Chemokine blockade: first positive findings for new drug class

The first study of an agent that can blockade the CCR5 chemokine receptors on CD4 lymphocytes that provide additional entry routes for HIV was reported on Monday at the Ninth Annual Retroviruses Conference in Seattle. A drug that blocks HIV binding to the CCR5 receptor would provide another class of anti-HIV agent, and may be an important option for people with extensive treatment experience.

Attempts to develop an inhibitor of another chemokine receptor, CXCR4, have so far been unsuccessful, so the results are likely to encourage further focus on CCR5 as a target.

At last year’s Retroviruses Conference, Schering Plough reported the first data on two chemokine antagonists in development, SCH-C and SCH-D. Today, researchers reported on the first study of SCH-C in treatment-naïve HIV-positive individuals.

Twelve people with CD4 counts above 250 cells/mm3 and average viral load of approximately 40,000 copies/ml received 25mg of SCH-C orally twice daily for ten days. No other antiretroviral therapy was taken alongside SCH-C. Ten out of 12 participants had at least a 0.5 log reduction from baseline during dosing, with 4 participants experiencing viral load reductions of at least 1 log.

After stopping therapy at day 10, participants were monitored for a further 18 days, during which period viral load slowly returned to baseline levels. However, this rebound was slow, taking on average around ten days. The study also found that SCH-C did not begin to show significant effects on viral load for some days after treatment commenced, suggesting that the antiviral impact of down-regulating chemokine receptors is less immediate than anti-viral methods that interfere directly with the lifecycle of HIV

However, two patients had no viral load reduction, and experiments against a variety of wild type isolates prior to this study have found that at least one variant, a Russian isolate, showed significantly reduced sensitivity to SCH-C compared to other isolates, raising the question of whether substantial variation exists in sensitivity to chemokine antagonists.

SCH-D appears to be ten times more potent than SCH-C, according to test tube experiments, but has not yet been tested in humans.

Another agent that inhibits HIV entry was also reported today. It appears to act against a different target from the fusion inhibitors T-2-0 and T-1249, which inhibit the activity of an HIV envelope protein, gp41. It is also distinct from the chemokine antagonist reported by Schering Plough, suggesting considerable potential for combination therapy.

The new compound, under investigation by BMS Pharma, interferes with the interaction between the envelope protein gp120 and the CD4 receptor on T-lymphocytes by competing with the gp120 to bind onto the CD4 receptor.

The compound is orally bioavailable, which means that it can be formulated into a tablet, unlike the fusion inhibitors T-20 and T-1249, which, as proteins vulnerable to breakdown in the stomach, must be injected.