Phase III STARTMRK clinical study on ISENTRESS in comparison to efavirenz

ISENTRESS^® , an integrase inhibitor from Merck & Co., Inc., was studied in comparison to efavirenz in maintaining viral load suppression to undetectable levels (less than 50 copies/mL) and at improving CD4 cell counts in previously untreated (treatment-naïve) HIV-1-infected patients through 96 weeks in a Phase III study called STARTMRK. In STARTMRK, ISENTRESS patients received either ISENTRESS or efavirenz in combination therapy. The data was presented today at the 49^th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco, CA.

The U.S. Food and Drug Administration (FDA) recently approved an expanded indication for ISENTRESS on July 8, 2009, to include the treatment of adult patients starting HIV-1 therapy for the first time, as well as treatment-experienced adult patients, in combination with other antiretroviral (ARV) medicines. The expanded indication for ISENTRESS was based on analyses of plasma HIV-1 RNA levels through 48 weeks in three double-blind controlled studies. Two of these studies were conducted in clinically advanced, three-class antiretroviral [nonnucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI)] treatment-experienced adults. The third study was a 48-week analysis of the STARTMRK trial in treatment-naïve patients.

ISENTRESS is used in combination with other ARV medicines for the treatment of HIV-1 infection in adult patients. The safety and efficacy of ISENTRESS have not been established in pediatric patients. The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.

“Results from the 96 week analysis of STARTMRK showed that ISENTRESS in combination therapy was as effective as efavirenz at suppressing HIV viral load and increasing immune system function,” said Edwin de Jesus, M.D., F.A.C.P., medical director of the Orlando Immunology Center in Orlando, Florida. "These results further confirm the findings from the 48 week analysis of this ongoing study.”

ISENTRESS studied through 96 weeks in 563 previously untreated adult patients

In this ongoing, multi-center, double-blind, randomized, active-controlled Phase III STARTMRK trial, 563 treatment-naïve adult patients received either 400 mg ISENTRESS administered orally twice daily in combination with tenofovir/emtricitabine or 600 mg efavirenz administered orally once daily in combination with the same agents. The primary endpoints were reductions in HIV-1 viral load to less than 50 copies/mL and an evaluation of safety and tolerability at Week 48. Secondary endpoints included ARV activity as measured by the proportion of patients achieving HIV viral load to less than 50 copies/mL, less than 400 copies/mL and change from baseline in CD4 count at Week 96, as well as tolerability and safety at Week 96.

Patients who entered the study were required to have HIV viral loads greater than 5,000 copies/mL. At baseline, geometric mean viral load levels for patients on the regimen including ISENTRESS was 103,205 copies/mL>3 and 217.4 cells/mm³ for the groups receiving ISENTRESS and efavirenz, respectively.

Viral load reductions and increase in CD4 cell counts maintained through 96 weeks

After 96 weeks of treatment, the ISENTRESS-based regimen suppressed HIV RNA levels below 50 copies/mL at a rate comparable to the regimen containing efavirenz (81 percent versus 79 percent, respectively); the treatment difference was two percent favoring ISENTRESS with an associated 95 percent confidence interval (CI) of (-4.3, 9.0). Results also showed that patients on the regimen containing ISENTRESS in combination therapy experienced a statistically similar yet numerically greater mean increase in CD4 cell count (240 cells/mm³) than those on the regimen containing efavirenz (225 cells/mm³). The treatment difference was 15 with an associated 95 percent CI of (-13, 42).

Impact on lipid levels and tolerability profile of ISENTRESS

At 96 weeks, ISENTRESS in combination therapy had less impact on lipid levels, including total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, as well as triglycerides than the regimen containing efavirenz in previously untreated adults:

Additionally, 47.0 percent of patients taking the regimen containing ISENTRESS experienced drug-related side effects versus 78.0 percent of patients receiving the efavirenz-based regimen; p-value <0.00.

In the study, the most commonly reported clinical adverse experiences (AEs) in the regimens containing ISENTRESS and efavirenz, respectively, were:

Additional posters on ISENTRESS presented at ICAAC

Three additional posters being presented at the ICAAC meeting described studies that evaluated the safety profile and efficacy of ISENTRESS in combination therapy. These posters include:

• Metabolic analysis and body composition changes from the 48-week findings in STARTMRK (Poster 329 )
• A review of the effect of ISENTRESS on the pharmacokinetics of methadone (Poster 1295)
• The lack of a clinically important effect of rifabutin on raltegravir pharmacokinetics (Poster 29)