By Myles Helfand
July 19, 2010
When it comes to health problems in people with HIV, inflammation is the flavor of the day. In the case of TBR-652, a CCR5 inhibitor in the earliest stages of testing in humans, that’s an awfully good thing. What sets TBR-652 apart from other CCR5 inhibitors — heck, all other antiretrovirals on the market today — is that it’s also designed specifically to block another receptor, CCR2.
CCR2 has nothing to do with HIV, but appears to have quite a bit to do with inflammation. Drugs that can inhibit CCR2 are being explored as potential treatments for a number of health problems tied to inflammation, including rheumatoid arthritis, asthma, multiple sclerosis and psoriasis.
In TBR-652, we may well end up with a case of the right drug being developed at the right time. Well, if the drug actually works, that is. Here at AIDS 2010, David E. Martin, Pharm.D, presented results from a proof-of-concept study on TBR-652: A 10-day monotherapy study involving 54 HIV-infected people. Hopefully we’ll be able to post the slides soon, but the gist is that the drug looked good enough to warrant starting a Phase 2b trial in early 2011.
Five different doses of TBR-652 were tested (there was also a placebo arm). Among the four highest doses, HIV-1 RNA levels dropped between 1.4 log and 1.8 log over the 10-day trial, a decent showing for an antiretroviral taken as monotherapy. Side effects were, generally speaking, similar to those seen among people taking placebo, with the exception of the highest-dose (150 mg) arm. A greater number of side effects occurred in that arm, though Martin noted that these side effects weren’t any more severe or longer-lasting than those experienced at other doses. The drug appears to have both a long half-life (30 to 40 hours) and a long “ramp-up” time (2 to 3 days), however, so there’s much left to learn about both its efficacy and safety over the longer term.
The impact of TBR-652 on inflammation was gauged by assessing levels of MCP-1, a protein that contributes to inflammatory responses when it binds with CCR2. If TBR-652 is doing its job as a CCR2 inhibitor, one would expect free-floating MCP-1 levels to increase, since the protein is unable to bind with CCR2. And, indeed, levels were found to increase in each of the five groups taking TBR-652 (with the difference compared to placebo reaching statistical significance in three of the dosing groups). Martin also offered up a brief case study of one patient in particular who began the study with low levels of MCP-1 and high levels of C-reactive protein (CRP), another marker of inflammation. MCP-1 levels jumped from virtually nil up to more than 160 pg/mL by day 10, and CRP levels dropped from around 15 mg/L to 5 mg/L.
Of course, this is all much ado about very little at this point. Sure, the drug looks pretty good as an antiretroviral and as a CCR2 inhibitor, but we’re talking about 10 days of monotherapy. The drug’s long-term efficacy and safety as part of an optimized antiretroviral regimen will be explored in research set to begin next year. During the question-and-answer period after Martin’s presentation, a couple of people raised the question of what impact blocking CCR2 might have on a person’s body over the long term. One person noted that CCR2 inhibition has been associated with tuberculosis risk, while others touched on a pretty key point: Despite the bad name it gets in the current HIV care climate, inflammation is a fundamental part of the body’s response to infections. If you take away a chunk of that inflammatory response, do you potentially make a person more susceptible to immune system damage? It’d be a bitter irony if a drug designed to hurt HIV’s ability to suppress the immune system ends up suppressing the immune system itself. Martin assured the audience that close attention would be paid to all of these issues as TBR-652 progressed through phase 2b study.
There’s also a conundrum down the road even if TBR-652 is proven safe and effective: namely, that it’s a CCR5 antagonist. CCR5 antagonists are most likely to work in people with HIV who recently became HIV positive. The longer a person has been living with HIV, the more likely he or she is to have CXCR4-tropic or dual/mixed-tropic virus, which means a CCR5 antagonist won’t work for them. Yet it is precisely those long-term HIV survivors who may be most at risk for inflammation-related complications.
I don’t mean to be a buzzkill here. After all, in a year that has featured precious few drugs in development to get remotely excited about, it’s nice to see one that’s actually moving forward through clinical trials. But at this very early stage in its development, a cautious hope about TBR-652 seems the prudent approach.