Millennium Pharmaceuticals, Inc (CAMBRIDGE, Massachusetts) announced the initiation of a randomized, double-blind, placebo-controlled, multicenter phase II study of MLN3897, an orally active, small-molecule antagonist of the chemokine receptor CCR1, in patients with rheumatoid arthritis (RA). CCR1 is involved in the recruitment of white blood cells in response to sites of inflammation. The study will assess the efficacy, safety, and tolerability of MLN3897 in combination with methotrexate (MTX). The study will enroll up to 186 patients with RA, all of whom must have been taking MTX for a minimum of 6 months prior to screening. Patients will continue the MTX regimen and will be randomized to receive MLN3897 or placebo. The primary endpoint of the study is ACR20 response rate. Results from the phase I studies showed MLN3897 to be well-tolerated and to exhibit dose-dependent blockage of the CCR1 receptor.

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The Rheumatologic Perspective
CCR1 is a chemokine receptor expressed on the surface of various cells in the immune system (including macrophages and T-lymphocytes) that participate in inflammatory responses. Several different chemokines can bind to CCR1, including macrophage-inflammatory protein 1-α (MIP-1α) and RANTES. CCR1 and its ligand MIP-1α are also important in bone disease.

MLN3897 is part of Millennium's larger development program for inflammatory diseases that includes six product candidates and is one of several small-molecule therapies included in the company's collaboration with sanofi-aventis (sanofi-aventis AVE9897). The two companies'  alliance is focused on developing and commercializing small-molecule drugs for the treatment of inflammatory diseases such as RA and multiple sclerosis. The companies have been sharing discovery-stage assets in their inflammation pipelines and sharing costs equally. Candidate compounds under the collaboration will be jointly developed and marketed by Millennium and sanofi-aventis in North America and by sanofi-aventis in the rest of the world.

Preclinical- and clinical-stage investigational candidates in addition to MLN3897 are:  MLN0002 (a humanized monoclonal antibody targeting a T-cell integrin [α4β7], for Crohn's disease and ulcerative colitis); MLN1202 (an antagonist of the MCP-CCR2 pathway, designed to prevent infiltration of immune cells into inflammatory sites, for multiple sclerosis); MLN3701 (like MLN3897, an orally active, small-molecule antagonist of CCR1, for RA); MLN0415 (an IKK2 antagonist for RA); and MLN6095 (target and indication undisclosed).

--A. Techman


The Rheumatologic Perspective

MLN3897 is one of a number of inhibitors of CCR1 that are in clinical or preclinical development. Its advantage may be its oral bioavailability. CCR1 is a chemokine receptor that has three ligands, CCL3 (macrophage inflammatory protein - 1α, MIP-1α), CCL5 (Regulated on activation, normal T-cell expressed and secreted, RANTES), and CCL7 (monocyte chemotactic protein -3, MCP-3). There are many reasons to anticipate that CCR1 and its ligands might play a role in rheumatoid inflammation, including the presence of increased amounts of CCL3 and CCL5 in rheumatoid synovial fluid and tissue and the effectiveness of CCR1 blockade in animal models of inflammatory arthritis. However, there are concerns about the precise role of CCR1 in rheumatoid inflammation owing to the species specificity of many of the receptor antagonists and the differing distributions of CCR1 in mice and humans. Many of the CCR1 antagonists have specificity for the human receptor and therefore cannot be adequately evaluated in animal models. In addition, there is a differing distribution of CCR1 in human and murine cells that can alter the effects of antagonists. For example, CCRI plays an important role in neutrophil migration in mice, whereas it is more prominently involved in monocyte chemotaxis in humans. Very little information about MLN3897 is in the public domain. Hopefully, full public disclosure of the results of the proposed trial will provide some information about the role of CCR1 ligands in rheumatoid inflammation and whether antagonism of this chemokine receptor will be a useful approach to treat rheumatoid arthritis safely.



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