Maraviroc, a CCR5 Antagonist, Aims to Halt HIV Outside of Cells
by Chael Needle
LifeGuide
[Treatment Horizons]
As multiresistant strains of HIV continue to become a treatment challenge for those patients living with HIV, researchers have been eager to continue to provide a second line of defense against HIV and, if possible, drugs with novel mechanisms of action. At the recent 14th Conference on Retroviruses and Opportunistic Infections, for instance, researchers presented promising trials data on maraviroc, Pfizer’s CCR5 antagonist candidate for those with HIV-1.
During an interview with Dr. Jay Lalezari, one of the trials’ lead investigators and the director of Quest Clinical Research, among other appointments, I mention that this is exciting news. He agrees, but then broadens his enthusiasm for the entire movement of second-chance drugs down a pipeline that is otherwise “not rich” at the moment: “It is an exciting and unique moment in the history of the AIDS epidemic—to have several new potent drugs, with different mechanisms of action, that are active in salvage patients [and] are available at the same time.” Integrase inhibitors are high on the list, with maraviroc and TMC-125, a non-nuke, also generating excitement for those who have exhausted options. “If this were cancer, people would be dancing in the streets.”
Interim results from a twenty-four week analysis of the ongoing multicenter, double-blind, placebo-controlled Phase 2b/3 MOTIVATE 1 and 2 trials showed that approximately twice as many patients receiving either a once or twice-daily dosing of maraviroc with an optimized background therapy (OBT) regimen achieved an undetectable viral load than in those who received a placebo plus OBT. Additionally, researchers found that CD4 cells increased nearly twofold in patients receiving maraviroc plus OBT than in the study group receiving OBT alone. Regardless of once or twice-daily dosing, the groups receiving maraviroc plus OBT had a low rate of discontinuation due to adverse events. Patients enrolled in the study had CCR5-tropic virus only at entry. (Ongoing study results of maraviroc’s potential benefit for treatment-naive patients have not yet been released.)
Maraviroc, an oral drug which works to block HIV from entering immune cells, is designed as a treatment for those patients whose cells’ infection is predominantly effected via the CCR5 coreceptor, or CCR5-tropic. The CCR5 and CXCR4 coreceptors, located on the cell surface, serve as the secondary entryways for HIV, after HIV binds to a CD4 molecule. A patient’s virus population may contain strains that are CCR5-tropic, CXCR4-tropic, or mixed/dual tropic. Almost exclusively, individuals are initially infected with CCR5-tropic virus. In about half of patients with advanced disease, however, the infection process may shift focus and enter cells via the CXCR4 coreceptor, and could possibly lead to virologic failure for those on CCR5 antagonists.
“The majority of patients who fail virologically on maraviroc do so by having an outgrowth of the X4 subtype of virus, not resistance to maraviroc per se,” says Dr. Lalezari in response to a question about the candidate’s drug-resistance profile, which like long-term safety data, cannot yet be compiled. CCR5-tropic virus predominates in the early course of the disease, he explains, but, as T cells decrease, the X4-tropic virus becomes more prevalent. “So people with low T-cell counts have a fifty-fifty chance of either having pure R5 or mixed population,” he says, adding that, while Trofile, the assay that Pfizer plans to offer alongside the drug to determine CCR5 tropism, has been remarkably effective at showing which patients might benefit from maraviroc, its sensitivity is limited by the fact that “the subspecies of the R5 or the X4 has to be present in ten to twenty percent of the [patient’s virus] population.” He continues: “Given all those caveats, a lot of patients we’re testing and [who] come back R5-tropic [do] have X4 virus—it’s just below the level of detection. So when they go on maraviroc and have virological breakdown, what you see is not resistance to maraviroc but an outgrowth of that X4 subpopulation, which was undoubtedly there before they started the drug.”
Compared to integrase, which seems to work well for everyone, says Dr. Lalezari, the downside of maraviroc as part of a salvage regimen seems to lie in its strength, that is, its targeting of CCR5-tropic patients. At last year’s International AIDS Conference, results from Study 1029 showed that patients identified by the assay as having a mixed-tropic virus population did not respond virologically to maraviroc. What is not known, Dr. Lalezari hastens to add, is whether or not maraviroc plus an integrase inhibitor might be effective in those with mixed tropic virus. “That’s one of the most urgent questions that Pfizer needs to address.…One could imagine that, if patients are R5, going on a combination of integrase and maraviroc will seal the deal. They’re both well-tolerated, extremely potent, and that should work in just about anybody.
“I’m very pleased about how patients have done on the study,” notes Dr. Lalezari. “We’re in San Francisco and God knows there are a lot of salvage patients here.…[I]t was clear to me very early on the drug was not only well-tolerated but that it was working very well. Patients who otherwise wouldn’t be alive today went on this study and did well and it has been very gratifying. It’s what makes this job fun.”
Chael Needle wrote about bevirimat, a maturation inhibitor, in the February issue.
March 2007 |
