional Subgroup Analysis, ISENTRESS Helped to Increase CD4 Cell Counts and Decrease Viral Load in Patients Predicted to be Poor Responders
WHITEHOUSE STATION, N.J.- ISENTRESS® (raltegravir), Merck’s first-in-class HIV-1 integrase inhibitor, suppressed HIV-1 viral load and increased CD4 cell counts through 48 weeks of combination therapy with other anti-HIV medicines compared to placebo in combination with other anti-HIV medicines in HIV-infected patients with triple-class resistant virus failing current therapy. These results from two pivotal Phase III studies of 699 treatment-experienced patients who were failing other antiretroviral therapies (ARTs) were published today in the New England Journal of Medicine.
In October 2007, the U.S. Food and Drug Administration (FDA) granted ISENTRESS accelerated approval for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication with HIV-1 strains resistant to multiple antiretroviral agents. The approval was based on analyses of viral load reductions and CD4 cell count increases from baseline through 24 weeks in two Phase III studies of ISENTRESS, which are ongoing. The 48-week data reported today in the New England Journal of Medicine represent additional data from those studies.
The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response. The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients. There are no study results demonstrating the effect of ISENTRESS on clinical progression of HIV-1 infection.
“HIV disease is very complex and is especially difficult to manage in patients whose virus has become resistant to therapy. The 48-week results for ISENTRESS show that when paired with other anti-HIV medicines, ISENTRESS effectively lowered the amount of virus in the blood to undetectable levels in 62 percent of patients versus 33 percent of patients receiving placebo plus other anti-HIV medicines. Also, combination therapy with ISENTRESS helped the immune system to rebound. ISENTRESS acts at a step in HIV replication that’s different from the targets of prior drugs,” said Roy Steigbigel M.D., professor of medicine, pathology, microbiology and pharmacology, Stony Brook University School of Medicine and lead study investigator for one of the studies.
ISENTRESS studied in nearly 700 patients with virus resistant to multiple anti-HIV medicines
The data published today in the New England Journal of Medicine are Week 48 results from two identical ongoing multi-center, double-blind, randomized, placebo-controlled Phase III studies (BENCHMRK-1 and BENCHMRK-2) that compare ISENTRESS in combination with optimized background therapy (OBT) to placebo plus OBT. The primary endpoint of this ongoing study is the percentage of patients that achieve HIV RNA virus levels less than 400 copies/mL at Week 16. Patients in the studies had HIV resistant to at least one drug in each of three classes [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)] of oral ARTs.
Patients in BENCHMRK-1 were enrolled in Europe, Asia, Australia and South America (Peru). The baseline viral load (geometric mean) was approximately 41,000 copies/mL for patients treated with ISENTRESS and 32,000 copies/mL for patients treated with the placebo regimen. The median baseline CD4 cell counts were 140 cells/mm³ for patients treated with ISENTRESS and 105 cells/mm³ for patients treated with the placebo regimen.
Patients in BENCHMRK-2 were enrolled in North and South America. The baseline viral load (geometric mean) was approximately 48,000 copies/mL for patients in both groups. The median baseline CD4 cell counts were 102 cells/mm³ for patients treated with ISENTRESS and 132 cells/mm³ for patients treated with the placebo regimen.
Patients received ISENTRESS 400 mg or placebo, each dosed orally twice daily in combination with OBT. OBT was determined based on each patient’s prior treatment history and results from HIV resistance testing; and represents the best available antiviral drug combination individualized for each patient. In order to allow for the best possible treatment regimen to be constructed for each patient, darunavir and tipranavir, which were investigational medicines in many countries at the time of this study, were permitted for use in OBT.
Consistent suppression of viral load and increase in CD4 cell counts observed through 48 weeks of treatment with ISENTRESS
Results at Week 48 were consistent across both BENCHMRK studies. The results reported in the New England Journal of Medicine include both individual study results and a combined analysis of both studies at 48 weeks. At 48 weeks, the percentage of patients who achieved HIV RNA levels below 400 copies/mL were nearly two times greater for patients receiving ISENTRESS plus OBT (72 percent of patients; 332 of 459) compared to patients receiving placebo plus OBT (37 percent of patients; 88 of 237). In addition, ISENTRESS plus OBT suppressed viral load to undetectable levels (below 50 copies/mL) in significantly more patients compared to placebo plus OBT; 62 percent of patients (285 of 459) versus 33 percent of patients (78 of 237), respectively
After 48 weeks, mean CD4 cell counts were more than doubled in patients receiving ISENTRESS plus OBT compared to patients receiving placebo plus OBT. Specifically, patients receiving ISENTRESS plus OBT achieved mean increases in CD4 cell counts from baseline of 109 cells/mm³ compared to 45 cells/mm³ for patients receiving placebo plus OBT
“The efficacy results shown after 48 weeks of treatment with ISENTRESS when used in combination with other anti-HIV medicines are consistent with observations at 24 weeks,” said David Cooper M.D., D.Sc., professor of medicine and director of the National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia.
Safety results at 48 weeks
Also, the combined analysis showed that 4 of 462 patients (0.9 percent) receiving ISENTRESS plus OBT and 1 of 237 patients (0.4 percent) receiving placebo plus OBT discontinued therapy due to drug-related adverse experiences. Overall, 11 of 462 patients (2.4 percent) receiving ISENTRESS plus OBT and 7 of 237 patients (3.0 percent) receiving placebo plus OBT experienced serious drug-related adverse events. The most commonly reported (reported in at least two percent of patients) study drug-related side effects in patients receiving raltegravir plus OBT were diarrhea, nausea, injection site pain or reaction (due to enfuvirtide) and headache.
Study results also showed that at 48 weeks, 16 of 462 patients (3.5 percent) receiving ISENTRESS plus OBT and 4 of 237 (1.7 percent) patients receiving placebo plus OBT were diagnosed as having new, recurrent or progressive cancer. Statistical analysis indicated these rates, adjusted for how much time the patients were on treatment, were not different, with relative risk of 1.54 and 95 percent confidence interval including 1 (0.50 to 6.34).
Subgroup analyses of patients with predicted poor response to antiretroviral therapy
Results from subgroup exploratory analyses examining factors that would predict disease progression due to poor response to antiretroviral therapy were also published in the same issue of the New England Journal of Medicine. The combined data from both studies showed that, after 48 weeks, ISENTRESS in combination with OBT showed greater response rates for lowering HIV viral load and increasing CD4 cell count over placebo plus OBT in patients with high levels of HIV-1 RNA (100,000 copies/mL), very low CD4 cell counts (50 cells/mm³) or low Phenotypic or Genotypic Sensitivity Scores [(PSS or GSS) for OBT 1] at study enrollment.
PSS and GSS scores help report the number of anti-HIV medicines in the OBT regimen to which a patient’s HIV is susceptible, and represents the number of active agents in the OBT at the beginning of the study. A low PSS or GSS indicates that there are few or no active agents in the patients OBT regimen, and is a reflection that a patient’s HIV had developed resistance to a greater number of anti-HIV medicines prior to the study.
Study results showed that in patients with the fewest active drugs in their OBT, those with a GSS of 0, the virus was suppressed to undetectable levels in more patients receiving ISENTRESS plus OBT compared to patients receiving placebo plus OBT, 45 percent versus 3 percent, respectively; and mean increases in CD4 cell counts from baseline in these patients were 81 and 11 cells/mm³, respectively. In patients who were more likely to respond to treatment, those with more active OBT (GSS of 2), 77 percent of patients receiving ISENTRESS plus OBT achieved undetectable viral loads versus 62 percent of patients receiving placebo plus OBT; and mean increases in CD4 cell counts were 145 and 87 cells/mm³, respectively.
By week 48, 23 percent of patients (105 of 462) receiving ISENTRESS plus OBT had virologic failure (HIV viral RNA greater than 400 copies/mL). Resistance testing done on viruses isolated from 94 of the 105 patients with virologic failure showed that 68 percent (64) had genotypic evidence of resistance to ISENTRESS. Seventy-five percent of the patients with evidence of genotypic resistance (48) had two or more ISENTRESS resistance-associated mutations.
Important safety information about ISENTRESS after 24 weeks of therapy
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 ART, which may necessitate further evaluation and treatment.
At 24 weeks, the most commonly reported adverse experiences of any severity (mild, moderate or severe) for ISENTRESS plus OBT versus placebo plus OBT, respectively, regardless of drug relationship were diarrhea (16.6 percent vs. 19.5 percent), nausea (9.9 percent vs. 14.2 percent), headache (9.7 percent vs. 11.7 percent) and fever (4.9 percent vs. 10.3 percent).
Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have 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.
Results from pooled safety analyses from three separate studies (BENCHMRK-1, BENCHMRK-2 and a Phase II dose ranging study) in treatment-experienced patients taking 400 mg of ISENTRESS dosed twice daily plus OBT or placebo plus OBT showed that after 24 weeks of therapy the rates of discontinuation of therapy due to adverse experiences were 2.0 percent in patients receiving ISENTRESS plus OBT and 1.4 percent in patients receiving placebo plus OBT. In addition, drug-related clinical adverse events of moderate to severe intensity occurring in greater than or equal to 2.0 percent of patients were diarrhea (3.7 percent vs. 4.6 percent), nausea (2.2 percent vs. 3.2 percent) and headache (2.4 percent vs. 1.4 percent) for ISENTRESS plus OBT and placebo plus OBT, respectively.
Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of ISENTRESS is required when coadministered with other antiretroviral agents. Preclinical studies showed that ISENTRESS is not metabolized by cytochrome P450 enzymes, but is primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1; therefore, caution should be used when coadministering ISENTRESS with strong inducers of UGT 1A1 (e.g., rifampin), which may reduce plasma concentrations of ISENTRESS.
ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. ISENTRESS does not require boosting with ritonavir.
ISENTRESS is the first medicine to be approved in a new class of antiretroviral drugs called integrase inhibitors. ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme. Inhibiting integrase from performing this essential function limits 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-1 replication process – protease and reverse transcriptase – but ISENTRESS is the only drug approved that inhibits the integrase enzyme.
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 for HIV and AIDS have been under way for more than 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.
Prevalence of HIV and AIDS
In 2006, more than one million Americans were living with HIV and AIDS, and it is estimated that approximately 40,000 new cases of HIV and AIDS are diagnosed each year in the United States.
Worldwide, an estimated 33 million people are infected with HIV and AIDS, and more than two million new infections occurred in 2007.
Merck’s commitment to providing access to treatment
Merck is committed to ensuring access to our antiretroviral medicines (ARVs) through a differential pricing policy that provides our ARVs at dramatically lower prices-at which Merck does not profit-to people living in the world’s least developed countries and those hardest hit by the pandemic, as defined by various United Nations indices.
Also, Merck is committed to seeking additional ways to reduce the cost of its ARVs for people living in the world’s poorest countries and those hardest hit by the pandemic, including through partnering with external manufacturers and suppliers to achieve incremental efficiencies and cost savings.
This news content was configured by WebWire editorial staff. Linking is permitted.
News Release Distribution and Press Release Distribution Services Provided by WebWire.