Merck Announces Interim Results from Phase II Study of MK-0518, an Investigational Oral HIV Integrase Inhibitor

Merck also presented results a Phase 2 study of its oral integrase inhibitor MK-0518 in a late breaker session at the 13^th Retrovirus Conference in Denver, CO. Interim results from this Phase 2 trial in 167 patients showed that in combination with optimized background therapy (OBT), the experimental medication at all three doses studied (200 mg, 400 mg, and 600 mg orally twice daily) had greater anti-retroviral activity than placebo with OBT. 

Study results also showed that MK-0518 in combination with OBT was generally well tolerated in these patients with advanced HIV infection who were failing antiretroviral therapy (ART), who had viruses resistant to at least one drug of each of the three available classes of oral ARTs and who had limited active ARTs as options for treatment. 

"The efficacy of MK-0518 provides additional evidence that demonstrates the antiviral activity of HIV integrase inhibitors as a new and promising class of anti-retroviral agents," said Bach-Yen T. Nguyen, M.D., senior director, Infectious Diseases and Clinical Research, Merck Research Laboratories.  "MK-0518, when used in combination with optimized background therapy, was generally well tolerated and significantly suppressed viral replication compared to placebo plus OBT in patients with complicated HIV treatment histories."

Study Design

This multi-center, randomized, double-blinded, dose-ranging, placebo-controlled study compared MK-0518 plus OBT to placebo plus OBT in terms of reduction in HIV viral load, improvement in CD4 cell count and safety and tolerability.  Patients received either MK-0518 200 mg, 400 mg, 600 mg or placebo, each dosed orally twice daily and in combination with OBT.  Optimized background therapy was selected based on patient's prior treatment history and results from HIV resistance testing. 

Patients at study entry were infected with HIV that was resistant to one or more drugs in each of the three oral anti-retroviral drug classes [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside RTIs (NNRTIs), and protease inhibitors (PI)], were receiving ART for more than three months and had HIV viral loads greater than 5,000 copies/mL and CD4 counts greater than 50 cells/mm3.

Study Results

Interim study results from a total of 167 enrolled patients showed that at week 16, the percent of patients achieving HIV RNA< 400 copies/mL ranged from 64 percent (18 out of 28 patients) to 84 percent (21 out of 25 patients) for MK-0518 plus OBT across all doses studied (200 mg, 400 mg, and 600 mg orally twice daily) versus 22 percent (six out of 27 patients) for placebo plus OBT.

Also, at week 16, the percent of patients achieving HIV RNA< 50 copies/mL ranged from 56 percent (15 out of 27 patients) to 72 percent (18 out of 25 patients) for MK-0518 plus OBT across all doses studied (200 mg, 400 mg, and 600 mg orally twice daily) versus 19 percent (five out of 27 patients) for placebo plus OBT

The median duration for prior use of ARTs was approximately 10 years for all groups, mean baseline HIV viral load ranged from 4.6 to 4.8 log10 copies/mL and mean baseline CD4 cell counts ranged from 220 to 283 cells/mm3.

The regimen of MK-0518 plus OBT was generally well tolerated and comparable to the regimen of placebo plus OBT.  The most commonly reported study therapy-related side effects (occurring in at least five percent or two patients in any treatment group) were diarrhea, nausea, fatigue, injection-site reaction, headache, and itching. 

Initial Phase II efficacy and tolerability results with MK-0518 as 10-day monotherapy in ART-naïve (previously untreated) patients were presented at the European AIDS Clinical Society in November 2005.

"The results presented at CROI combined with those from the previously presented study in treatment-naïve patients are compelling," said Robin Isaacs, M.D., executive director, Infectious Disease and HIV Vaccine Clinical Research, Merck Research Laboratories.  "The Phase III studies (BENCHMRK-1 and -2) which are being initiated, and for which we are actively seeking patients, will provide greater insights into the efficacy and tolerability of MK-0518."

HIV Drug Resistance Is Increasing

It is estimated that up to 78 percent of patients who fail antiretroviral drugs have developed resistance to more than one therapeutic class of these medicines and increased drug resistance has been noted even in drug-naïve individuals.  The proportion of treatment-naïve patients who carry resistant virus has grown to more than 20 percent today from eight percent in 1999. This situation highlights the requirement for a new class of antiretroviral drugs that can offer new treatment options who are currently without viable therapeutic options.

Merck's research of HIV integrase inhibitors began 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 antiviral efficacy in vitro and in vivo.

02/10/06