Maraviroc

Despite the availability of several approved drugs for the treatment of human immunodeficiency virus (HIV) infection, the limited effectiveness of current antiretroviral regimens, mainly due to the emergence of resistance, makes the development of new agents necessary. Several novel compounds are being added to existing classes, but the discovery and development of newer classes of antiretroviral drugs, such as HIV entry inhibitors, represents a significant advance in the treatment of AIDS and HIV.

HIV enters the host cell by a sequential process that requires engagement with CD4 followed by binding to a coreceptor: either the chemokine CCR5 receptor (R5 strains) or CXCR4 (RX strains). The chemokine CCR5 receptor is a G-protein-coupled, 7-transmembrane receptor expressed on monocytes, macrophages, T cells and B cells that binds the CC chemokines MIP-1-alpha, MIP-1-beta and RANTES with high affinity. It also binds viral MIP-2 with high affinity and has been shown to bind cyclophilin-18 and histidyl-tRNA synthetase. CCR5 acts as a coreceptor with CD4 for HIV-1 infection and functions as a fusion cofactor for macrophage-tropic and T-cell line-tropic isolates of HIV-1. In general, during the early stages of HIV infection, viral isolates use CCR5 for viral entry, while later isolates use CXCR4. Antagonism of this receptor may therefore be effective in the prevention and treatment of HIV infection.

Maraviroc (Selzentry™; Pfizer), the first member of the CCR5 antagonist class to cross the finish line, received accelerated approval from the U.S. FDA last August and was launched for the first time in September 2007. The drug acts by blocking the CCR5 coreceptor, thereby blocking viral entry into T cells. It is indicated for use in combination antiretroviral treatment of adults infected with CCR5-tropic HIV-1, evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. The FDA approval was based on 24-week data from the ongoing double-blind, controlled MOTIVATE clinical trials, in which approximately twice as many patients receiving maraviroc plus optimized background therapy achieved undetectable viral load at 24 weeks compared to those on optimized background therapy alone. In September, Pfizer presented 48-week data supporting these initial findings, and announced the commercial availability of maraviroc in the U.S. Pfizer has also filed for regulatory approval of maraviroc in Europe, where it will be known as Celsentri, and has received a positive opinion from the CHMP.