Cenicriviroc (CVC), an oral CCR5/CCR2 antagonist in development, showed non-inferiority and better tolerability when compared to efavirenz (Sustiva, Stocrin), as well as strong anti-inflammatory indications, according to study results presented at EACS 2013 in Brussels, Belgium.
The 48-week, phase 2b study results, presented by Judith Feinberg, M.D., showed that CVC was effective and well-tolerated, and a potent inhibitor of CCR2 receptors on monocytes, which could reduce the inflammation issues so frequently seen in HIV-infected patients.
The study followed 143 patients, of which 94% were male, 62% were Caucasian, 32% were African American and 24% were Hispanic. All were treatment-naive and had an average viral load of 31,623 copies/mL and an average CD4+ cell count of 402 cells/mm3. All had CCR5-tropic viruses and no primary resistance to NRTIs (nucleoside reverse transcriptase inhibitors) or NNRTIs (non-nucleoside reverse transcriptase inhibitors). The participants were randomized to 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, with placebos replacing CVC in the 100-mg and efavirenz arms. They also had to take one efavirenz pill (or placebo) on an empty stomach at bedtime, and one tenofovir/emtricitabine pill at any time.
At week 48, both CVC groups performed at least as well as the standard-of-care efavirenz. The rate of virologic success (defined as a viral load below 50 copies/mL) was 68% for those taking CVC at 100 mg, 64% for those taking CVC at 200 mg and 50% for those taking efavirenz, a greater level of difference than was observed in the 24-week results presented earlier this year. Conversely, however, virologic non-response rates appeared higher among those in the CVC groups: 15% for those taking CVC at 100 mg, 20% for those taking CVC at 200 mg and 11% for those taking efavirenz.
The average increase in CD4+ cell count was higher for the CVC groups than the efavirenz group: 205 for those taking CVC at 100 mg, 211 for those taking CVC at 200 mg and 147 for those taking efavirenz.
CVC was generally well-tolerated, with 2% discontinuing due to adverse events in the 200-mg group and 0% in the 100-mg group. In contrast, 21% discontinued due to adverse events in the efavirenz group, among whom neurologic complications (such as abnormal dreams and insomnia) were far more common. Treatment-related adverse events occurred in 50% of the 100-mg group, 44% of the 200-mg group and 71% in the efavirenz group.
Of the 11 patients who experienced virologic failure (defined as either a viral load above 400 copies/mL on or after week 12 or never achieving a viral load below 50 by week 24), NRTI resistance mutations emerged in 3 out of 4 patients in the group taking CVC at 100 mg, 2 out of 6 patients in the group taking CVC at 200 mg and 0 out of 1 taking efavirenz.
The study also monitored markers that have been associated with 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 48 weeks, the sCD14 levels for both CVC groups had steadied and were significantly lower than the sCD14 levels in the efavirenz group, which showed an upward trend.
The researchers will be moving on to phase 3 studies of CVC, with the hopes of testing a single-tablet formulation with improved bioavailability, as well as a fixed-dose pill in combination with lamivudine (3TC, Epivir) that would be compared to tenofovir/emtricitabine.