Several pharmaceutical companies are attempting to develop drugs associated with the CCR5 cellular co-receptor, which HIV utilizes for entry into susceptible cells. Studies on these CCR5 antagonists are important because of the need to develop new classes of anti-HIV compounds that are effective against HIV variants that are resistant to inhibitors of the viral reverse transcriptase and protease targets. There is hope that antagonists of CCR5 will not suffer from problems of resistance to the same extent as non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside/tide reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs).

One of these CCR5 antagonists in development is termed UK-427,857, or maraviroc. It has previously been shown by scientists at Pfizer, Inc., to be highly effective at preventing HIV infection of CCR5-expressing cells in tissue culture. More importantly, maraviroc has been shown to result in significant reductions in HIV viral load when administered to HIV-infected individuals in phase 1/2a studies.¹

The current study, by Mary McHale et al at Pfizer Global Research and Development in the United Kingdom, reviewed data from 5 multiple-dose, phase 1/2a, double-blinded, placebo-controlled studies of maraviroc and one drug interactions study with contraceptives. These studies included 259 HIV-uninfected volunteers and HIV-infected patients who received maraviroc monotherapy over 7 days at doses as high as 1,200 mg once daily and over 28 days at doses as high as 300 mg twice daily.

The data from these studies show that maraviroc appears to be well tolerated. Most adverse effects, which included nausea, rhinitis, dizziness and headache, were moderate -- and, in many cases, indistinguishable from placebo.

Although some individuals who received maraviroc showed elevations in levels of transaminases, those effects were not considered to be severe, nor were occasional reports of modest elevations in creatinine levels.

Postural hypotension was found to be the dose-limiting adverse event. This complication only occurred at higher rates than placebo in patients receiving a maraviroc dose of 600 mg or greater.

Most importantly, 10-day monotherapy studies of this drug resulted in mean detectable viral RNA reductions of 1.60 log₁₀ copies/mL with a dose of 300 mg once daily and 1.84 log₁₀ copies/mL with a dose of 300 mg twice daily. Maraviroc was shown to be less effective at lower doses, demonstrating the existence of a dose-response relationship in therapy. Accordingly, it is not surprising that Pfizer has now selected both the 300 mg once-daily and 300 mg twice-daily doses for further study in more advanced clinical trials.

Little is yet known as to which of the other CCR5 antagonists presented at this conference -- GlaxoSmithKline's GSK873140 (click here for the presentation summary) or Schering-Plough's SCH 417690 (click here for the presentation summary) -- may prove most effective, or whether combinations of some of these drugs may be possible in the context of highly active antiretroviral therapy (HAART).

It is also not known to what extent the selection of viruses that employ an alternate co-receptor, i.e., CXCR4, will occur in patents receiving long-term therapy with CCR5 antagonists.

In sum, there continues to be a great excitement about the development of this and other drugs in the CCR5 antagonist family. Maraviroc has already moved on to phase 2b/3 studies, in which 300 mg once-daily and twice-daily doses of the drug are being examined in combination with other antiretrovirals in treatment-naive and treatment-experienced patients. These studies are currently recruiting patients at sites throughout the United States and Canada, as well as in Australia, Belgium, Germany, Italy, Netherlands, Spain, South Africa, Sweden, Switzerland and the United Kingdom. Click here for more clinical trial information.

Footnote

1. Fätkenheuer G, Pozniak AL, Johnson M, et al. Evaluation of dosing frequency and food effect on viral load reduction during short-term monotherapy with UK-427,857 a novel CCR5 antagonist. In: Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract TuPeB4489.