New CCR5 antagonist enters phase II trials
Drug would be first-line therapy
A new CCR5 receptor antagonist called vicriviroc may become a key weapon in the antiretroviral arsenal.
The drug is in phase II trials, studying its use as a first-line therapy for treatment-naïve, HIV-infected patients with R5-type virus.
CCR5 receptor antagonists have been developed in response to earlier research findings that link a specific genetic difference among people with European descent who were exposed to HIV and were not becoming infected, says Joseph C. Gathe, MD, FACP, FIDSA, clinical instructor in the department of internal medicine at Baylor College of Medicine in Houston, TX. Gathe is involved in vicriviroc research.
"People who had protection against the Black Plague had CCR5 deletions," Gathe explains. "The gene became established and selected for because if you didn't get the Black Plague, you survived and lived on."
So when HIV tries to enter through CCR5 receptor in a person with this deletion, the virus cannot take hold.
"There is a thought that perhaps if you could come up with an agent that blocks CCR5 receptors you could block the ability to establish infection," Gathe says.
Unfortunately, HIV also can enter through a CXCR4 receptor, and the virus potentially can mutate and change from the CCR5 receptor to a CXCR4 entry, Gathe notes.
"One of the biggest concerns is if we block the CCR5 receptor then we'll create a new population of viruses that mutate and use the CXCR4 entry point," Gathe says. "And the main concern is that a virus that uses the CXCR4 entry is more virulent; those patients have lower CD4 cell counts and faster progression to AIDS."
The longer HIV-infected patients are infected and the longer they're exposed to treatment, the greater chance they'll have a virus that uses both CCR5 and CXCR4 receptors, he adds.
Before a CCR5 receptor antagonist can be used, clinicians need to perform a tropism assay to see whether a patient has a virus that uses the CCR5 receptor as opposed to the CXCR4 receptor, Gathe says.
Researchers now believe that a CCR5 antagonist does not create the problem with CXCR4, but it might clear away the more dominant CCR5 virus and allow the existing CXCR4 virus to become detectable, says Robert Consalvo, spokesman for global product communications and advocacy relations for Schering-Plough Corp. of Kenilworth, NJ.
"So the risk is largely diminished, and what we're certain is the X4 is already there," Consalvo says.
"We've done studies in treatment-experienced patients, and we get potent and sustained treatment suppression," Consalvo says. "Those studies have been successful in that they show potent viral suppression that is maintained for a long time."
With the current phase II study that looks at a treatment naïve population, vicriviroc is administered as a convenient and potent regimen, he says.
Study participants receive one daily, 30-mg dose of vicriviroc in combination with ritonavir-boosted atazanavir. The control group receives emtricitabine and tenofovir (Truvada) plus ritonavir-boosted atazanavir, which is a recommended first-line therapy.
"Our goal is to suppress their virus to below detectable levels and keep it down long before resistance occurs," Consalvo says. "The longer a person can stay on the initial treatment regimen, the better."
HIV is a smart, resilient virus that has great survival skills, Gathe says.
"When you push the virus in a certain direction with certain drugs, it will tend to push back," he says. "So we have to have treatments that are totally suppressive and don't allow the virus to grow and mutate."
Thanks to researchers and the pharmaceutical industry's push for new HIV drugs and new classes of HIV drugs, there is a much larger arsenal of antiretrovirals available, Gathe notes.
"Four to five years ago you might have only one drug left to use for those patients who are failing drugs," he says. "In general, we wanted to wait for new drugs to come on the market but often weren't able to do that."
Now, there are new integrase inhibitors, new protease inhibitors, and the CCR5 antagonists that can bring patients' viral loads down to 50 copies even in cases of triple-class failure, Gathe says.
"That's why vicriviroc is so important — because it represents another new class of drugs to which the virus in one class of patients cannot resist," Gathe adds.
Another reason clinicians might be drawn to vicriviroc if it succeeds and makes it to market is because some of the emphasis these days is on finding regimens that are less toxic to HIV patients, Consalvo says.
"Some drugs we use for a long time have inherent toxicity issues with side effects, and when people were dying from AIDS we didn't worry about long-term toxicity," he says. "But today we can treat HIV infection as a chronic condition."
Since the vicriviroc regimen being studied does not use nucleoside reverse transcriptase inhibitors (NRTIs), there is an expectation that patients will avoid the renal toxicities, neuropathy, lipodystrophy, and other problems associated with NRTIs, Consalvo explains.
Pfizer received approval last summer to market its CCR5 receptor antagonist maraviroc (Selzentry) for treating treatment-experienced HIV patients.
Vicriviroc would have at least one advantage over maraviroc in that it could be used as a first-line therapy, Consalvo says.
Since treatment-naïve patients are more likely to be eligible for a CCR5 receptor antagonist than are patients who have been on other antiretroviral therapy for years, it makes more sense to start with this drug, Gathe says.
"Clinically, it's as efficacious as the current starting regimens we have," Gathe says. "So we want to start with a drug that will have the most potential to help more people."
This way, when the CCR5 receptor antagonist begins to fail, the patient still will be susceptible to the traditional antiretroviral drugs, including NRTIs, he adds.
"This is an interesting stage we're in where researchers are looking at how to come up with newer, treatment-naïve regimens where you're not longer simply trying to keep patients alive, but are looking for more patient-friendly regimens," Consalvo says. "They're likely going to be on HIV drugs for a long time with no hope for a vaccine or cure, so you want to effectively treat HIV, but not cause cardiac or metabolism problems for the patients."
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