FDA Advisory Committee Recommends Approval of Maraviroc

By Liz Highleyman

MARAVIROC Expanded Access Program (EAP)

On April 24, the Antiviral Drug Advisory Committee of the U.S. Food and Drug Administration (FDA) unanimously voted to recommend accelerated approval of Pfizer's maraviroc, which was recently given the brand name Celsentri.

Maraviroc is the first CCR5 inhibitor to be considered for approval. The drug prevents HIV entry by blocking viral attachment to the CCR5 coreceptor of the surface of host cells. It has a different mechanism of action than enfuvirtide (Fuzeon; T-20), the sole approved HIV entry inhibitor.

Different strains of HIV use 2 different coreceptors to enter cells, CCR5 and CXCR4. People with 2 copies of a mutation in the gene than encodes CCR5 are naturally resistant to HIV infection -- a phenomenon researchers hope to mimic with drugs that prevent the virus from using CCR5.

Promising Study Results

As previously reported, investigators presented 24-week data on maraviroc at the 14th Conference on Retroviruses and Opportunistic Infections this past February. The Phase III MOTIVATE-1 and MOTIVATE-2 trials* together included more than 1000 heavily treatment-experienced patients with extensive antiretroviral resistance. Participants were randomly assigned to receive oral maraviroc or placebo in combination with an optimized background regimen. Those whose background regimens included a boosted protease inhibitor, excluding tipranavir (Aptivus), received 150 mg maraviroc once daily, while all others received 150 mg twice daily.

In both studies, virological response rates were about twice as high in the maraviroc arms compared with the placebo arms. After 24 weeks, 45%-48% of patients in the twice-daily maraviroc arms and 41%-42% in the once-daily maraviroc arms achieved HIV viral loads below 50 copies/mL, compared with 21%-25% in the placebo arms. Among patients with no active background drugs in their background regimens, 29%, 18%, and 3%, respectively, achieved virological suppression. CD4 cell counts increased by 100-112 cells/mm3 in the maraviroc arms and 52-64 cells/mm3 in the placebo arms.

The MOTIVATE studies are scheduled to continue through 48 weeks of follow-up, and Pfizer is conducting another ongoing Phase III trial of maraviroc in treatment-naive patients. Since most MOTIVATE participants were white men, the FDA panel requested additional data on use of the drug in women and people of other racial/ethnic groups, as well as in more patients with hepatitis coinfection.

Concerns About Potential Risks

If approved, maraviroc will be indicated only for use by patients with completely CCR5-tropic virus, as shown using the Monogram Biosciences tropism assay Pfizer plans to sell with the drug. Experts have expressed concern that CCR5 inhibitors may encourage the evolution of HIV strains that use CXCR4, which are associated with more advanced disease. In the MOTIVATE trials, some participants in the maraviroc arms experienced a shift from CCR5-tropic to CXCR4-tropic or dual/mixed-tropic virus (possibly due to low levels of pre-existing CXCR4-tropic HIV), so patients will likely require ongoing monitoring to track viral coreceptor use.

There is also concern about the potential toxicity of CCR5 inhibitors, since the normal biological function the receptor and the consequences of blocking it over the long term are not well understood. Some early animal studies suggested CCR5 inhibitors could cause heart rhythm disturbances. Development of another CCR5 inhibitor candidate, GlaxoSmithKline's aplaviroc, was discontinued in 2005 after it caused severe liver toxicity in early clinical trials. In addition, a small number of patients developed lymphoma in trials of Schering-Plough's vicriviroc.

In the MOTIVATE studies, 4%-5% of participants in both the maraviroc and placebo arms discontinued therapy due to adverse events (though most patients across all arms experienced mild-to-moderate side effects). There were no excess cases of serious liver toxicity or lymphoma in the maraviroc arms compared with placebo, and only a slightly higher rate of infections. However, regulatory authorities will be keeping a close eye on longer-term safety data.

While the FDA is not obligated to accept the independent advisory committee's recommendations, it usually does so. It is expected that a final decision on maraviroc's approval may come by the end of June.


04/27/07

Sources

JC Dooren. FDA Panel Backs HIV Drug. Wall Street Journal. April 25, 2007.

Pfizer Inc. FDA Advisory Committee Recommends Accelerate Approval of Pfizer's Maraviroc for Treatment-Experienced Patients Infected with CCR5-Tropic HIV-1. Press release. April 24, 2007.

*M Nelson, G Fatkenheuer, I Konourina, and others. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia and North America: 24 week results. 14th Conference on Retroviruses and Opportunistic Infections (CROI). Los Angeles, February 25-28, 2007. Abstract 104aLB.

*J Lalezari, J Goodrich, E DeJesus, and others. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24 week results from a phase 2b/3 study in the US and Canada. 14th CROI. Los Angeles, February 25-28, 2007. Abstract 104bLB.