Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial

Abstract

Introduction: 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).

Methods: This 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.

Results: Sixteen 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%).

Conclusions: Maraviroc 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 registration: ClinicalTrials.gov: NCT00427934.

Figure 1

Study design. (A) Open-label safety/PK component (4 weeks). (B) Double-blinded proof-of-concept component (12 weeks). *Patients without any disease activity requirements. BID, twice daily; MTX, methotrexate; PK, pharmacokinetics.

Figure 2

Patient disposition. (A) Safety/PK component. (B) Proof-of-concept component. *Discontinued because the study was terminated by the sponsor. AE, adverse event; BID, twice daily; LOE, lack of efficacy; NLW, no longer willing (to participate in study).

Figure 3

POC Component: Key Efficacy Endpoints (A) Effect of maraviroc on ACR20 response rate over time. (B) Least squares mean change from baseline in CRP over time. (C) Least squares mean change from baseline in DAS28-4 (CRP) over time; all figures used data from the full analysis set (FAS) with last observation carried forward(LOCF). ACR20, American College of Rheumatology 20% improvement criteria; BID, twice daily; CRP, C-reactive protein; DAS, disease activity score; DAS28-4 (CRP), disease activity score, 28-joint count, using C-reactive protein; FAS, full analysis set; LOCF, last observation carried forward; SEM, standard error of the mean.