Cenicriviroc (CVC), an investigational CCR5 antagonist, showed non-inferiority when compared to efavirenz (Sustiva, Stocrin) and strong anti-inflammatory indications, according to phase-2b study results presented at CROI 2013 in Atlanta.
The study findings, presented by Joseph Gathe Jr., M.D., showed that CVC was a potent inhibitor of CCR2 receptors on monocytes, which could reduce the inflammation issues so frequently seen in HIV-infected patients.
"Monocyte activation has been shown to be implicated in a variety of clinical circumstances: Liver fibrosis, hepatic steatosis, diabetic neuropathy, metabolic syndrome and cardiovascular issues. So the dual mechanism of action of CVC may have activity of not only being an effective anti-HIV agent, but also perhaps have some activity, if this pathway is important in the development of these issues, blocking that pathway and decreasing some of these issues," Gathe explained.
The study followed 143 treatment-naive patients, of which 94% were male, 62% were Caucasian, 32% were African American and 24% were Hispanic. They were randomized into three groups:
- CVC at 100 mg with tenofovir/emtricitabine (Truvada) (59 patients)
- CVC at 200 mg with tenofovir/emtricitabine (56 patients)
- efavirenz at 600 mg with tenofovir/emtricitabine (28 patients)
Because this was a double blind, dose-finding study, participants in all groups had to take six pills every day. At the time of the study, CVC was only available in a 50-mg formulation, so the participants had to take four tablets every morning with breakfast. They also had to take one efavirenz pill on an empty stomach at bedtime, and one tenofovir/emtricitabine pill at any time.
At week 24, both CVC groups performed similarly to the standard-of-care efavirenz. All three groups had high rates of virologic success (defined as a viral load below 50 copies/mL): 76% for those taking CVC at 100 mg, 73% for those taking CVC at 200 mg and 71% for those taking efavirenz.
CVC was generally well tolerated, with only 2% discontinuing due to adverse events in the 200-mg group and 0% in the 100-mg group. In contrast, 18% discontinued due to adverse events in the efavirenz group, among whom neurologic complications (such as abnormal dreams and insomnia) were far more common.
The percentage of patients experiencing virologic non-response (those who did not achieve viral loads under 50 copies/mL) was 12% in the 100-mg group, 14% in the 200-mg group and 4% in the efavirenz group. However, Gathe suggested that this had more to do with adherence issues, stating, "Much of the lack of virologic success was driven by drug bioavailability. In other words, if the patients took their drugs and they had high levels of CVC in a minimum concentration, you saw a trend toward better virologic outcome." Gathe reminded the audience that, because this was a dose-finding study, pill counts were higher and dosing schedules stricter, potentially increasing the likelihood of poor adherence.
Perhaps most notably, the study monitored markers that showed effective blocking of CCR2, suggesting strong activity in the monocyte pathway. In particular, it monitored a marker called soluble CD14 (sCD14), which was shown by the SMART Study to be an independent predictor of death in HIV-infected patients. At 24 weeks, Gathe and his team saw a decline of sCD14 levels for both CVC groups, as compared to a trend toward a rise of the sCD14 marker in the efavirenz group. "We may be having some effect on some of these inflammatory pathways that may be leading to morbidity and mortality," Gathe suggested.
The researchers will be moving on to phase-3 studies of CVC, with the hopes of testing a single-tablet formulation and a fixed-dose pill in combination with other available antiretroviral drugs. They also hope to study drug interaction data and further investigate CVC's effects on inflammatory and metabolic factors.
"I think the endpoints of this study are not just viral load control, not just CD4 increases, but whether or not we're having action and activity against inflammatory pathways, and whether or not we're having action against the metabolic effects that we're seeing in patients," Gathe concluded.