Raltegravir recommended for approval

October 2007

The FDA Antiviral Drugs Advisory Committee voted unanimously Sept. 5 to recommend accelerated approval for raltegravir in combination with other antiretroviral therapy in treatment-experienced patients with HIV who have ongoing viral replication.

If approved, raltegravir (Isentress, Merck) will be the first in a new class of integrase inhibitors for patients with HIV.

FDA officials gave raltegravir priority review status. Merck is also filing regulatory applications for the drug in countries outside the United States.

Experts said the approval of raltegravir may represent an important new treatment option for patients with HIV. “Clinicians are tremendously encouraged by the imminent approval of raltegravir, as it significantly expands treatment options for patients with drug-resistant HIV-1,” said Elizabeth Connick, MD, associate professor of medicine at the University of Colorado Health Sciences Center, director of the University of Colorado Center for AIDS Research Immunology Core, and member of the Infectious Disease News editorial advisory board. “Further studies must be done to determine whether raltegravir has utility in first-line treatment regimens. Both its potency and good side-effect profile, however, suggest that it may be useful for treatment naive patients as well.”

Raltegravir trials

Raltegravir inhibits the insertion of HIV DNA into human DNA through the viral integrase enzyme. This blocks the ability of the virus to replicate and infect new cells. In vitro, raltegravir is active against HIV-1 and all subtypes.

Drugs are in use that inhibit two other enzymes critical to HIV replication, protease and reverse transcriptase, but none inhibit integrase.

Sixteen-week efficacy data from two identical phase-3 raltegravir trials, called BENCHMRK, were presented at the 14th Conference on Retroviruses and Opportunistic Infections in February. Trials were continuing to 154 weeks. One trial is being held in Australia, Europe and the other is being held in North and South America, excluding Peru.

Patients were randomly assigned to either raltegravir 400 mg twice daily or placebo each with optimized background therapy based on genotype and phenotype or placebo.

Patients were a median age of 40 years and were predominantly men. At baseline, mean viral load was 4.5 logs and patients’ CD4 counts were less than 150. Patients were triple-class antiretroviral treatment-experienced with resistance to a drug in each class.

At week 16, 77% of patients treated with raltegravir achieved fewer than 400 copies HIV DNA and had an average CD4 gain of about 100 cells. In combined efficacy, 70% of participants in both trials achieved less than 400 copies of HIV DNA. The placebo group had an efficacy 43%.

Adverse events reported in the raltegravir and placebo arms were similar.

For more information:

• Cooper D, Gatell J, Rockstrob J, et al. Results of BENCHMRK-1, a phase 3 study evaluating the efficacy and safety of MK-0158, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Presented at: 14th Conference on Retroviruses and Opportunistic Infections; Feb. 25-28, 2007; Los Angeles.
• Steigbigel R, Kumar P, Eton J, et al. Results of BENCHMRK-2, a phase 3 study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Presented at: 14th Conference on Retroviruses and Opportunistic Infections; Feb. 25-28, 2007; Los Angeles.