Phase 1/2a Safety and Efficacy Data of CCR5 Antagonist Maraviroc (UK-427,857)

CCR5 antagonists, a type of entry inhibitor, have shown early promise in the treatment of HIV infection. In the current study, researchers at Pfizer summarize safety and efficacy data from selected multiple dose Phase 1/2a studies of the CCR5 antagonist maraviroc (UK-427,857), in healthy volunteers and HIV positive patients.

Six multiple dose studies where maraviroc was adminstered alone were reviewed. These studies included 7 days of dosing at the maximum dose studied of 1200mg QD and 28 days of dosing at the highest proposed clinical dose of 300mg BID.

Results

·  A total of 195 subjects (66 HIV+) were dosed with maraviroc, including 40 women.

·  The most common treatment related adverse events were headache, dizziness, nausea, asthenia, flatulence and rhinitis. The majority of the adverse events were graded as mild or moderate.

· At doses up to and including 300mg BID the adverse event profile was similar to that of placebo.

·  No serious adverse events were reported, with few (5) treatment-related discontinuation (3 with postural hypotension [2 on 600mg QD and 1 on placebo], 1 with elevated transaminases [3mg BID] and 1 with rash [placebo]).

·  Clinically significant increases in liver function tests occurred in 7 subjects at varying doses of maraviroc with no clear frequency/dose relationship (4 subjects had >3xULN transaminases and 3 subjects had >1.25 to <2xULN bilirubin).

·  Mild/moderate elevations in creatinine (<2xULN) were noted in one study at 1200mg QD and placebo.

· There was no dose related change in QTcF.

· Ten-day monotherapy with maraviroc at doses of 300mg QD and 300mg BID in HIV+ patients resulted in mean maximum HIV RNA reductions of 1.60 and 1.84 _log10, respectively.

In conclusion, the authors note, “The development program to date has demonstrated that maraviroc is well tolerated at doses up to and including 300mg BID and that 10 day monotherapy resulted in significant reductions in viral load.”

“These results indicate that further evaluation of maraviroc for the treatment of HIV infection is merited.”

Pfizer Global Research and Development, Sandwich, UK.

07/27/05

Reference
M McHale and others. Overview of phase 1 and 2a safety and efficacy data of maraviroc (UK-427,857). Abstract TuOa0204 (oral). 3^rd IAS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil.