With maraviroc as the only CCR5 receptor inhibitor that has been FDA-approved as an anti-HIV

med, and another CCR5 receptor inhibitor, vicriviroc, now focusing solely on clinical trials with treatment-naive patients after treatment-experienced trials did not meet endpoints, this class of drugs could use some good news.

Though it is much too early to celebrate, a new CCR5 receptor inhibitor candidate called TBR-652 is being studied as a treatment for CCR5-tropic HIV-1.

CCR5 is one of two primary receptors on the surface of cells through which HIV enters CD4 cells and macrophages. CXCR4 is the other one.

Developed by Tobira Therapeutics as a “next-generation CCR5 receptor antagonist,” TBR-652 has been formulated for once-daily dosing without a boosting agent. A Phase IIa study, led by Calvin J. Cohen, MD, showed TBR-652’s proof of concept to be viable as the monotherapy reduced viral load in a double-blind, placebo-controlled dose-escalation trial that involved fifty-four treatment-experienced CCR5-tropic HIV-positive male participants taking the ten-day course of the regimen. All were CCR5 receptor inhibitor-naive. No clinically significant adverse events were reported; no one discontinued the study because of drug-related reasons. Any liver function test elevations that occurred were mild. TBR-652 also has a long half-life in the body (thirty-five to forty hours) and has a favorable pharmacokinetic profile. In the lab, TBR-652 was shown to have a high barrier to resistance.

Kathleen E. Squires, MD, professor of medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Tobira scientific advisory board, weighed in on the candidate. For her, there are two hurdles which any candidate has to clear. “For me, in the HIV field, is it potent? If it’s not potent and/or able to be combined in a potent regimen, it’s not going to go anywhere. And certainly this proof of concept trial did say that this [agent] has activity, and very reasonable activity. The other big issue is side effects or toxicity. Now again the drug has only been used in a relatively few number of patients over a relatively short period of time, [and] there certainly wasn’t any major signal there.”

The study demonstrated TBR-652’s potential dual mechanism of action, inhibiting CCR5 as well as another chemokine receptor, CCR2. CCR2 has been associated with inflammatory diseases, such as atherosclerosis and metabolic syndrome, among others.

“This inhibitor…may have activity not only as an antiretroviral but activity as an anti-inflammatory agent,” says Squires. “Now while it certainly has that activity whether it will translate into that kind of activity in the field of HIV is still something that needs to be understood.” (TBR-652 is also being studied separately for anti-inflammatory indications in general.)

As people who are living longer with HIV are increasingly affected by inflammatory diseases, this potential effect may be a benefit. Says Squires: “The data that is accumulating says that [HIV-positive] people, even in those who have well controlled HIV disease [in terms of viral load]…tend to have higher levels of inflammatory markers than people who are HIV-negative, when matched for age and a number of other factors. So despite the fact that we’ve done the best that we can, using the armamentarium available to us, we still have a heightened inflammatory state in patients.”

Whether or not heightened inflammatory states always progress to disease is still an open question, however, notes Squires. Across the board, the aging process has been theorized as a state of immunosenescence, says Squires. “Older people tend to have a higher inflammatory state, and is that what’s causing the fact that we all develop concurrent conditions? We all break down, for lack of a better term. So in HIV, is the combination of getting older—because people are living longer—plus the fact that it looks like simply HIV, even treated HIV, leads to a hyperinflammatory state a kind of a double whammy? Is that why perhaps we’re going to see that there is an increased risk of cardiovascular disease, kidney disease, all the kind of chronic disease states we get as we get older?”

An agent with these two advantages—viral suppression, when used in combination with other anti-HIV meds, and anti-inflammation—would be “intriguing,” suggests Squires. CCR2 inhibition, however, does have an effect on macrophage function, “and macrophages are very important for controlling many of the diseases and infections that we see in HIV, like tuberculosis and so on.” And so the clinical trials would have to look at this carefully as they progress so that any anti-inflammatory benefit is weighed against increased risk of these infections, notes Squires. Patients would need to be screened with this macrophage inhibition in mind, and followed closely, she adds.

Chael Needle wrote about changing U.S. foreign policy approaches to women’s health in the May issue.