Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
A Phase 2 Study to Assess the Efficacy and Safety of Maraviroc, a CCR-5 Antagonist in the Treatment of Rheumatoid Arthritis
Fleishaker1, D., Wang2, X., Menon2, S., Zeiher3, Bernhardt G., Stock2, T.C.
Maraviroc (MVC) is an antagonist of the human chemokine receptor 5 (CCR5) and has been approved for use in treatment of patients infected with the CCR5-tropic human immunodeficiency virus, Type-1 (HIV). Presence of a nonfunctional receptor of the CCR-5 gene resulting from a 32-base pair deletion has been associated with a reduced incidence and severity of rheumatoid arthritis (RA). Levels of the CCR-5 receptors ligands, RANTES, MIP-1a, MIP-1b are also increased in synovial fluid of RA subjects. Maraviroc 300 mg BID was investigated in this study to determine whether CCR-5 antagonism would prove safe and effective in the treatment of RA patients on background methotrexate (MTX).
This study was divided into two components: Safety/PK (data not shown) and Proof-of-Concept (POC). The Safety/PK component enrolled 16 subjects and demonstrated that MVC 300 mg BID was well tolerated and there was no drug-drug interaction with MTX. The POC component was a randomized, multi-center, double-blind, placebo-controlled, parallel group study. Subjects with active RA, receiving stable weekly MTX (>= 10 mg and <=25 mg) for at least 12 weeks were eligible for enrollment if they had at least 6 tender and swollen joints and CRP >=7.0 mg/L. Subjects were randomized 2:1 to MVC or placebo treatment for 12 weeks and the primary endpoint was ACR20 response. Subjects on background biologic therapy, other oral DMARDs (except antimalarials) and those homozygous for the CCR5D32 mutation were excluded from entry.
The study was terminated at the time of a planned interim analysis for futility. 110 subjects were enrolled: 77 (MVC 300 mg BID) and 33 (placebo BID) with similar demographic features across both treatment groups. There was no significant difference between MVC and placebo in ACR20 responder rate utilizing the full analysis set (MVC: 27.27% vs. placebo: 18.18%; p value=0.155); ACR50 and ACR70 were not different. Components of the ACR response, including CRP were not changed. MVC was safe and well tolerated with the majority of AEs mild to moderate in nature. The most common all causality AEs in the MVC-treated group were constipation (7.8%), nausea (5.2%), fatigue (5.2%), urinary tract infection (3.9%) and respiratory tract infection (2.9%) compared to placebo. There were no clinically significant findings in vital signs, ECG measurements or clinical laboratories including transaminases. There were no SAEs reported in the treated population.
Selective antagonism of CCR-5 using MVC failed to improve the signs and symptoms of RA in subjects with active disease on background MTX. Treatment with MVC was safe and well tolerated in RA subjects over 12 weeks. No impact in transaminases was noted in subjects receiving MVC vs. placebo despite background MTX use in this population.
To cite this abstract, please use the following information:
Fleishaker, D., Wang, X., Menon, S., Zeiher, Bernhardt G., Stock, T.C.; A Phase 2 Study to Assess the Efficacy and Safety of Maraviroc, a CCR-5 Antagonist in the Treatment of Rheumatoid Arthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :397