Mesoblast Limited Sets Their Sights on Rheumatoid Arthritis

The regenerative medicine company Mesoblast Limited recently announced positive results obtained from a large animal model for rheumatoid arthritis (RA). These positive results were obtained after only one intravenous injection of their proprietary allogenic (in other words it is classified as “off-the-shelf”), immunomodulatory adult Mesenchymal Precursor Cells (MPCs).

The Chief Executive Professor for Mesoblast, Silviu Itescu, has indicated that the results show that their immunomodulatory MPCs may contain a mechanism of action which is different from any other biological therapies. In short, it has shown that it is capable of simultaneously shutting down multiple cytokine pathways. Indeed, this has the potential to become a first line treatment for patients with rheumatoid arthritis. So far, it seems to have the potential to be superior at reducing inflammation and preventing joint destruction, while also providing a sustained effect.

People who have been diagnosed with rheumatoid arthritis suffer from inflammation which is driven and preserved by pro-inflammatory cytokines such as IL-6, IL-17, and TNF-alpha. New RA treatments, which have been designed to target only these pathways, have so far only been moderately effective at reducing the symptoms of this autoimmune disease. Most need to be constantly administered, and they can cause some adverse side effects. However, researchers have found that a single intravenous injection of allogeneic MPCs in a sheep with collagen-induced arthritis produced a simultaneous shutdown of multiple cytokine pathways (namely the IL-6, and IL-17, and TNF-alpha). Eventually, these single injections led to an improvement in the joint pathology of the sheep.

Researchers found that the sheep (after the collagen was introduced) would develop severe inflammation in the synovial membrane of the joints, just like a human being who has been diagnosed with rheumatoid arthritis. Eventually this inflammation can cause severe loss of cartilage and some bone erosion. During the pilot RA clinical study, researchers were able to identify a significant number of allogeneic MPCs in the involved joints or lymph nodes of the arthritic sheep only 24 hours after the initial intravenous injection. However, none were found in the joints of the normal sheep, which indicated that the MPCs have the ability to selectively migrate to the sites of autoimmune related inflammation.

Next, medical researchers conducted a placebo-controlled study utilizing 30 sheep with established cases of arthritis. During the study, they would administer a single intravenous injection of allogeneic MPCs at one of three different doses (the doses measured 0.3, 1, and 2 million MPCs/kg). The researchers then examined synovial tissues from the joints of sheep following a 30 day interim period. Compared to the control group who had been treated with saline, there was an 88% mean reduction in IL-6 levels, an 83% mean reduction in TNF-alpha levels, and a 53% mean reduction in IL-17 levels for the sheep who had received a single injection of 2 million MPCs/kg.

The subjects which had been treated with the MPCs ended up showing a 31% mean reduction in histopathology severity scores when compared to the control group for this rheumatoid arthritis clinical trial. Not surprisingly, researchers noted an intermediate range for the subjects that had received 1 million MPCs/kg, and the lowest effect in the subjects which had been administered the lowest MPC dose. These results show that the MPCs can regulate the immune system and concurrently work to suppress the activation and spread of the monocytes, T-cells, and synoviocytes which are present in rheumatoid arthritis. Interestingly, the data has suggested that the MPCs mechanism of action involves inhibiting the Th17 CD4 T cell subset, followed by the simultaneous reduction of the key cytokines, TNF-alpha, IL-6, and IL-17.

Currently, Mesoblast Limited has scheduled an upcoming meeting with the Food and Drug Administration (FDA) in order to discuss advancing this new potential RA treatment to Phase 2 clinical trials on human patients with rheumatoid arthritis. Once they have received clearance from the FDA, the company intends to begin a randomized, placebo-controlled Phase 2 RA clinical trial at the end of this year.



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