Abstract
IntroductionThe purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX).MethodsThis phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics (PK) of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof-of-concept (POC) component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily (BID) for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components.ResultsSixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%).ConclusionsMaraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX.Trial RegistrationClinicalTrials.gov: NCT00427934
Highlights
The purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX)
Results from the safety/PK portion of this study demonstrated that maraviroc 150 and 300 mg twice daily (BID) were well tolerated over 4 weeks and not associated with a drug-drug interaction (DDI) with MTX
Several early studies highlighted concerns about the possible class-specific, long-term hepatotoxic side effects of CCR5 antagonists [5,28], and the prescribing information for maraviroc contains a black-box warning for hepatotoxicity [24]; these warnings initially stemmed from studies using the chemokine antagonist, aplaviroc, in which several cases of severe liver toxicity emerged in patients receiving the drug, and trials were halted [29,30]
Summary
The purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX). Maraviroc is an orally active, noncompetitive, reversible antagonist of the human CC chemokine receptor 5 (CCR5), which is the primary chemokine receptor expressed by rheumatoid synovial T cells [1,2]. Preclinical work in a rhesus monkey collagen-induced arthritis model demonstrated suppression of C-reactive protein (CRP) and altered antibody response toward type II collagen with a CCR5-antagonist, SCH-X [12]. In another preclinical study, use of Met-RANTES, which blocks both CCR1 and CCR5, caused the amelioration of adjuvant-induced arthritis in Lewis rats [13]. There is evidence to suggest that the CCR5Δ32 mutation, which leads to reduced CCR5 expression at the cell surface, is associated with a protective effect in patients with RA [14,15,16]; this finding has not been consistent [17,18]
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