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FDA Advisory Committee Recommends Approval of CCR5 Antagonist Maraviroc (Selzentry) for Treatment-naive Patients

An advisory committee to the U.S. Food and Drug Administration (FDA) voted 10-4 last week to recommend that the first-in-class CCR5 antagonist maraviroc (Selzentry) be approved for use in first-line antiretroviral therapy (ART). The committee acknowledged that the drug appears to be well-tolerated, but some members expressed concern about its effectiveness. The panel ultimately voted in favor of approval to offer patients a wider range of treatment options.

By Liz Highleyman

Maraviroc, developed by Pfizer, was approved for treatment-experienced patients in August 2007 based on data from the MOTIVATE trials showing that it worked well in patients with HIV that was resistant to older classes of antiretroviral drugs.

HIV uses one of 2 co-receptors -- CCR5 or CXCR4 -- along with the CD4 receptor to enter host cells. Only patients with HIV that exclusively uses CCR5 (determined by a tropism test) are eligible to use maraviroc. People with recent infection are more likely to have only CCR5-tropic virus, suggesting maraviroc may be well-suited for this population.

However, some experts have expressed concerns about the efficacy of maraviroc for first-line therapy. In the Phase 3 MERIT trial, treatment-naive patients with high viral load were less likely than those taking efavirenz (Sustiva) to achieve viral suppression < 50 copies/mL.

But a retrospective analysis (known as MERIT ES) using a more sensitive viral tropism assay found that some of the patients initially classified as having exclusively CCR5-tropic HIV actually had dual or mixed-tropic virus. When these patients were excluded (since they should not have used the drug in the first place), maraviroc and efavirenz worked equally well.

Maraviroc caused fewer side effects than efavirenz overall, especially neuropsychiatric symptoms such as insomnia, and had a favorable lipid profile. Data from the FDA released prior to last week's meeting revealed no new or unexpected safety concerns. As a newer drug, however, the possibility remains that unexpected toxicities could show up with longer-term use.

Studies have also shown that maraviroc increases CD4 cell counts more than other antiretroviral classes and seems to plays a role in reducing inflammation, which may confer benefits beyond viral load suppression.

On the other hand, maraviroc is less convenient, since it must be taken twice daily. It addition, it requires the expensive Trofile tropism test, which discourages some providers from using it. A recent study, however, suggests that a lower cost genotypic tropism test may work equally well in classifying likely responders.

The FDA panel -- which included agency officials, independent researchers and clinicians, pharmaceutical company representatives, and patient advocates -- ultimately decided that while there are other highly effective antiretroviral drugs available, it is an advantage to have a wider selection of medications to choose from when tailoring individual regimens. "We're not looking for the absolute best, we're looking for an option," said committee member Victoria Cargill, MD, from the National Institutes of Health Office of AIDS Research.

"Pfizer is pleased that the Committee has recognized the effectiveness and safety profile of maraviroc in patients who are starting HIV therapy," said Pfizer executive director Howard Mayer in a press release issued by the company. "Today's discussion marks an important step in expanding available treatment options for patients with HIV infection and we look forward to working with the FDA to further address the points raised by the panel."

The panel members asked Pfizer to collect more data, including from studies of pregnant women and patients with tuberculosis or hepatitis B or C coinfection.

The full FDA is not required to accept its advisory panels' recommendations, but it typically does so.

10/13/09

Sources

CDC National Prevention Information Network. US FDA Panel Backs Wider Use of Pfizer HIV Drug. October 9, 2009.

Pfizer, Inc. FDA Advisory Committee Recommends Approval of Pfizer's Selzentry for Use in Patients Starting HIV Therapy for the First Time. Press release. October 8, 2009.

J Levin. FDA antiviral advisory committee testimony excerpts. October 8-9, 2009.