Cell Therapy Provides Positive Results in Biologic-Refractory RA

Mesenchymal precursor cells improve disease activity

Mesoblast Limited, an Australian company, has announced that a single intravenous (IV) infusion of its proprietary allogeneic mesenchymal precursor cell (MPC) product candidate MPC-300-IV was well tolerated and demonstrated dose-related improvements in clinical symptoms, physical function, and disease activity compared with placebo through the 12-week primary endpoint in a phase 2 clinical trial involving patients with biologic-refractory rheumatoid arthritis (RA).

The study recruited 48 patients with active RA who were receiving a stable regimen of methotrexate and who had shown an inadequate clinical response to at least one anti-tumor necrosis factor (TNF) agent. Of the 48 patients, 30 (63%) had received one or two biologic agents. The patients were randomly assigned to receive a single IV infusion of one million MPCs/kg (1 M/kg; n = 16); two million MPCs/kg (2 M/kg; n = 16); or placebo (n = 16). The study consisted of a 12-week primary study period with a 40-week follow-up period, for a total duration of 52 weeks.

The trial’s primary objective was to evaluate the safety and tolerability of a single IV MPC infusion in these biologic-refractory RA patients through 12 weeks of treatment. Additional objectives included evaluating clinical efficacy at the primary 12-week endpoint and assessing the durability of effects and the treatment’s safety profile through the full 52-week study.

There were dose-related improvements in many of the individual components of the American College of Rheumatology (ACR) composite after MPC treatment. The 2-M/kg group who had previously received one or two biologics showed a significant improvement compared with placebo in each of the following categories: swollen joint counts, the investigator’s global assessment, the patient’s global assessment, and pain scores.

ACR70 responses (at least a 70% improvement in the number of tender and swollen joints, and at least a 70% improvement in various clinical assessments) showed a dose-related effect after a single MPC infusion, with the greatest effect seen in the 2-M/kg group who had previously received one or two biologics compared with placebo (36% versus 0%, respectively). ACR50 responses showed a dose-related effect after a single MPC infusion, with the greatest effect seen in the 2-M/kg group who had previously received one or two biologics compared with placebo (55% versus 11%). ACR20 responses were greater in both the 2-M/kg and 1-M/kg groups who had received one or two biologics than in the placebo group (55% and 60% versus 33%).

MPC-300-IV consists of two million immunoselected and culture-expanded MPCs per kilogram, which are delivered intravenously. Current biologic therapies target individual cytokine pathways thought to be involved in the pathogenesis of RA, including TNF-alpha, interleukin (IL)-6, or IL-17, but not concomitantly. According to Mesoblast, there are at least two mechanisms of action by which MPC-300-IV may affect clinical RA outcomes through the concomitant inhibition of multiple cytokine networks:

  • Immunomodulation. Proinflammatory monocytes/macrophages and activated T cells are involved in the pathogenesis of RA via joint inflammation and the secretion of multiple proinflammatory cytokines. In preclinical studies, the activation of MPCs by these proinflammatory cytokines through specific surface receptors resulted in the release by MPCs of anti-inflammatory mediators, including prostaglandin E2 (PGE2) and indoleamine 2,3-dioxygenase (IDO), which act on inflammatory target cells. Allogeneic human MPCs secreting PGE2 and IDO, when co-cultured with donor immune cells, switch proinflammatory monocytes producing TNF-alpha or IL-6 to an anti-inflammatory phenotype producing IL-10, and switch proinflammatory T cells producing IL-17 to anti-inflammatory FoxP3 T regulatory cells producing IL-10.
  • Synoviocyte inhibition. Proinflammatory synoviocytes in RA joints show high proliferation and secrete multiple cytokines involved in the pathogenesis of RA disease. The biomolecules PGE2 and transforming growth factor-beta (TGF-beta), secreted by MPCs after cell-surface signaling by inflammatory cytokines, act directly on RA synoviocytes to inhibit the pleiotropic signaling molecule NF-kappaB, resulting in reduced synoviocyte proliferation and decreased production by the synoviocytes of the proinflammatory factors TNF-alpha, IL-1, IL-6, IL-8, and monocyte chemoattractant protein-1, as well as various metalloproteinases involved in joint inflammation and destruction.

Source: Mesoblast; August 8, 2016.